Contribution of HCN1 variant to sinus bradycardia: A case report.

BACKGROUND: Missense mutations in the hyperpolarization-activated cyclic nucleotide-modulated (HCN) channel 4 (HCN4) are one of the genetic causes of cardiac sinus bradycardia. OBJECTIVE: To investigate possible HCN4 channel mutation in a young patient with profound sinus bradycardia. METHODS: Direct sequencing of HCN4 and whole-exome sequencing were performed on DNA samples from the indexed patient (P), the patient's son (PS), and a family unrelated healthy long-distance running volunteer (V). Resting heart rate was 31 bpm for P, 67 bpm for PS, and 50 bpm for V. Immunoblots, flow cytometry, and immunocytofluorescence confocal imaging were used to study cellular distribution of channel variants. Patch-clamp electrophysiology was used to investigate the properties of mutant HCN1 channels. RESULTS: In P no missense mutations were found in the HCN4 gene; instead, we found two heterozygous variants in the HCN1 gene: deletion of an N-terminal glycine triplet (72GGG74, "N-del") and a novel missense variant, P851A, in the C-terminal region. N-del variant was found before and shared by PS. These two variations were not found in V. Compared to wild type, N-del and P851A reduced cell surface expression and negatively shifted voltage-activation with slower activation kinetics. CONCLUSION: Decreased channel activity HCN1 mutant channel makes it unable to contribute to early depolarization of sinus node action potential, thus likely a main cause of the profound sinus bradycardia in this patient.

Transcriptome profiling reveals novel BMI- and sex-specific gene expression signatures for human cardiac hypertrophy.

How obesity or sex may affect the gene expression profiles of human cardiac hypertrophy is unknown. We hypothesized that body-mass index (BMI) and sex can affect gene expression profiles of cardiac hypertrophy. Human heart tissues were grouped according to sex (male, female), BMI (lean<25 kg/m2, obese>30 kg/m2), or left ventricular hypertrophy (LVH) and non-LVH nonfailed controls (NF). We identified 24 differentially expressed (DE) genes comparing female with male samples. In obese subgroup, there were 236 DE genes comparing LVH with NF; in lean subgroup, there were seven DE genes comparing LVH with NF. In female subgroup, we identified 1,320 significant genes comparing LVH with NF; in male subgroup, there were 1,383 significant genes comparing LVH with NF. There were seven significant genes comparing obese LVH with lean NF; comparing male obese LVH with male lean NF samples we found 106 significant genes; comparing female obese LVH with male lean NF, we found no significant genes. Using absolute value of log2 fold-change > 2 or extremely small P value (10-20) as a criterion, we identified nine significant genes (HBA1, HBB, HIST1H2AC, GSTT1, MYL7, NPPA, NPPB, PDK4, PLA2G2A) in LVH, also found in published data set for ischemic and dilated cardiomyopathy in heart failure. We identified a potential gene expression signature that distinguishes between patients with high BMI or between men and women with cardiac hypertrophy. Expression of established biomarkers atrial natriuretic peptide A (NPPA) and B (NPPB) were already significantly increased in hypertrophy compared with controls.

Effect of changes in number of doses and anatomic location for administration of an Escherichia coli bacterin on serum IgG1 and IgG2 concentrations in dairy cows.

OBJECTIVE: To determine effects of injection site on antibody response to J5 Escherichia coli bacterin. ANIMALS: 28 adult Holstein cows. PROCEDURES: Cows were randomly assigned as control cattle (n = 4 cows), not administered J5 E coli bacterin; 3X (8), administered 3 doses of bacterin SC in the left side of the neck; 5XN (8), administered 5 doses of bacterin SC in the left side of the neck; or 5XSR (8), administered 5 doses of bacterin SC sequentially in the left side of the neck, right side of the neck, right side of the thorax, left side of the thorax, and left side of the neck. Blood samples were collected from the cows to determine anti-J5 E coli IgG1 and IgG2 concentrations. RESULTS: Vaccinated cows had higher mean serum anti-J5 E coli IgG1 concentrations than did control cows. The 5XN and 5XSR cows had higher mean serum anti-J5 E coli IgG1 concentrations than did 3X cows. Additionally, 5XSR cows had higher mean serum anti-J5 E coli IgG1 concentrations than did 5XN cows. Vaccinated cows had higher mean serum anti-J5 E coli IgG2 concentrations than did control cows. The 5XN and 5XSR cows had higher mean serum anti-J5 E coli IgG2 concentrations than did 3X cows. The 5XSR cows had higher mean serum anti-J5 E coli IgG2 concentrations than did all other groups at 84 days after the fifth vaccination. CONCLUSIONS AND CLINICAL RELEVANCE: Sequential doses of core-antigen bacterins administered at different anatomic locations may improve antibody response in dairy cattle.