Shanklin D. Radford
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PreprintCerebropulmonary 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.
PreprintCellular magnesium acquisition : an anomaly in embryonic cation homeostasis( 2007-03-14) Shanklin, D. RadfordThe 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.