Several barrier epithelia such as renal collecting duct, urinary bladder, and gastric mucosa maintain high osmotic pH and solute gradients between body compartments and the blood by means of apical membranes of exceptionally low permeabilities. Although the mechanisms underlying these low permeabilities have been only poorly defined, low fluidity of the apical membrane has been postulated. The solubility diffusion model predicts that lower membrane fluidity will reduce permeability by reducing the ability of permeant molecules to diffuse through the lipid bilayer. However, litde data compare membrane fluidity with permeability properties, and it is unclear whether fluidity determines permeability to all, or only some substances. We therefore studied the permeabilities of a series of artificial large unilamellar vesicles (LUV) of eight different compositions, exhibiting a range of fluidities encountered in biological membranes. Cholesterol and sphingomyelin content and acyl chain saturation were varied to create a range of fluidities. LUV anisotropy was measured as steady state fluorescence polarization of the lipophilic probe DPH. LUV permeabilities were determined by monitoring concentration-dependent or pH-sensitive quenching of entrapped carboxyfluorescein on a stopped-flow fluorimeter. The relation between DPH anisotropy and permeability to water, urea, acetamide, and NH3 was well fit in each instance by single exponential functions (r > 0.96), with lower fluidity corresponding to lower permeability. By contrast, proton permeability correlated only weakly with fluidity. We conclude that membrane fluidity determines permeability to most nonionic substances and that transmembrane proton flux occurs in a manner distinct from flux of other substances.

Many Mendelian traits are likely unrecognized owing to absence of traditional segregation patterns in families due to causation by de novo mutations, incomplete penetrance, and/or variable expressivity. Genome-level sequencing can overcome these complications. Extreme childhood phenotypes are promising candidates for new Mendelian traits. One example is early onset hypertension, a rare form of a global cause of morbidity and mortality. We performed exome sequencing of 40 unrelated subjects with hypertension due to primary aldosteronism by age 10. Five subjects (12.5%) shared the identical, previously unidentified, heterozygous CACNA1HM1549V mutation. Two mutations were demonstrated to be de novo events, and all mutations occurred independently. CACNA1H encodes a voltage-gated calcium channel (CaV3.2) expressed in adrenal glomerulosa. CACNA1HM1549V showed drastically impaired channel inactivation and activation at more hyperpolarized potentials, producing increased intracellular Ca2+, the signal for aldosterone production. This mutation explains disease pathogenesis and provides new insight into mechanisms mediating aldosterone production and hypertension.DOI: http://dx.doi.org/10.7554/eLife.06315.001

Abstract-To determine whether carotid intima media thickness is increased in children with primary hypertension, the current study compared carotid intima media thickness in hypertensive children with that of normotensive control subjects matched closely for body mass index and determined the relationship between carotid intima media thickness and hypertension severity determined by ambulatory blood pressure monitoring. Children with newly diagnosed office hypertension (nϭ28) had carotid intima media thickness, left ventricular mass index, and ambulatory blood pressure monitoring performed. Carotid intima media thickness was performed in normotensive control subjects (nϭ28) matched pairwise to hypertensive subjects for age (Ϯ1 year), gender, and body mass index (Ϯ10%). Eighty-two percent of subjects were overweight or obese (body mass index Ն85th percentile). The median carotid intima media thickness of hypertensive subjects was greater than that of matched controls (0.67 versus 0.63 mm; Pϭ0.045). In the hypertensive subjects, carotid intima media thickness correlated strongly with several ambulatory blood pressure monitoring parameters, with the strongest correlation for daytime systolic blood pressure index (rϭ0.57; Pϭ0.003). In the hypertensive group, the prevalence of left ventricular hypertrophy was 32%, but unlike carotid intima media thickness, left ventricular mass index did not correlate with ambulatory blood pressure monitoring. Together, the findings that hypertensive subjects had increased carotid intima media thickness compared with matched controls and that higher carotid intima media thickness correlated with more severe hypertension by ambulatory blood pressure monitoring provide strong evidence that carotid intima media thickness is increased in childhood primary hypertension, independent of the effects of obesity.

Objective To compare the health related quality of life (HRQOL) of children with chronic kidney disease (CKD) to healthy children; to evaluate the association between CKD severity and HRQOL; to identity demographic, socioeconomic and health-status variables associated with impairment in HRQOL in children with mild to moderate CKD. Patients and Methods This is a cross-sectional assessment of HRQOL in children aged 2-16 with mild to moderate CKD using the Varni PedsQL™. Overall HRQOL and PedsQL domain means for parents and youth were compared to previously published norms using independent sample t-tests. Study participants were categorized according to kidney disease stage (measured by iohexol based glomerular filtration rate, iGFR) and group differences in HRQOL were evaluated using ANOVA and Cuzick trend tests. The association between hypothesized predictors of HRQOL and PedsQL scores was evaluated with linear and logistic regression analyses. Results The study sample was comprised of 402 participants (Mean age =11 yrs, 60% male, 70% Caucasian, 40% anemic, median iGFR=42.5 ml/min/1.73m2, median CKD duration= 7 yrs). Youth with CKD had significantly lower physical, school, emotional and social domain scores than healthy youth (p<.001). IGFR was not associated with HRQOL. Longer disease duration and older age was associated with higher PedsQL scores in the domains of physical, emotional and social functioning (p<.05). Older age was associated with lower school functioning domain scores (p<.05). Maternal education ≥16 years was associated with higher PedsQL scores in the domains of physical, school, and social functioning (p<.05). Short stature was associated with lower scores in the physical functioning domain (p<.05). Conclusions Children with mild to moderate CKD, in comparison to healthy children, report poorer overall HRQOL as well as poorer physical, school, emotional and social functioning. Early intervention to improve linear growth and to address school functioning difficulties is recommended.