Long-Term Effects of Sevelamer on Vascular Calcification, Arterial Stiffness, and Calcification Propensity in Patients Receiving Peritoneal Dialysis: The Randomized Pilot SERENE (Sevelamer on Vascular Calcification, Arterial Stiffness) Trial.

RATIONALE & OBJECTIVE: There is a concern regarding increased risk of vascular calcification with the use of calcium-based phosphorus binders. This study aimed to compare the effects of sevelamer used as a second-line, low-dose therapy with calcium-based phosphorus binders with those of sevelamer used as a first-line, high-dose therapy on coronary artery and heart valve calcification, aortic pulse wave velocity (PWV), and calcification propensity over 2 years in patients with hyperphosphatemia receiving peritoneal dialysis (PD). STUDY DESIGN: A 2-year-long prospective, multicenter, open-label, randomized pilot study. SETTING & PARTICIPANTS: Prevalent patients with hyperphosphatemia receiving PD from 2 university-affiliated hospitals in Hong Kong. INTERVENTIONS: The patients were randomized to receive sevelamer either as a first-line therapy at a high dose of 800 mg thrice daily (can titrate up to 1,200 mg thrice daily as required) or a second-line therapy at a low dose of 400 mg thrice daily with calcium carbonate to achieve a serum phosphorus target of ≤5.5 mg/dL. OUTCOMES: The primary endpoints were changes in coronary artery calcium score and aortic PWV over 104 weeks. The secondary endpoints were changes in heart valve calcium scores, calcification propensity measure, and biochemical parameters of chronic kidney disease-mineral bone disease over 104 weeks. RESULTS: Among 60 prevalent patients receiving PD, with a mean age of 53 ± 10 years and with 57% men, changes in the coronary artery calcium score (median [interquartile range], 225 [79-525] vs 223 [56-1,212], respectively; P = 0.21), aortic PWV (mean ± standard error, 0.3 ± 0.1 vs 0.8 ± 0.2 m/s, respectively; P = 0.31), heart valve calcium score, maturation or transformation time, serum calcium levels, and phosphorus levels over 104 weeks were similar for the second-line, low-dose and first-line, high-dose sevelamer groups. Alkaline phosphatase and intact parathyroid hormone levels increased and low-density lipoprotein cholesterol decreased in both the groups, with no significant between-group differences. LIMITATIONS: The sample size was small, and the dropout rates were relatively high. CONCLUSIONS: Low-dose sevelamer used as a second-line therapy for hyperphosphatemia in combination with a calcium-based phosphorus binder had similar effects on vascular calcification, valvular calcification, and arterial stiffness compared with high-dose sevelamer used as a first-line therapy. This approach may be considered in resource-constrained countries to minimize calcium loading. FUNDING: The study was supported by a competitive grant from SK Yee Medical Foundation. T50 assays and other biochemical assays were funded by a research grant from Sanofi Renal Corporation. TRIAL REGISTRATION: NCT00745589.

Stimulation of Hair Growth by Small Molecules that Activate Autophagy.

Hair plays important roles, ranging from the conservation of body heat to the preservation of psychological well-being. Hair loss or alopecia affects millions worldwide, but methods that can be used to regrow hair are lacking. We report that quiescent (telogen) hair follicles can be stimulated to initiate anagen and hair growth by small molecules that activate autophagy, including the metabolites α-ketoglutarate (α-KG) and α-ketobutyrate (α-KB), and the prescription drugs rapamycin and metformin, which impinge on mTOR and AMPK signaling. Stimulation of hair growth by these agents is blocked by specific autophagy inhibitors, suggesting a mechanistic link between autophagy and hair regeneration. Consistently, increased autophagy is detected upon anagen entry during the natural hair follicle cycle, and oral α-KB prevents hair loss in aged mice. Our finding that anagen can be pharmacologically activated in telogen skin when natural anagen-inducing signal(s) are absent has implications for the treatment of hair loss patients.

L-Carnosine: multifunctional dipeptide buffer for sustained-duration topical ophthalmic formulations.

OBJECTIVES: The use of l-carnosine as an excipient in topical ophthalmic formulations containing gellan gum, a carbohydrate polymer with in-situ gelling properties upon mixing with mammalian tear fluid, was developed as a novel platform to extend precorneal duration. Specific utilisation of l-carnosine as a buffer in gellan gum carrying vehicles was characterised. METHODS: Buffer capacity was evaluated using 7.5, 13.3, and 44.2 mm l-carnosine in a pH range of 5.5-7.5. Accelerated chemical stability was determined by HPLC at l-carnosine concentrations of 5-100 mm. Combinations of 7.5 mm l-carnosine with 0.06-0.6% (w/v) gellan gum were characterised rheologically. l-Carnosine-buffered solutions of gellan gum were tested for acute topical ocular tolerance in vivo in pigmented rabbits. A unique formulation combining timolol (which lowers intraocular pressure) in l-carnosine-buffered gellan gum was compared with Timoptic-XE in normotensive dogs. KEY FINDINGS: l-Carnosine exhibited optimal pharmaceutical characteristics for use as a buffer in chronically administered topical ocular formulations. Enhancement trends were observed in solution-to-gel transition of l-carnosine-buffered vehicles containing gellan gum vs comparators. Topical tolerability of l-carnosine-buffered gellan gum formulations and lowering of intraocular pressure were equivalent with timolol and Timoptic-XE. CONCLUSIONS: Functional synergy between excipients in gellan gum formulations buffered with l-carnosine has potential for topical ocular dosage forms with sustained precorneal residence.

A mouse forward genetics screen identifies LISTERIN as an E3 ubiquitin ligase involved in neurodegeneration.

A mouse neurological mutant, lister, was identified through a genome-wide N-ethyl-N-nitrosourea (ENU) mutagenesis screen. Homozygous lister mice exhibit profound early-onset and progressive neurological and motor dysfunction. lister encodes a RING finger protein, LISTERIN, which functions as an E3 ubiquitin ligase in vitro. Although lister is widely expressed in all tissues, motor and sensory neurons and neuronal processes in the brainstem and spinal cord are primarily affected in the mutant. Pathological signs include gliosis, dystrophic neurites, vacuolated mitochondria, and accumulation of soluble hyperphosphorylated tau. Analysis with a different lister allele generated through targeted gene trap insertion reveals LISTERIN is required for embryonic development and confirms that direct perturbation of a LISTERIN-regulated process causes neurodegeneration. The lister mouse uncovers a pathway involved in neurodegeneration and may serves as a model for understanding the molecular mechanisms underlying human neurodegenerative disorders.

Impaired clock output by altered connectivity in the circadian network.

Substantial progress has been made in elucidating the molecular processes that impart a temporal control to physiology and behavior in most eukaryotes. In Drosophila, dorsal and ventral neuronal networks act in concert to convey rhythmicity. Recently, the hierarchical organization among the different circadian clusters has been addressed, but how molecular oscillations translate into rhythmic behavior remains unclear. The small ventral lateral neurons can synchronize certain dorsal oscillators likely through the release of pigment dispersing factor (PDF), a neuropeptide central to the control of rhythmic rest-activity cycles. In the present study, we have taken advantage of flies exhibiting a distinctive arrhythmic phenotype due to mutation of the potassium channel slowpoke (slo) to examine the relevance of specific neuronal populations involved in the circadian control of behavior. We show that altered neuronal function associated with the null mutation specifically impaired PDF accumulation in the dorsal protocerebrum and, in turn, desynchronized molecular oscillations in the dorsal clusters. However, molecular oscillations in the small ventral lateral neurons are properly running in the null mutant, indicating that slo is acting downstream of these core pacemaker cells, most likely in the output pathway. Surprisingly, disrupted PDF signaling by slo dysfunction directly affects the structure of the underlying circuit. Our observations demonstrate that subtle structural changes within the circadian network are responsible for behavioral arrhythmicity.

Limb type-specific regulation of bric a brac contributes to morphological diversity.

The insect antenna and leg are considered homologous structures, likely to have arisen via duplication and divergence from an ancestral limb. Consistent with this, the antenna and leg are derived from primordia with similar developmental potentials. Nonetheless, the adult structures differ in both form and function. In Drosophila, one conspicuous morphological difference is that the antenna has fewer distal segments than the leg. We propose that this is due in part to the variations in the regulation of bric a brac. bric a brac is required for joint formation, and loss of bric a brac function leads to fusion of distal antennal and leg segments, resulting in fewer total segments. Here, we address how bric a brac is regulated to generate the mature expression patterns of two concentric rings in the antenna versus four concentric rings in the leg. We find that bric a brac expression is activated early throughout most of the Distal-less domain in both antenna and leg and subsequently is restricted to the distal portion and into rings. Although bric a brac expression in the antenna and in all four tarsal rings of the leg requires Distal-less, only the proximal three tarsal rings are Spineless-dependent. Thus bric a brac is regulated differentially even within a single appendage type. The restriction of bric a brac expression to the distal portion of the Distal-less domain is a consequence of negative regulation by distinct sets of genes in different limb types. In the leg, the proximal boundary of bric a brac is established by the medial-patterning gene dachshund, but dachshund alone is insufficient to repress bric a brac, and the expression of the two genes overlaps. In the antenna, the proximal boundary of bric a brac is established by an antenna-specifying gene, homothorax, in conjunction with dachshund and spalt, and there is much less overlap between the bric a brac and the dachshund domains. Thus tissue-specific expression of other patterning genes that differentially repress bric a brac accounts for antenna-leg differences in bric a brac pattern. We propose that the limb type-specific variations in expression of bric a brac repressors contribute to morphological variations by controlling distal limb segment number.