Publications

Mutations in genes that encode components of the sarcomere are well established as the cause of hypertrophic and dilated cardiomyopathies. Sarcomere genes, however, are increasingly being associated with other cardiomyopathies. One phenotype more recently recognized as a disease of the sarcomere is restrictive cardiomyopathy (RCM). We report on two patients with RCM associated with multiple mutations in sarcomere genes not previously associated with RCM. Patient 1 presented with NYHA Class III/IV heart failure at 22 years of age. She was diagnosed with RCM and advanced heart failure requiring heart transplantation. Sequencing of sarcomere genes revealed previously reported homozygous p.Glu143Lys mutations in MYL3, and a novel heterozygous p.Gly57Glu mutation in MYL2. The patient's mother is a double heterozygote for these mutations, with no evidence of cardiomyopathy. Patient 2 presented at 35 years of age with volume overload while hospitalized for oophorectomy. She was diagnosed with RCM and is being evaluated for heart transplantation. Sarcomere gene sequencing identified homozygous p.Asn279His mutations in TPM1. The patient's parents are consanguineous and confirmed heterozygotes. Her father was diagnosed with HCM at 42 years of age. This is the first report of mutations in TPM1, MYL3, and MYL2 associated with primary, non-hypertrophied RCM. The association of more sarcomere genes with RCM provides further evidence that mutations in the various sarcomere genes can cause different cardiomyopathy phenotypes. These cases also contribute to the growing body of evidence that multiple mutations have an additive effect on the severity of cardiomyopathies.

Here, we compile the Biopharmaceutics Drug Disposition Classification System (BDDCS) classification for 927 drugs, which include 30 active metabolites. Of the 897 parent drugs, 78.8% (707) are administered orally. Where the lowest measured solubility is found, this value is reported for 72.7% (513) of these orally administered drugs and a dose number is recorded. The measured values are reported for percent excreted unchanged in urine, LogP, and LogD (7.4) when available. For all 927 compounds, the in silico parameters for predicted Log solubility in water, calculated LogP, polar surface area, and the number of hydrogen bond acceptors and hydrogen bond donors for the active moiety are also provided, thereby allowing comparison analyses for both in silico and experimentally measured values. We discuss the potential use of BDDCS to estimate the disposition characteristics of novel chemicals (new molecular entities) in the early stages of drug discovery and development. Transporter effects in the intestine and the liver are not clinically relevant for BDDCS class 1 drugs, but potentially can have a high impact for class 2 (efflux in the gut, and efflux and uptake in the liver) and class 3 (uptake and efflux in both gut and liver) drugs. A combination of high dose and low solubility is likely to cause BDDCS class 4 to be underpopulated in terms of approved drugs (N = 53 compared with over 200 each in classes 1-3). The influence of several measured and in silico parameters in the process of BDDCS category assignment is discussed in detail.

BACKGROUND

The presence of pets in a home during the prenatal period and during early infancy has been associated with a lower prevalence of allergic sensitization and total IgE levels in middle childhood. No studies have examined the effect of pet exposure in a population-based cohort by using multiple early-life measures of serum total IgE.

OBJECTIVE

We sought to examine within-individual longitudinal trends in total IgE levels during early childhood and assess the effect of indoor prenatal pet exposure on those trends. Also, we sought to use a statistical method that was flexible enough to allow and account for unequally spaced study contacts and missing data.

METHODS

Using the population-based Wayne County Health, Environment, Allergy and Asthma Longitudinal Study birth cohort (62% African American), we analyzed 1187 infants with 1 to 4 measurements of total IgE collected from birth to 2 years of age. Effects of pet exposure on the shape and trajectory of IgE levels were assessed by using a multilevel longitudinal model, accommodating repeated measures, missing data, and the precise time points of data collection.

RESULTS

The best-fit shape to the trajectory of IgE levels was nonlinear, with an accelerated increase before 6 months. Total IgE levels were lower across the entire early-life period when there was prenatal indoor pet exposure (P < .001). This effect was statistically significantly stronger in children delivered by means of cesarean section versus those delivered vaginally (P < .001 and P < .06, respectively) and in those born to non-African American (P < .001) versus African American (P < .3) mothers.

CONCLUSION

Pet exposure and delivery mode might be markers of infant exposure to distinct microbiomes. The effect of exposures might vary by race, suggesting a differential effect by ancestry.