The genetic basis of Turner syndrome aortopathy

Our goal is to identify the genetic underpinnings of bicuspid aortic valve and aortopathy in Turner syndrome. We performed whole exome sequencing on 188 Turner syndrome study subjects from the GenTAC registry. A gene‐based burden test, SKAT‐O, was used to evaluate the data using bicuspid aortic valve (BAV) and aortic dimension z‐scores as covariates. This revealed that TIMP3 was associated with BAV and increased aortic dimensions at exome‐wide significance. It had been previously shown that genes on chromosome Xp contribute to aortopathy when hemizygous. Our analysis of Xp genes revealed that hemizygosity for TIMP1, a functionally redundant paralogue of TIMP3, increased the odds of having BAV aortopathy compared to individuals with more than one TIMP1 copy. The combinatorial effect of a single copy of TIMP1 and TIMP3 risk alleles synergistically increased the risk for BAV aortopathy to nearly 13‐fold. TIMP1 and TIMP3 are tissue inhibitors of matrix metalloproteinases (TIMPs) which are involved in development of the aortic valve and protection from thoracic aneurysms. We propose that the combination of TIMP1 haploinsufficiency and deleterious variants in TIMP3 significantly increases the risk of BAV aortopathy in Turner syndrome, and suggest that TIMP1 hemizygosity may play a role in euploid male aortic disease.     

ApoE genotype accounts for the vast majority of AD risk and AD pathology

In this review, evidence is provided that apolipoprotein E (apoE) genotype accounts for the majority of Alzheimer's disease (AD) risk and pathology. The three major human isoforms, apoE2, apoE3, and apoE4, are encoded by different alleles (2, 3, 4) and regulate lipid metabolism and redistribution. ApoE isoforms differ in their effects on AD risk and pathology. Clinical and epidemiological data have indicated that the 4 allele may account for 50% of AD in the United States. Further, the rarity of AD among carriers of the 2 allele suggests that allelic variations in the gene encoding this protein may account for over 95% of AD cases. ApoE4 disrupts memory function in rodents. Further studies have indicated that fragments of apoE may contribute to both plaque and tangle formation. Thus, the epidemiologic and basic science evidence suggest that apoE genotype accounts for the vast majority of AD risk and pathology.     

Evaluation of anhydride oligomers within polymer microsphere blends and their impact on bioadhesion and drug delivery in vitro

The effect of the addition of small molecular weight anhydride oligomers to polymer microspheres was evaluated and increased bioadhesion of the composite was demonstrated. Blends of low molecular weight anhydride oligomers with thermoplastic poly(fumaric-co-sebacic anhydride) [p(FASA)] and polycaprolactone were examined. The effects of anhydride oligomers on polymer microsphere degradation, crystallinity, and surface morphology were also explored. The results demonstrated that fumaric anhydride oligomer remained within polymer microspheres for several hours after exposure to phosphate buffer, formed a homogenous crystalline blend, increased bioadhesion as measured on rat intestine, and enhanced drug delivery in vitro as measured by the everted sac technique.     

Significance of right ventricular filling for left ventricular enddiastolic pressure-volume relationship under acute hypoxia in the dog

Summary In 14 closed-chest dogs, the significance of right ventricular filling for left ventricular enddiastolic pressure-volume relationship was investigated under acute hypoxia by means of single plane cineventriculography and simultaneous intraventricular pressure recording.Both after 5 min asphyxia (respirator switched off) (n=5) and after 3 min hypoxia (ventilation with pure N₂) (n=9), there was a significant leftward shift (p<0.005) of the left ventricular enddiastolic pressure-volume curve as compared to the control curves under normoxia. To simulate the elevated filling of the right ventricle under acute hypoxia, rapid intraventricular infusion was applier under normoxic conditions to raise right ventricular enddiastolic pressure to the same values as that measured under hypoxia. The extent of the ensuing leftward shift of the left ventricular enddiastolic pressurevolume curve was on average 60% of the shift under hypoxia in both sets of experiments. Neither the slope of the relationship between volume stiffness and enddiastolic pressure, nor the relationship between tangent elastic modulus and left ventricular wall stress, was affected by hypoxia or asphyxia.Thus, the shift of the left ventricular enddiastolic pressure-volume curve in the early stage of hypoxia is predominantly due to the influence of increased right ventricular filling. Since the increased volume of the atria under acute hypoxia limits left ventricular distensibility additionally, the changes in left ventricular enddiastolic pressure-volume relationships, observed in the early stage of hypoxia are mainly, or even entircly, the result of interaction of the various heart compartments, and not a reflection of alterations in myocardial tissue elasticity.Preliminary results were presented at the symposium on Cardiac adaptation to hemodynamic overload, training and stress in Tübingen (1983)Supported by the Deutsche Forschungsgemeinschaft     

Evaluating the Impact of a Novel Peer-to-Peer Educational Modality on Knowledge and Attitudes About Perinatal Mood and Anxiety Disorders

Maternal and Child Health Journal - This study assessed whether the use of a peer-to-peer educational book, written and illustrated by women who experienced common mental disorders (CMDs) in the...