Biomedical subjects
Publications and source records attributed to L Mitchell.
A case of chronic aortic dissection is presented, in which computed tomography and magnetic resonance imaging both demonstrated the abnormality non-invasively. Velocity flow patterns within the true and false lumens obtained by magnetic resonance imaging, using a flow-mapping technique, gave a more thorough analysis.
A case of malignant fibrous histiocytomas arising in a burn scar is described. Burn scar sarcomas are exceedingly rare tumors whose precise behavior, pathogenesis, and treatment remain to be elucidated.
The half-lives for coagulation factors in the healthy newborn infant are not known and may be different than for the adult. We measured the half-life for fetal sheep fibrinogen and compared it to the half-life of adult sheep fibrinogen. Fibrinogen was purified from adult and fetal sheep plasma and radiolabeled with either 125I or 131I. The half-lives for these fibrinogens were determined in the adult sheep and newborn lamb. In addition, the fetal and adult sheep fibrinogens were compared by reptilase time, thrombin clotting time, sialic acid content, and the behavior of the N-glycans derived from these fibrinogens on the immobilized lectin, Sepharose-concanavalin A. Finally, the in vivo response of coinjected radiolabeled fibrinogens to increasing doses of infused thrombin was determined. The fetal sheep fibrinogen differed from the adult as indicated by a prolonged reptilase time and an increased sialic acid content (fetal: 10-11 residues/340 Kd versus adult: 8-9 residues/340 Kd). The latter was also reflected in differing chromatographic profiles for the N-glycans on Sepharose-concanavalin A. The half-lives for both the adult and fetal fibrinogen were significantly more rapid in the newborn lamb (fetal: 47 +/- 2.0 h; adult: 46 +/- 2.4 h, mean +/- SEM) than in the adult (fetal: 116 +/- 6.5 h; adult: 121 +/- 6.9 h). Finally, the adult and fetal sheep fibrinogen responded to thrombin in an identical fashion in the intact animal. In summary, both adult and fetal fibrinogen have faster half-lives in the lamb compared tot he adult, despite a higher sialic acid content for the fetal fibrinogen.(ABSTRACT TRUNCATED AT 250 WORDS)
This study was designed to determine the postnatal development of the human coagulation system in the healthy premature infant. Consecutive mothers of healthy premature infants born at either St Joseph's Hospital or McMaster University Medical Centre in Hamilton were asked for consent. One hundred thirty-seven premature infants (30 to 36 weeks of gestational age) entered the study. The premature infants did not have any major health problems and did not require ventilation or supplemental oxygen. Demographic information and a 20-mL blood sample were obtained in the postnatal period on days 1, 5, 30, 90, and 180. Between 40 and 96 premature infants were studied on each day for each of the following tests: prothrombin time, activated partial thromboplastin time, thrombin clotting time, plasminogen; 13 factor assays [fibrinogen, II, V, VII, VIII, IX, X, XI, XII, XIII, high-mol-wt kininogen (HMWK), prekallikrein (PK), von Willebrand factor (vWF)] and eight inhibitors [antithrombin III (AT-III), heparin cofactor II, alpha 2-antiplasmin, alpha 2-macroglobulin, alpha 1-antitrypsin, C1 esterase inhibitor, protein C (PC), and protein S (PS)]. A combination of biologic and immunologic assays were used. Between 30 to 36 weeks there was a minimal effect of gestational age for levels of AT-III, PC, and factors II and X only; therefore, the entire data set was used to generate reference ranges for these components of the coagulation system for premature infants. Next, the results for the premature infants were compared with those of a previously published study in 118 fullterm infants and with those for adults. An effect of gestational age was shown for plasminogen, fibrinogen, factors II, V, VIII, IX, XI, XII, HMWK, and all eight inhibitors. In general, the postnatal maturation towards adult levels was accelerated in premature infants as compared with the fullterm infants. By 6 months of age, most components of the coagulation system in premature infants had achieved near adult values.
Heparin is commonly used to treat neonatal thrombosis. Drug monitoring often involves assays that measure the inhibition of added factor Xa or thrombin by the antithrombin III (AT-III) heparin complex. We examined whether the neonatal AT-III deficiency affects heparin recovery in such assays at therapeutic drug concentrations (0.1 to 0.6 U/ml). The chromogenic anti-factor Xa assay (Teien AN, Lie M, Abildgaard U. Thromb Res 1976;8:413-6) and the protamine titration test were performed in eight pooled cord plasma samples and in normal adult plasma. Only 65% to 70% of heparin activity detected in adult plasma was recovered by the assay of Teien et al. In cord plasma; recovery by the protamine test was 80% or less. Heparin recovery in cord plasma was significantly improved by raising the AT-III concentration to normal adult levels in both assays. We conclude that heparin assays underestimate drug levels in neonatal plasma unless the neonatal AT-III deficiency is fully corrected in the test system. The use of standard assays may lead to over-heparinization of newborn infants, thereby placing them at a higher risk of bleeding.
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The preaggregative period of Dictyostelium discoideum is composed of two sequential rate-limiting components. The timing mutant FM-1 exhibits a decrease in the length of the preaggregative period and the interval between the maxifinger and early culminate II stage. In contrast, it is normal in all aspects of growth, in the sequence of morphogenetic stages, in spore formation, in the capacity to rapidly recapitulate morphogenesis, and in the erasure event and subsequent program of dedifferentiation. By the reciprocal shift experiment, it is demonstrated that FM-1 is completely missing the first of the two rate-limiting components comprising the preaggregative period. The FM-1 mutation is heritable and behaves as a single mutation mapping to linkage group II. However, the FM-1 variant switches at relatively high frequency to several other timing phenotypes with longer preaggregative periods which in turn switch at high frequency. The FM-1 phenotype is considered in terms of timing regulation, and the process of high frequency switching between timing phenotypes is compared to other newly discovered switching systems.
The investigation of many hemostatic defects in the newborn is limited by the lack of normal reference values. This study was designed to determine the postnatal development of the human coagulation system in the healthy full-term infant. Consecutive mothers of healthy full-term infants born at St Joseph's Hospital in the city of Hamilton were approached for consent. One hundred eighteen full-term infants (37 to 42 weeks' gestational age) were entered into the study. Demographic information and a 2-mL blood sample were obtained in the postnatal period on days 1, 5, 30, 90, and 180. Between 40 and 79 full-term infants were studied on each day for each of the coagulation tests. Plasma was fractionated and stored at -70 degrees C for batch assaying of the following tests: prothrombin time, activated partial thromboplastin time, thrombin clotting time, and factor assays (biologic): fibrinogen, II, V, VII, VIII, IX, X, XI, XII, and high-molecular weight kininogen. Factor XIII subunits A and S, von Willebrand factor, and the inhibitors antithrombin III, alpha 2-antiplasmin, alpha 2-macroglobulin, alpha 1-antitrypsin, C1 esterase inhibitor, protein C, and protein S were measured immunologically. Plasminogen, prekallikrein, and heparin cofactor II were measured by using chromogenic substrates. The large number of infants studied at each time point allowed us to determine the following: the range of normal for each test at five time points in the postnatal period; that coagulation tests vary with the postnatal age of the infant; that different coagulation factors show different postnatal patterns of maturation; and that near-adult values are achieved for most components by 6 months of life. In summary, this large cohort of infants studied consecutively in the postnatal period allowed us to determine the normal development of the human coagulation system in the full-term infant.
Standard heparin and a LMWH, CY222 do not cross the placenta nor alter fetal coagulation when injected into the pregnant ewe. We found that another LMWH, Pharmuka-10169 (PK-10169) alters fetal coagulation without crossing the placenta in the pregnant sheep. To characterize this anticoagulant we measured the in vitro and in vivo effects of 125I-PK-10169 in maternal and fetal plasmas following administration of PK-10169 to the mother or fetus. The fetal anticoagulant activity was not neutralizable by protamine sulphate and was attributable to the inhibition of thrombin but not factor Xa. In vitro, the fetal anticoagulant activity had properties similar to dermatan sulphate; both catalyzed the inhibition of thrombin but not factor Xa by sheep plasma; and neither was neutralizable by protamine sulphate. These effects were due to the enhanced neutralization of thrombin by heparin cofactor II. We conclude that PK-10169 does not cross the placenta, but does induce the release of an endogenous dermatan sulphate-like substance which alters fetal coagulation.
Appropriate animal experimentation can enhance our understanding of thrombotic and hemorrhagic problems in the human neonate. Which newborn animal species' coagulation system most closely resembles the human neonate is unknown. The objective of the study was to assess the newborn coagulation system in four animal species and compare them with the human neonate. Blood samples were drawn on days 1 and 7 of life from lambs (n = 10), piglets, (n = 12), rabbit pups (n = 12), and beagle pups (n = 7). Coagulation screening tests, specific factor assays, and specific inhibitors of the coagulation system were measured. All factor assays were expressed as a percent of the respective species pooled adult plasma. The results from the animals were compared to normal values from our laboratory for healthy full-term infants. The coagulation systems of all species tested, except the rabbit pup, were immature at birth with most factor levels being lower than the adult of their species. The coagulation systems were influenced by the postnatal age of the animal and the factor levels reached adult values in fewer days relative to the human. The coagulation system for the piglet most closely approximated the human neonate. The shared characteristics were prolonged screening tests, increased factor VIII:C, generally low levels for the contact and vitamin K-dependent factors, and low antithrombin III levels relative to the adult. The beagle pup also showed many similar characteristics but in contrast to the human neonate factor VIII:C and V were low on day 1 of life and prekallikrein was not measurable in the adult or newborn beagle.(ABSTRACT TRUNCATED AT 250 WORDS)
The specific activities of the enzymes alpha-mannosidase and N-acetylglucosaminidase increase immediately after the initiation of the development of bacterially grown cell cultures of Dictyostelium discoideum. The regulation of these two enzymes was found to be dissociable in the developmental timer mutant, FM-1, which aggregates 4.5 h earlier than wild-type cells due to the absence of the first rate-limiting component of the preaggregative period. The increase in alpha-mannosidase activity occurs in the absence of the first rate-limiting component, but the increase in N-acetylglucosaminidase activity does not. These results indicate the following: (1) the increase in the specific activity of alpha-mannosidase is not related to the timing of subsequent developmental stages; (2) the increase in the specific activity of N-acetylglucosaminidase is not necessary for the subsequent developmental program; and (3) either the increase in the specific activity of N-acetylglucosaminidase is dependent upon progress through the first rate-limiting component, or the increase in this enzyme activity and the first rate-limiting component are both dependent upon an early event for which FM-1 is defective. In addition to early development, we monitored the two enzyme activities during dedifferentiation. The results demonstrate that there is no difference between dedifferentiating wild-type cells and dedifferentiation-defective mutant HI-4 cells. Changes in enzyme specific activity accompanying dedifferentiation are dependent upon the composition of the dedifferentiation-inducing media and are consistent with the levels of these enzymes observed in cells growing in the different nutrient media.
The induction of pathologic changes with hormone steroids has been studied in rodents, although comprehensive studies are lacking on the potential reversibility of these lesions. For these purposes, groups of rats were treated with quingestanol acetate and quinestrol, a progestogen-estrogen combination, for 50 weeks and observed for a subsequent 30-week period. Treatment resulted in a significant body weight gain suppression and reduction of food consumption which recovered after withdrawal. Other significant treatment-related effects were hair loss, ataxia due to pituitary enlargement, mammary chain masses with histologic adenocarcinoma, lens opacities, ovarian atrophy with follicular arrest, and uterine atrophic changes with suppurative inflammation throughout 50 weeks. Cessation of treatment did not effect hair loss or lens opacities, while mammary chain masses decreased in size and in incidence; mammary gland tumors showed regressive changes including the disappearance of adenocarcinoma, and the incidence of ataxia diminished together with reduced pituitary weights. Chromophobe cell hyperplasia with decreased eosinophils and acidophils and hemorrhage into the pituitary was observed up to 50 weeks and the tinctorial affinity of basophils and acidophils returned after withdrawal. Ovaries and uteri, which become atrophic and sustained chronic suppurative inflammation in the treatment phase, showed reduction of inflammatory reaction and disappearance of suppuration after withdrawal, and endometrial regeneration occurred with luteal cells seen in the ovaries. These results revealed the regressive characteristics of some of the mammary gland carcinomas as well as steroid-induced endocrine and pathologic lesions other than tegumentary and ocular changes in rats receiving high levels of steroids for prolonged periods of time.
Antithrombin III, a major inhibitor of activated coagulation factors has low immunologic levels in the human infant. The objective of this study was to determine if the antithrombin III molecule is fully functional in sick premature infants. The populations studied included: adult controls (n = 20), full term healthy infants (n = 18), sick premature infants on day 1 (n = 16) and at greater than 7 days of age (n = 10), and infants with disseminated intravascular coagulation (n = 11). This was diagnosed in the presence of prolonged screening tests, decreased levels of fibrinogen, and platelets along with elevated fibrin degradation products. Plasma antithrombin III levels were measured biologically (chromogenic substrate S2238) and immunologically (radialimmunodiffusion), and expressed as a percent of adult pooled plasma. Crossed immunoelectrophoresis were performed in the presence and absence of heparin. The antithrombin III biologic/immunologic ratios for adults, healthy full term infants, and sick premature infants on day 1 of life were all near unity. In contrast sick premature infants beyond the 1st wk of life and infants with disseminated intravascular coagulation had lower biologic activity compared to immunologic (B/I = 0.77 +/- 0.28, 0.78 +/- 0.17, p less than 0.01), respectively. In all groups, the antithrombin III molecule was normal on crossed immunoelectrophoresis except for one infant with disseminated intravascular coagulation. Sick premature infants may acquire a dysfunctional antithrombin III molecule in the postnatal period.
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A fracture mechanics approach has been used to quantify the failure of tooth coloured restorative materials which are subjected to tensile forces. The materials examined included silicates, glass ionomers, composites (both chemically and photo-initiated) and bonding resins for composites. The parameter chosen was the plane strain critical stress intensification factor, KIC. Silicate and glass ionomer are both brittle and have values for KIC inferior to those of composites. Composites have fracture toughnesses in a range from marginally higher than that of the bonding resin to almost three times that figure. The reason for this is discussed in terms of the dispersion toughening theories.
A new method has been developed to assess the minimum complexity and relationships of those pathways (developmental timers) which time the consecutive stages of a developing system (Soll, 1983). This method has been applied to the morphogenetic program of Dictyostelium discoideum and has resulted in (1) a minimum estimate of the number of components comprising the timers for the first seven stages of morphogenesis, (2) a characterization of the temperature sensitivities of these components including demonstration of a reversible timer component, (3) detained temporal definition of a number of transition points between rate-limiting components including a major branch point for the onset of several independent timer components coincident with the onset of aggregation, and (4) a temporal model for the relationships between the timers of the seven consecutive morphogenetic stages, including several examples of parallel timers.