Dosage considerations in the combined use of ocular-specific vitamins and nutrients and multivitamin products: A systemic review and analysis.

OBJECTIVES: To provide guidance for safe and appropriate vitamin and mineral supplementation regimens for patients who use vitamins marketed for ocular use concurrently with general-purpose multivitamin (MVI) supplementation. DATA SOURCES: Primary and tertiary evidence was compiled from secondary literature reference databases. STUDY SELECTION: Dosage exposure with the use of supplements marketed for the prevention of ocular disease, including those recommended by the Age-Related Eye Disease Studies (AREDS), when used in combination with conventional MVI/nutrient products was determined. An analysis of the data was performed to suggest appropriate supplement recommendations. DATA EXTRACTION: Combined dosages for single and duplicate ingredients found in ocular supplements and select MVI/nutrient supplements were compared with U.S. Food and Drug Administration--recommended daily value intake levels and the National Academy of Medicine recommendations on vitamin and nutrient tolerable upper intake levels (TUILs). RESULTS: With the exception of copper, all studied product components that conformed to AREDS guidelines for vitamin and nutrient levels far exceeded U.S. Food and Drug Administration--recommended daily value intake level limits. Furthermore, vitamin A and zinc exceeded the National Academies of Medicine TUIL when a multivitamin product was combined with an ocular-specific vitamin or nutrient that conformed with AREDS-recommended dosage levels. Several products marketed specifically for ocular use failed to provide AREDS-recommended vitamin or nutrient levels even when combined with MVI products. CONCLUSION: With the exception of vitamin A and zinc, the addition of typical multivitamin preparations to AREDS-recommended vitamin and nutrient regimens do not result in vitamin and mineral dosages that exceed TUIL as outlined by the National Academy of Medicine. However, combined AREDS and MVI regimens can create a substantial vitamin or mineral burden that is not appropriate for all older adult populations, particularly those with comorbidities, contributing to susceptibility of component toxicity.

Whole exome sequencing identifies a POLRID mutation segregating in a father and two daughters with findings of Klippel-Feil and Treacher Collins syndromes.

We report on a father and his two daughters diagnosed with Klippel-Feil syndrome (KFS) but with craniofacial differences (zygomatic and mandibular hypoplasia and cleft palate) and external ear abnormalities suggestive of Treacher Collins syndrome (TCS). The diagnosis of KFS was favored, given that the neck anomalies were the predominant manifestations, and that the diagnosis predated later recognition of the association between spinal segmentation abnormalities and TCS. Genetic heterogeneity and the rarity of large families with KFS have limited the ability to identify mutations by traditional methods. Whole exome sequencing identified a nonsynonymous mutation in POLR1D (subunit of RNA polymerase I and II): exon2:c.T332C:p.L111P. Mutations in POLR1D are present in about 5% of individuals diagnosed with TCS. We propose that this mutation is causal in this family, suggesting a pathogenetic link between KFS and TCS.

Microarray expression profiling of p53-dependent transcriptional changes in an immortalized mouse embryo fibroblast cell line.

The ability of p53 to transcriptionally regulate genes involved with cell cycle progression and apoptosis is critical to its role as a tumor suppressor. Although numerous p53 regulated genes have been identified over the last several years, ablation of any one of these genes cannot account for the full p53-mediated cellular response. Therefore, we performed microarray analysis using two related p53 temperature sensitive cell lines, Val5 and Vm10, to identify novel p53 regulated genes. The Val5 cells undergo p53-mediated cell cycle arrest and the Vm10 cells undergo p53-mediated apoptosis when p53 is in the wild-type conformation. By using these two cell lines, we can compare which genes are regulated by p53 in two different conditions as well as analyze which genes are common to both cell lines. Using the information obtained in the microarray analysis, we confirmed whether a small sub-set of the genes was regulated by p53 using northern blot analysis. By identifying and confirming the regulation of specific genes by p53, we can further characterize biologically why p53 transcriptionally regulates these genes.

Identification of a novel gene for diabetic traits in rats, mice, and humans.

The genetic basis of type 2 diabetes remains incompletely defined despite the use of multiple genetic strategies. Multiparental populations such as heterogeneous stocks (HS) facilitate gene discovery by allowing fine mapping to only a few megabases, significantly decreasing the number of potential candidate genes compared to traditional mapping strategies. In the present work, we employed expression and sequence analysis in HS rats (Rattus norvegicus) to identify Tpcn2 as a likely causal gene underlying a 3.1-Mb locus for glucose and insulin levels. Global gene expression analysis on liver identified Tpcn2 as the only gene in the region that is differentially expressed between HS rats with glucose intolerance and those with normal glucose regulation. Tpcn2 also maps as a cis-regulating expression QTL and is negatively correlated with fasting glucose levels. We used founder sequence to identify variants within this region and assessed association between 18 variants and diabetic traits by conducting a mixed-model analysis, accounting for the complex family structure of the HS. We found that two variants were significantly associated with fasting glucose levels, including a nonsynonymous coding variant within Tpcn2. Studies in Tpcn2 knockout mice demonstrated a significant decrease in fasting glucose levels and insulin response to a glucose challenge relative to those in wild-type mice. Finally, we identified variants within Tpcn2 that are associated with fasting insulin in humans. These studies indicate that Tpcn2 is a likely causal gene that may play a role in human diabetes and demonstrate the utility of multiparental populations for positionally cloning genes within complex loci.