Familial Associations of Prevalence and Cause-Specific Mortality for Thoracic Aortic Disease and Bicuspid Aortic Valve in a Large-Population Database.

BACKGROUND: Thoracic aortic disease and bicuspid aortic valve (BAV) likely have a heritable component, but large population-based studies are lacking. This study characterizes familial associations of thoracic aortic disease and BAV, as well as cardiovascular and aortic-specific mortality, among relatives of these individuals in a large-population database. METHODS: In this observational case-control study of the Utah Population Database, we identified probands with a diagnosis of BAV, thoracic aortic aneurysm, or thoracic aortic dissection. Age- and sex-matched controls (10:1 ratio) were identified for each proband. First-degree relatives, second-degree relatives, and first cousins of probands and controls were identified through linked genealogical information. Cox proportional hazard models were used to quantify the familial associations for each diagnosis. We used a competing-risk model to determine the risk of cardiovascular-specific and aortic-specific mortality for relatives of probands. RESULTS: The study population included 3 812 588 unique individuals. Familial hazard risk of a concordant diagnosis was elevated in the following populations compared with controls: first-degree relatives of patients with BAV (hazard ratio [HR], 6.88 [95% CI, 5.62-8.43]); first-degree relatives of patients with thoracic aortic aneurysm (HR, 5.09 [95% CI, 3.80-6.82]); and first-degree relatives of patients with thoracic aortic dissection (HR, 4.15 [95% CI, 3.25-5.31]). In addition, the risk of aortic dissection was higher in first-degree relatives of patients with BAV (HR, 3.63 [95% CI, 2.68-4.91]) and in first-degree relatives of patients with thoracic aneurysm (HR, 3.89 [95% CI, 2.93-5.18]) compared with controls. Dissection risk was highest in first-degree relatives of patients who carried a diagnosis of both BAV and aneurysm (HR, 6.13 [95% CI, 2.82-13.33]). First-degree relatives of patients with BAV, thoracic aneurysm, or aortic dissection had a higher risk of aortic-specific mortality (HR, 2.83 [95% CI, 2.44-3.29]) compared with controls. CONCLUSIONS: Our results indicate that BAV and thoracic aortic disease carry a significant familial association for concordant disease and aortic dissection. The pattern of familiality is consistent with a genetic cause of disease. Furthermore, we observed higher risk of aortic-specific mortality in relatives of individuals with these diagnoses. This study provides supportive evidence for screening in relatives of patients with BAV, thoracic aneurysm, or dissection.

Thermal acclimation alters both basal heat shock protein gene expression and the heat shock response in juvenile lake whitefish (Coregonus clupeaformis).

Long-term temperature shifts associated with seasonal variability are common in temperate regions. However, these natural shifts could place significant strain on thermal stress responses of fishes when combined with mean increases in water temperatures predicted by climate change models. We examined the relationship between thermal acclimation, basal expression of heat shock protein (hsp) genes and the activation of the heat shock response (HSR) in lake whitefish (LWF; Coregonus clupeaformis), a cold water species of cultural and commercial significance. Juveniles were acclimated to either 6, 12, or 18°C water for several months prior to the quantification of hsp mRNA levels in the presence or absence of acute heat shock (HS). Acclimation to 18°C increased basal mRNA levels of hsp70 and hsp47, but not hsc70 or hsp90ß in gill, liver and white muscle, while 6°C acclimation had no effect on basal hsp transcription. Fish in all acclimation groups were capable of eliciting a robust HSR following acute HS, as indicated by the upregulation of hsp70 and hsp47. An increase of only 2°C above the 18°C acclimation temperature was required to trigger these transcriptional changes, suggesting that the HSR may be frequently initiated in LWF populations living at mildly elevated temperatures. Collectively, these expression profiles show that environmental temperature influences both basal hsp levels and the HSR in LWF, and indicate that these fish may have a greater physiological and ecological susceptibility to elevated temperatures than to cooler temperatures.

Augmented KCa2.3 Channel Feedback Regulation of Oxytocin Stimulated Uterine Strips from Nonpregnant Mice.

Uterine contractions prior to 37 weeks gestation can result in preterm labor with significant risk to the infant. Current tocolytic therapies aimed at suppressing premature uterine contractions are largely ineffective and cause serious side effects. Calcium (Ca2+) dependent contractions of uterine smooth muscle are physiologically limited by the opening of membrane potassium (K+) channels. Exploiting such inherent negative feedback mechanisms may offer new strategies to delay labor and reduce risk. Positive modulation of small conductance Ca2+-activated K+ (KCa2.3) channels with cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine (CyPPA), effectively decreases uterine contractions. This study investigates whether the receptor agonist oxytocin might solicit KCa2.3 channel feedback that facilitates CyPPA suppression of uterine contractions. Using isometric force myography, we found that spontaneous phasic contractions of myometrial tissue from nonpregnant mice were suppressed by CyPPA and, in the presence of CyPPA, oxytocin failed to augment contractions. In tissues exposed to oxytocin, depletion of internal Ca2+ stores with cyclopiazonic acid (CPA) impaired CyPPA relaxation, whereas blockade of nonselective cation channels (NSCC) using gadolinium (Gd3+) had no significant effect. Immunofluorescence revealed close proximity of KCa2.3 channels and ER inositol trisphosphate receptors (IP3Rs) within myometrial smooth muscle cells. The findings suggest internal Ca2+ stores play a role in KCa2.3-dependent feedback control of uterine contraction and offer new insights for tocolytic therapies.

Expression and activity of lipid and oxidative metabolism enzymes following elevated temperature exposure and thyroid hormone manipulation in juvenile lake whitefish (Coregonus clupeaformis).

Temperature has unequivocal effects on several aspects of fish physiology, but the full extent of its interaction with key endocrine signaling systems to influence metabolic function remains unknown. The aim of the current study was to assess the individual and combined effects of elevated temperature and hyperthyroidism on hepatic metabolism in juvenile lake whitefish by quantifying mRNA abundance and activity of key metabolic enzymes. Fish were exposed to 13 (control), 17 or 21 °C for 0, 4, 8 or 24 days in the presence or absence of low-T4 (1 µg × g body weight-1) or high-T4 (10 µg × g body weight-1) treatment. Our results demonstrate moderate sensitivity to elevated temperature in this species, characterized by short-term changes in mRNA abundance of several metabolic enzymes and long-term declines in citrate synthase (CS) and cytochrome c oxidase (COX) activities. T4-induced hyperthyroidism also had several short-term effects on mRNA abundance of metabolic transcripts, including depressions in acetyl-coA carboxylase ß (accß) and carnitine palmitoyltransferase 1ß (cpt1ß), and stabilization of cs mRNA levels; however, these effects were primarily limited to elevated temperature groups, indicating temperature-dependent effects of exogenous T4 treatment in this species. In contrast, maximal CS and COX activities were not altered by hyperthyroidism at any temperature. Collectively, our data suggest that temperature has the potential to manipulate thyroid hormone physiology in juvenile lake whitefish and, under warm-conditions, hyperthyroidism may suppress certain elements of the ß-oxidation pathway without substantial impacts on overall cellular oxidative capacity.

Exogenous thyroid hormones regulate the activity of citrate synthase and cytochrome c oxidase in warm- but not cold-acclimated lake whitefish (Coregonus clupeaformis).

Thermal acclimation is known to elicit metabolic adjustments in ectotherms, but the cellular mechanisms and endocrine control of these shifts have not been fully elucidated. Here we examined the relationship between thermal acclimation, thyroid hormones and oxidative metabolism in juvenile lake whitefish. Impacts of thermal acclimation above (19°C) or below (8°C) the thermal optimum (13°C) and exposure to exogenous thyroid hormone (60µg T4/g body weight) were assessed by quantifying citrate synthase and cytochrome c oxidase activities in liver, red muscle, white muscle and heart. Warm acclimation decreased citrate synthase activity in liver and elevated both citrate synthase and cytochrome c oxidase activities in red muscle. In contrast, induction of hyperthyroidism in warm-acclimated fish stimulated a significant increase in liver citrate synthase and heart cytochrome c oxidase activities, and a decrease in the activity of both enzymes in red muscle. No change in citrate synthase or cytochrome c oxidase activities was observed following cold acclimation in either the presence or absence of exogenous thyroid hormones. Collectively, our results indicate that thyroid hormones influence the activity of oxidative enzymes more strongly in warm-acclimated than in cold-acclimated lake whitefish, and they may play a role in mediating metabolic adjustments observed during thermal acclimation.

Infantile Lhermitte-Duclos Disease Treated Successfully With Rapamycin.

Lhermitte-Duclos disease is a rare hamartomatous tumor of the cerebellum resulting from a mutation in the phosphatase and tensin homolog (PTEN) gene: it has been reported in fewer than 10 infants. Rapamycin treatment has not yet been described in Lhermitte-Duclos disease. The infant underwent shunt placement shortly after birth for aqueductal stenosis. Her clinical progression included failure to thrive, seizures, episodes of decerebrate posturing, loss of respiratory drive, and pituitary insufficiency from mass effect. The characteristic "tiger stripe" sign on imaging prompted diagnosis. Rapamycin therapy was initiated at 18 months. Within 5 months, our patient has become responsive to her surroundings and had return of spontaneous breathing. Repeat magnetic resonance imaging (MRI) reveals lack of brainstem compression or distortion of pituitary stalk. Rapamycin should be considered in cases of Lhermitte-Duclos disease where surgical removal may not be an option, as in our case where the cerebellum was entirely involved.