Effect of limited transportation on medication adherence in patients with epilepsy.

OBJECTIVE: To determine whether limited transportation affects medication adherence in patients with epilepsy. DESIGN: Descriptive, nonexperimental, cross-sectional study. SETTING: United States and worldwide, February to April 2007. PATIENTS: 143 patients with epilepsy. INTERVENTION: A 22-item survey was developed to ask patients with epilepsy or their caregivers about the impact of limited transportation on adherence with medications. The survey was placed on Zoomerang.com. An invitation to participate in the survey was sent via e-mail to members of the Epilepsy.com website, and an invitation with a link to the survey was placed on Epilepsy.com. MAIN OUTCOME MEASURES: Whether patients with epilepsy have difficulty picking up prescriptions on time because of transportation problems and whether they felt they would miss fewer doses if transportation was not an issue. RESULTS: 143 individuals with epilepsy completed part or all of the survey. Of patients who were unable to drive, 45% reported that fewer doses would be missed if transportation was not a problem. Patients who were unable to drive had an odds ratio of 4.2 (P < 0.0001) of being unable to get medications on time. No differences were observed in the number of patients missing prescription medications associated with availability of insurance, use of mail service pharmacies, or population size of patients' area of residence. Ability to drive and distance to the pharmacy were the only factors associated with nonadherence. CONCLUSION: Limited transportation may be a factor in poor medication adherence in patients with epilepsy.

Purinergic signaling in the lumen of a normal nephron and in remodeled PKD encapsulated cysts.

The nephron is the functional unit of the kidney. Blood and plasma are continually filtered within the glomeruli that begin each nephron. Adenosine 5' triphosphate (ATP) and its metabolites are freely filtered by each glomerulus and enter the lumen of each nephron beginning at the proximal convoluted tubule (PCT). Flow rate, osmolality, and other mechanical or chemical stimuli for ATP secretion are present in each nephron segment. These ATP-release stimuli are also different in each nephron segment due to water or salt permeability or impermeability along different luminal membranes of the cells that line each nephron segment. Each of the above stimuli can trigger additional ATP release into the lumen of a nephron segment. Each nephron-lining epithelial cell is a potential source of secreted ATP. Together with filtered ATP and its metabolites derived from the glomerulus, secreted ATP and adenosine derived from cells along the nephron are likely the principal two of several nucleotide and nucleoside candidates for renal autocrine and paracrine ligands within the tubular fluid of the nephron. This minireview discusses the first principles of purinergic signaling as they relate to the nephron and the urinary bladder. The review discusses how the lumen of a renal tubule presents an ideal purinergic signaling microenvironment. The review also illustrates how remodeled and encapsulated cysts in autosomal dominant polycystic kidney disease (ADPKD) and remodeled pseudocysts in autosomal recessive PKD (ARPKD) of the renal collecting duct likely create an even more ideal microenvironment for purinergic signaling. Once trapped in these closed microenvironments, purinergic signaling becomes chronic and likely plays a significant epigenetic and detrimental role in the secondary progression of PKD, once the remodeling of the renal tissue has begun. In PKD cystic microenvironments, we argue that normal purinergic signaling within the lumen of the nephron provides detrimental acceleration of ADPKD once remodeling is complete.

Heightened epithelial Na+ channel-mediated Na+ absorption in a murine polycystic kidney disease model epithelium lacking apical monocilia.

The Tg737 degrees (rpk) autosomal recessive polycystic kidney disease (ARPKD) mouse carries a hypomorphic mutation in the Tg737 gene. Because of the absence of its protein product Polaris, the nonmotile primary monocilium central to the luminal membrane of ductal epithelia, such as the cortical collecting duct (CCD) principal cell (PC), is malformed. Although the functions of the renal monocilium remain elusive, primary monocilia or flagella on neurons act as sensory organelles. Thus we hypothesized that the PC monocilium functions as a cellular sensor. To test this hypothesis, we assessed the contribution of Polaris and cilium structure and function to renal epithelial ion transport electrophysiology. Properties of Tg737 degrees (rpk) mutant CCD PC clones were compared with clones genetically rescued with wild-type Tg737 cDNA. All cells were grown as polarized cell monolayers with similarly high transepithelial resistance on permeable filter supports. Three- to fourfold elevated transepithelial voltage (V(te)) and short-circuit current (I(sc)) were measured in mutant orpk monolayers vs. rescued controls. Pharmacological and cell biological examination of this enhanced electrical end point in mutant monolayers revealed that epithelial Na(+) channels (ENaCs) were upregulated. Amiloride, ENaC-selective amiloride analogs (benzamil and phenamil), and protease inhibitors (aprotinin and leupeptin) attenuated heightened V(te) and I(sc). Higher concentrations of additional amiloride analogs (ethylisopropylamiloride and dimethylamiloride) also revealed inhibition of V(te). Cell culture requirements and manipulations were also consistent with heightened ENaC expression and function. Together, these data suggest that ENaC expression and/or function are upregulated in the luminal membrane of mutant, cilium-deficient orpk CCD PC monolayers vs. cilium-competent controls. When the genetic lesion causes loss or malformation of the monocilium, ENaC-driven Na(+) hyperabsorption may explain the rapid emergence of severe hypertension in a majority of patients with ARPKD.

Extracellular zinc and ATP-gated P2X receptor calcium entry channels: New zinc receptors as physiological sensors and therapeutic targets.

In this review, we focus on two attributes of P2X receptor channel function, one essential and one novel. First, we propose that P2X receptors are extracellular sensors as well as receptors and ion channels. In particular, the large extracellular domain (that comprises 70% of the molecular mass of the receptor channel protein) lends itself to be a cellular sensor. Moreover, its exquisite sensitivity to extracellular pH, ionic strength, and multiple ligands evokes the function of a sensor. Second, we propose that P2X receptors are extracellular zinc receptors as well as receptors for nucleotides. We provide novel data in multiple publications and illustrative data in this invited review to suggest that zinc triggers ATP-independent activation of P2X receptor channel function. In this light, P2X receptors are the cellular site of integration between autocrine and paracrine zinc signaling and autocrine and paracrine purinergic signaling. P2X receptors may sense changes in these ligands as well as in extracellular pH and ionic strength and transduce these sensations via calcium and/or sodium entry and changes in membrane potential.