Iron homeostasis and post-hemorrhagic hydrocephalus: A review

Iron physiology is regulated by a complex interplay of extracellular transport systems, coordinated transcriptional responses, and iron efflux mechanisms. Dysregulation of iron metabolism can result in defects in myelination, neurotransmitter synthesis, and neuronal maturation. In neonates, germinal matrix-intraventricular hemorrhage (GMH-IVH) causes iron overload as a result of blood breakdown in the ventricles and brain parenchyma which can lead to post-hemorrhagic hydrocephalus (PHH). However, the precise mechanisms by which GMH-IVH results in PHH remain elusive. Understanding the molecular determinants of iron homeostasis in the developing brain may lead to improved therapies. This manuscript reviews the various roles iron has in brain development, characterizes our understanding of iron transport in the developing brain, and describes potential mechanisms by which iron overload may cause PHH and brain injury. We also review novel preclinical treatments for IVH that specifically target iron. Understanding iron handling within the brain and central nervous system may provide a basis for preventative, targeted treatments for iron-mediated pathogenesis of GMH-IVH and PHH

The Influence of Paternal Separation, Paternal History of Alcohol Use Disorder Risk, and Early Substance Use on Offspring Educational Attainment by Young Adulthood

Objective: This study aimed to determine the associations among paternal alcohol problems, separation, and educational attainment in European American and African American offspring and whether offspring early alcohol/tobacco/marijuana use influenced these associations. Method: Families with offspring ages 13–19 years at intake were selected from state birth records and screened by telephone to determine high-risk or low-risk status (with/without paternal heavy drinking). Families of men with two or more driving-under-the-influence offenses were added as a very-high-risk group. Data from 340 African American and 288 European American offspring who were not enrolled in school at their last interview were analyzed. Educational attainment was modeled as less than high school, high school only (reference category), and some college or higher. Separation was defined as offspring report of not having lived continuously in the same household with their biological father from birth to age 14. Analyses were stratified by race. Results: In European Americans, neither family risk status nor early alcohol/tobacco/marijuana use was associated with educational outcomes. However, paternal separation significantly elevated the likelihood of not completing high school in all models (relative risk ratios [RRRs] = 6.0– 8.1, p <.001). For African American offspring, likelihoods of high school noncompletion were elevated marginally for paternal separation in only one model, but significantly for early marijuana use (RRRs = 2.8– 3.2, p < .05). Very-high-risk status significantly reduced the likelihood of post-high school education in an adjusted model (RRR = 0.4, p < .05). Conclusions: High school noncompletion was significantly associated with paternal separation in European Americans and with early marijuana use in African American offspring. In addition, very-high-risk status reduced the likelihood of post-high school education in African American offspring only, suggesting that research with ethnically diverse samples yields important differences when examining outcomes of both separation and substance use on offspring education

Molecular pathogenesis and heterogeneity in type 3 VWD families in US Zimmerman program

Background Type 3 von Willebrand Disease (VWD) is a rare and severe form of VWD characterized by the absence of von Willebrand factor (VWF). Objectives As part of the Zimmerman Program, we sought to explore the molecular pathogenesis, correlate bleeding phenotype and severity, and determine the inheritance pattern found in type 3 VWD families. Patients/Methods 62 index cases with a pre-existing diagnosis of type 3 VWD were analyzed. Central testing included FVIII, VWF:Ag, VWF:RCo, and VWFpp. Bleeding symptoms were quantified using the ISTH bleeding score. Genetic analysis included VWF sequencing, comparative genomic hybridization and predictive computational programs. Results 75% of subjects (46) had central testing confirming type 3, while 25% were re-classified as type 1-Severe or type 1C. Candidate VWF variants were found in all subjects with 93% of expected alleles identified. The majority were null alleles including frameshift, nonsense, splice site, and large deletions, while 13% were missense variants. Additional studies on 119 family members, including 69 obligate carriers, revealed a wide range of heterogeneity in VWF levels and bleeding scores, even amongst those with the same variant. Co-dominant inheritance was present in 51% of families and recessive in 21%, however 28% were ambiguous. Conclusion This report represents a large cohort of VWD families in the U.S. with extensive phenotypic and genotypic data. While co-dominant inheritance was seen in approximately 50% of families, this study highlights the complexity of VWF genetics due to the heterogeneity found in both VWF levels and bleeding tendencies amongst families with type 3 VWD

Scientific and Religious Perspectives on Evolution in the Curriculum: an Approach Based on Pedagogy of Difference

There is a long history of some students finding that the science instruction they receive in schools fails to address their deeply held concerns about the theory of evolution. Such concerns are principally religious, though there are also students with deeply held religious views who are perfectly comfortable with the theory of evolution. New instructional strategies are emerging, aimed at reducing the tensions that may exist between evolution and religion by making space for students to examine their own views and recognize the spectrum of views that exists between atheistic evolution and special creation, as well as the bounded nature of science and different ways of knowing. In this article, we discuss the teaching of evolution in societies where acceptance of the theory of evolution is far from universal, and argue that an approach based on pedagogy of difference has considerable potential to enhance students’ development of epistemic insight through recognition of the multiple perspectives that exist concerning the relationship between religion and science. In doing so, we explicate precisely what pedagogy of difference entails and introduce an approach that should enhance evolution education, and even aid students’ situating of science as a resource for making decisions about issues with scientific and societal aspects where the acknowledgement of multiple perspectives is valuable

Chain tilt and surface disorder in lamellar crystals. A FTIR and SAXS study of labeled long alkanes

Small-angle X-ray scattering (SAXS) and infrared spectroscopy (IR) are employed in a study of chain tilt and disorder in solution-crystallized long alkanes C198H398 and C12D25C192H384C12HD24 in extended and once-folded conformations. The as-grown crystals have chains perpendicular to the lamellar surface, but around 90 °C they start tilting relative to the layer normal. The tilt increases gradually to reach 35° just below melting point. The end-labeled alkane allows independent IR probing of molecular disorder at the deuterated surface layer and in the hydrogenous interior of the crystals. The initially small splitting of the CD2 bending mode doublet and the presence of a singlet component indicated a rough surface in as-grown crystals, with considerable translational disorder. The increase in splitting and decrease in absorbance of the singlet which occur on annealing at progressively higher temperatures showed a steady improvement in translational surface order, concomitant with an increase in chain tilt angle. Thus, it is concluded that the absence of tilt in as-grown crystals is not due to high surface order, as in the case of shorter odd n-alkanes, but rather to high nonequilibrium surface disorder with chain ends or folds protruding out of or sunk beneath the surface. It is also concluded that chain tilt only becomes necessary as the crystal surface becomes translationally more ordered and the crystal-amorphous interface sharpens. IR also demonstrated the reversible increase in conformational disorder in the surface layer with increasing temperature and an almost negligible increase in the crystal interior. The gradual change in tilt angle and the existence of noncrystallographic basal planes is interpreted in terms of translational molecular disorder at the surface. The increased central SAXS scatter during the tilting process indicates the creation of voids associated with ridge formation and corrugation of the lamellae</p