Shanklin D. Radford

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Shanklin
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D. Radford
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  • Preprint
    Cerebropulmonary dysgenetic syndrome
    ( 2008-04) Shanklin, D. Radford ; Mullins, Amanda C. ; Baldwin, Heather S.
    Ventilatory treatment of neonatal respiratory distress often results in bronchopulmonary dysplasia from congenital surfactant deficiency due to mutants of transporter protein ABCA3. Association of this condition with other severe disorders in premature newborns has not heretofore been reported. A neonatal autopsy included an in vivo whole blood sample for genetic tcsting. Autopsy revealed severe interstitial pulmonary fibrosis at age 8 days with heterozygotic mutation p.E292V of ABCA3 and severe dystrophic retardation of cerebral cortcx and cerebellum. Subsequently, 1300 archival neonatal autopsies, 1983-2006, were reviewed for comparable concurrent findings and bronchopulmonary dysplasia or retarded cerebral dystrophy lacking the other principal feature of this syndrome. Archival review revealed four similar cases and eight less so, without gene analysis. Further review for bronchopulmonary dysplasia revealed 59 cases, 1983-2006. Several other examples of similar retarded migration of germinal matrix and underdevelopment of cortical mantle, without pulmonary lesions of this type, were identified. The determination of an ABCA3 mutation in one case of severe pulmonary fibrosis with significant dystrophy of the brain and the identification of four highly similar archival cases and eight others with partial pathological findings supports the designation of an independent disorder, here referred to as the cerebroprrlmonary dysgenetic syndrome.
  • Preprint
    On the pulmonary toxicity of oxygen. 4. The thyroid arena
    ( 2011-11) Shanklin, D. Radford
    Normally developed thyroid function is critical to the transition from fetal to neonatal life with the onset of independent thermoregulation, the most conspicuous of the many ways in which thyroid secretions act throughout the body. A role for thyroid secretions in growth and maturation of the lungs as part of the preparation for the onset of breathing has been recognized for some time but how this contributes to tissue and cell processes and defenses under the duress of respiratory distress has not been well examined. Extensive archival autopsy material was searched for thyroid and adrenal weights, first by gestational age, and then for changes during the first hours after birth as ratios to body weight. After a gestational age of 22 weeks the fetal thyroid and adrenal glands at autopsy in those with hyaline membrane disease are persistently half the size of those in "normal" infants dying with other disorders. When the thyroid is examined shortly after birth it reveals a post natal loss of mass per body weight of similar orders of magnitude which does not occur in the control group. A clinical sample of premature infants with (12) and without (14) hyaline membrane disease was tested for T4, TSH, TBG, and total serum protein. The results also demonstrate a special subset with lower birth weights at the same gestational age, and lower serum T4 and total serum protein. Ventilatory distress in newborn rabbits was induced by bilateral cervical vagotomy at 24 hours post natal following earlier injection of thyroxine (T4) or thyroid stimulating hormone (TSH) and comparisons were made with untreated animals and by dose. Early life thyroidectomy was performed followed by exposure to either air or 100% oxygen. A final experiment in air was vagotomy after thyroidectomy. Composite analysis of these methods indicates that thyroid factors are both operative and important in the newborn animal with ventilatory distress. This work and the archival data indicate those infants destined to develop hyaline membrane disease through respiratory distress are a distinct developmental and clinical subset with the point of departure from otherwise normal development and maturation in the second or early third trimester. This interval is known to be a period of marked variation in the overview indicators of fetal progress through gestational time. The initiating factor or circumstance which then separates this special subset from normal future development is placed by these observations firmly into the period when human fetal TSH dramatically rises 7-fold (17.5-25.5 weeks) followed by a lesser 3 to 4 fold increase in T4 which is extended into the early third trimester. The earlier part of this interval is characterized by the thyrotrophic action of chorionic gonadotropin (hCG). The possibility that abnormalities in the intrauterine environment secondary to maternal infection play a role within this time frame is indicated by the demonstration that interleukin-2 (IL-2) induces an anterior pituitary release of TSH. Since IL-2 has this property and is not an acute phase cytokine, some form of chronic infection or an immunopathic process seems more likely as a possible active factor in pathogenesis.
  • Preprint
    Letters to the Editor : Challenges of forensic science
    ( 2012-07-09) Shanklin, D. Radford
    Letters: Challenges Of Forensic Science. Published August 6, 2012
  • Preprint
    On the pulmonary toxicity of oxygen. 5. Electronic structure and the paramagnetic property of oxygen
    ( 2012-06-01) Shanklin, D. Radford
    Oxygen uptake by the pulmonary circulation is a chemical reaction. The physicochemical attributesof oxygen are critical when studying pulmonary oxygen toxicity. Extent of lung injury depends onthe percentage of oxygen in an oxygen:nitrogen mix in polybaric circumstances (Shanklin, 1969). Further change in extent of lesion follows when other gases are used in the inhalant mix instead of nitrogen (Shanklin and Lester, 1972), with oxygen at 21-100% of the mix. Comparative subatmospheric oxygen levels down to 3% in hydrogen, helium, nitrogen, argon, or sulfurhexafluoride, were run with and without ventilatory distress by the Farber (1937) model, bilateralcervical vagotomy (BCV). This yielded coherent results indicating a need to consider molecular characteristics at the atomic level. Molecular mass and size, gas viscosity, and thermal conductivity yielded no obvious correlates to lung injury. Saturation of the outer electron shells of the diluents fit the empiric data, prospectively an interaction between oxygen and nitrogen from their electronegativity and closely approximate molecular mass, size, and shape. The lesion is essentially eliminated at 7% oxygen in nitrogen. At 3% oxygen, the least lesion is found with N2, H2, and SF6,all gases with incomplete outer electron shells, allowing for transient, possibly polarized, covalent bonding with oxygen as the significant minority component in the mix. Argon and helium do not interfere with oxygen. With 3% oxygen in argon without BCV, the experiments ran so long (>70hours) they were terminated once the point had been made. 3% oxygen in argon after BCV yielded a mean survival more than twice that of BCV in air, indicating a remarkable degree of nitrogen interference with oxygen in the respiratory medium of terrestrial animal life. Argon displayed other advantages for the lung compared to nitrogen. Hydrogen, nitrogen, and oxygen are diatomic molecules, a feature which does relate to the extent of lung injury, but only oxygen is paramagnetic. Magnetic effects on lesion formation were tested: [1] with ventilatory distress induced in newbornrabbits, and [2] in young adult female white mice exposed to 100% oxygen without addedmechanical distress. A noninvasive model for ventilatory distress, thoracic restraint (TR), withlonger mean survivals of 40-50 hours, was employed rather than the Farber model. Parallel runs with TR, one subset receiving 100% oxygen in a plastic chamber resting on six strong ring magnetswith measured fields up to +1200 gauss, the other plain 100% oxygen, were performed. Bothsubsets developed moderate metabolic acidosis with average weight losses circa 25%, but over different time courses, 82.89 ± 4.91 hours in magnetized oxygen, 55.4 per cent longer than the 53.34 ± 9.82 hours in plain oxygen ( p <0.001). The longer survival in magnetized oxygen meant extensive lung injury (99.57 ± 0.42% pleural surface, versus 83.86 ± 14.03%), but the rate of lesionformation was 30.89 per cent faster in plain oxygen (1.5722% per hour) than in magnetized oxygen(1.2012% per hour), a difference significant at p <0.001. The effect of oxygen without mechanical ventilatory distress was examined in female adult whitemice exposed to oxygen or magnetized oxygen. Similar survivals and weight losses were achieved. The rate of lung lesion formation was different, 1.2617% per hour in plain oxygen, 46.13 per centfaster than 0.8634% per hour in magnetized oxygen. A variable magnetic field, with animals moving and breathing in chambers flooded with oxygen, has both systemic and pulmonary effectswhich alter the rate of lesion formation due to oxygen toxicity. Paramagnetic oxygen in a magneticfield influences the effect of oxygen toxicity on the lung but at these strengths of field it does notovercome significant mechanical disturbance.
  • Preprint
    Cellular magnesium acquisition : an anomaly in embryonic cation homeostasis
    ( 2007-03-14) Shanklin, D. Radford
    The intracellular dominance of magnesium ion makes clinical assessment difficult despite the critical role of Mg++ in many key functions of cells and enzymes. There is general consensus that serum Mg++ levels are not representative of the growing number of conditions for which magnesium is known to be important. There is no consensus method or sample source for testing for clinical purposes. High intracellular Mg++ in vertebrate embryos results in part from interactions of cations which influence cell membrane transport systems. These are functionally competent from the earliest stages, at least transiently held over from the unfertilized ovum. Kinetic studies with radiotracer cations, osmolar variations, media lacking one or more of the four biological cations, Na+, Mg++, K+, and Ca++, and metabolic poison 0.05 mEq/L NaF, demonstrated: (1) all four cations influence the behavior of the others, and (2) energy is required for uptake and efflux on different time scales, some against gradient. Na+ uptake is energy dependent against an efflux gradient. The rate of K+ loss is equal with or without fluoride, suggesting a lack of an energy requirement at these stages. Ca++ efflux took twice as long in the presence of fluoride, likely due in part to intracellular binding. Mg++ is anomalous in that early teleost vertebrate embryos have an intracellular content exceeding the surrounding sea water, an isolated unaffected yolk compartment, and a clear requirement for energy for both uptake and efflux. The physiological, pathological, and therapeutic roles of magnesium are poorly understood. This will change: (1) when 28Mg is once again generally available at a reasonable cost for both basic research and clinical assessment, and (2) when serum or plasma levels are determined simultaneously with intracellular values, preferably as part of complete four cation profiles. Atomic absorption spectrophotometry, energy-dispersive x-ray analysis, and inductively coupled plasma emission spectroscopy on sublingual mucosal and peripheral blood samples are potential methods of value for coordinated assessments.
  • Preprint
    On the pulmonary toxicity of oxygen : III. The induction of oxygen dependency by oxygen use
    ( 2010-05) Shanklin, D. Radford
    Oxygen is central to the development of neonatal lung injury. The increase in oxygen exposure of the neonatal lung during the onset of extrauterine air breathing is an order of magnitude, from a range of 10-12 to 110-120 Torr. The contributions of oxygen and the volume and pressure relationships of ventilatory support to lung injury are not easily distinguished in the clinical setting. Sequential changes in inspired air or 100% oxygen were studied in 536 newborn rabbits without ventilatory support. Bilateral cervical vagotomies (BCV) were performed at 24 hours post natal to induce ventilatory distress which eventuates in hyaline membrane disease. The sequences applied yielded evidence for an induced state of oxygen dependency from oxygen use which was reflected in differences in survival and the extent of pulmonary injury. The median survival for animals kept in air throughout was 3 hours. Oxygen before vagotomy or during the first 3 hours afterwards extended the survival significantly but produced more extensive, more severe, and more rapid lung lesions. Returning animals to air after prior oxygen exposure reduced the number of survivors past 10 hours and shortened the maximum survival in those groups. These features indicate the development of a dependency of the defense mechanisms on the availability of oxygen at the higher level for metabolic and possibly other aspects of the pulmonary and systemic response to injury, beyond the usual physiological need. Subset analysis revealed additive and latent effects of oxygen and demonstrated a remarkable rapidity in onset of severe lesions under some circumstances, illustrating the toxicity of oxygen per se.