Developmental iron deficiency anemia (IDA) causes brain and behavioral deficits in rodent models, which cannot be reversed when treated at periods equivalent to later infancy in humans. This study sought to determine whether earlier iron treatment can normalize deficits of IDA in rats and what iron dose is optimal. The offspring of dams with IDA during gestation were cross-fostered at postnatal d (P) 8 to dams receiving diets with 1 of 3 iron concentrations until weaning (P21): 0.003-0.01 g/kg [totally iron deficient (TID)]; 0.04 g/kg [formerly iron deficient (FID-40)]; or 0.4 g/kg (FID-400). Always iron-sufficient control dams (CN-40) received a 0.04-g/kg iron diet. At P21, TID pups received a 0.01 g iron/kg diet; all others received a 0.04 g iron/kg diet. Hematocrit and brain iron and monoamine concentrations were assessed at P21 and P100. Pup growth, development, activity, object recognition, hesitancy, and watermaze performance were evaluated. Regional brain iron was restored by iron treatment. Regional monoamine and metabolite concentrations were elevated in FID-40 rats and reduced in FID-400 and TID rats compared with CN-40 rats. FID-40 offspring had motor delays similar to TID during lactation and FID-400 rats had elevated thigmotaxis similar to TID rats at P25 and P100 in the spatial watermaze. In conclusion, iron treatment at P8 in rats did not normalize all monoamine or behavioral measures after early IDA. Moderate iron treatment improved adult behavior, but higher iron treatment caused brain and behavioral patterns similar to TID in the short and long term.

Background Long-term prefrontal cortex and hippocampus-based cognitive deficits are the sequelae of perinatal iron deficiency, despite iron supplementation starting in the newborn period. Whether high dose iron supplementation prevents these deficits is not known. Methods Perinatal iron deficiency was induced in rat pups using low-iron (3 mg/kg diet) diet during gestation until postnatal day (P) 8. Iron was supplemented using standard (40 mg/kg diet) or 10-fold higher (400 mg/kg diet) iron-containing diet until P21. Prefrontal cortex and hippocampal neurochemistry was determined using in vivo 1H nuclear magnetic resonance spectroscopy at 9.4 tesla on P90. Results Both iron supplementation doses corrected anemia and brain iron deficiency by P21. The neurochemical profile of the prefrontal cortex in both supplementation groups was comparable to the control group. In the hippocampus, standard-dose iron supplementation resulted in lower N-acetylaspartate and phosphoethanolamine, and higher N-acetylaspartylglutamate and glycerophosphocholine + phosphocholine concentrations. High-dose iron supplementation resulted in lower phosphoethanolamine and higher glycerophosphocholine + phosphocholine concentrations. Conclusions The iron supplementation dose for perinatal iron deficiency differentially alters the neurochemical profile of the prefrontal cortex and hippocampus in adulthood. The neurochemical changes suggest altered glutamatergic neurotransmission, hypomyelination and abnormal phospholipid metabolism in the formerly iron-deficient hippocampus.

Background: The public health burden of cancer and dementia in the geriatric population is well documented. There is limited data on how dementia predicts mortality among geriatric patients with solid tumors. The objective of this study is to determine the prognostic significance of dementia on survival in patients with solid tumors. Methods: We performed a 5-year retrospective study on elderly subjects aged ≥60 years with and without dementia that were diagnosed with solid tumors. Results: Among 3,460 patients with solid tumors, 132 (3.8%) patients were found to have dementia. The median age at diagnosis was 71 years. Kaplan-Meier curves demonstrated that patients with dementia had an inferior median survival compared to the nondemented group (30 vs. 56 months; log-rank p < 0.001). Cox proportional hazard regression modeling identified age >80 years, female gender, diabetes mellitus, congestive heart failure, atrial fibrillation, chronic obstructive pulmonary disease, chronic kidney disease, dementia, and radiation therapy as risk factors for decreased overall survival. Conclusions: We demonstrated that dementia is associated with shorter overall survival in elderly patients with solid tumors.

PURPOSE:Mechanisms that limit recombinant factor VIII (rFVIII) within heterologous systems (eg. commercial rFVIII production or gene therapy applications) include: 1) inefficient expression of FVIII mRNA, 2) inefficient folding of the primary translation product within the endoplasmic reticulum (ER) with retention by chaperone proteins and 3) a requirement for facilitated transport from the ER to the Golgi apparatus. The B domain of FVIII shares no homology with any identified protein, is dispensable for functional activity and is extensively glycosylated (18 asparagine (N)-linked glycosylation attachment sites). B domain-deleted (BDD)-FVIII generates higher concentrations of mRNA compared to full-length FVIII and therefore increased primary translation product but exhibits a reduced rate of secretion and increased intracellular retention. Bioengineering of the FVIII B domain effectively improves the trafficking of rFVIII through facilitated ER-Golgi transport. METHODS:We have used a series of B domain variants to map key regions of the B domain that regulate mRNA levels and secretion efficiency. Each construct has increased B domain size (ranging from 29 to 774 amino acids (aa) and increased number of N-linked oligosaccharides (from 1 through 18).RESULTS: BDD-FVIII, FVIII wild-type (WT) and FVIII B domain variants were transfected into COS and CHO cell lines and the media harvested for analysis of FVIII activity and antigen. The addition of even a few N-linked oligosaccharides within a short B domain spacer (optimal at 226 aa and 6 N-linked oligosaccharides) improves secretion of BDD-FVIII approximately 5 to 10-fold. With additional increase in B domain size and oligosaccharide content, secretion efficiency declined in a stepwise fashion to similar levels observed for FVIII WT. An alternative construct was prepared in which the human FVIII B domain was replaced with the FVIII B domain from puffer fish (fugu rubripes). The fugu FVIII B domain is 224 aa and shares only 6% sequence identity to the human FVIII B domain, yet has a high density of N-linked oligosaccharides (11). This construct was secreted as efficiently as the 226aa/N6 human construct. CONCLUSIONS:The secretion efficiency of FVIII can be regulated by the size and oligosaccharide content of the B domain. The results suggest that it is primarily the presence of N-linked oligosaccharides that improves secretion efficiency. FVIII bioengineered for improved secretion will be an alternative for gene therapy strategies as well as recombinant FVIII production in manufacturing or transgenic strategies. ALTERATIONS IN EXPRESSION OF NEUROTROPHINS AND THEIR RE-CEPTORS IN RESPONSE TO HYPEROXIC LUNG INJURYEkekezie II, Truog WE, Rezaiekhaligh M, Mabry S, Xu D, Department of Pediatrics, Section of Neonatology, Children's Mercy Hospitals and Clinics, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri.Neurotrophins and their receptors have important roles in survival of neural tissues that may extend to cells of non neural origin. Their pres...

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