Use of denosumab to treat refractory hypercalcemia in a peritoneal dialysis patient with immobilization and tertiary hyperparathyroidism.

Hypercalcemia due to excess parathyroid hormone (PTH) production is a common condition among patients with end-stage renal disease (ESRD), often referred to as tertiary hyperparathyroidism. There are limited effective medical treatment options currently available for such patients. Denosumab is a monoclonal antibody that inhibits osteoclast activation, thereby reducing calcium release from bones. Denosumab has been used to treat medically-refractory hypercalcemia in non-ESRD patients with hyperparathyroidism. Denosumab has also been used to treat non-PTH-mediated hypercalcemia in patients with advanced chronic kidney disease and ESRD. In this case report, we describe the use of denosumab to successfully treat a case of medically refractory hypercalcemia due to immobilization in a patient on peritoneal dialysis with severe underlying tertiary hyperparathyroidism. In spite of persistently elevated PTH, hypercalcemia quickly resolved after a single dose of denosumab. The patient subsequently developed temporary hypocalcemia requiring medical intervention. Our case report, which is the first described use of denosumab for treatment of hypercalcemia in the setting of tertiary hyperparathyroidism in a peritoneal dialysis patient, adds to the body of literature suggesting denosumab is a useful therapeutic agent in patients with ESRD. Issues with post-treatment electrolyte management and other therapeutic considerations are also discussed.

Re-evaluating the role of ELT-3 in a GATA transcription factor circuit proposed to guide aging in C. elegans.

Budovskaya et al. (Cell. 134, 291-303, 2008) have proposed that the ELT-3 GATA factor regulates somatic aging genes, including those expressed in the intestine, and participates in a transcription factor circuit that "guides Caenorhabditis elegans aging". We have re-investigated two key features of this proposal: (i) expression of elt-3 in the C. elegans adult intestine where the majority of somatic aging genes are expressed, and; (ii) the ability of elt-3 loss-of-function to revert the extended lifespan of daf-2(e1370) mutants. We find that: (i) in agreement with our previously published results, ELT-3 expression is largely hypodermal and is not expressed at significant levels in the adult C. elegans intestine, and; (ii) the elt-3(vp1) zinc-finger deletion mutant does not significantly influence the extended lifespan of daf-2(e1370) mutants. We thus suggest that the role of ELT-3 in C. elegans aging should be re-evaluated.

Verification of in situ thresholds and integrated real-ear measurements.

BACKGROUND: Accurate prescriptive gain results in a more accurate fit, lower return rate in hearing aids, and increased patient satisfaction. In situ threshold measurements can be used to determine required gain. The Widex Corporation uses an in situ threshold measurement strategy, called the Sensogram. Real-ear measurements determine if prescriptive gain targets have been achieved. Starkey Laboratories introduced an integrated real-ear measurement system in their hearing aids. PURPOSE: To determine whether the responses obtained using the Widex Sensogram were equivalent to those obtained using current clinical threshold measurement methods. To determine the accuracy of the Starkey IREMS™ (Integrated Real Ear Measurement System) in measuring RECD (real-ear to coupler difference) values compared to a dedicated real-ear measurement system. RESEARCH DESIGN: A verification design was employed by comparing participant data measured from standard, benchmark equipment and procedures against new techniques offered by hearing-aid manufacturers. STUDY SAMPLE: A total of 20 participants participated in this study. Ten participants with sensorineural hearing loss were recruited from the Ohio University Hearing, Speech, and Language Clinic participated in the first experiment. Ten participants with normal hearing were recruited from the student population at Ohio University participated in both experiments. The normal-hearing group had thresholds of 15 dB HL or better at the octave frequencies of 250-8000 Hz. The hearing-impaired group had thresholds of varying degrees and configurations with thresholds equal to or poorer than 25 dB HL three-frequency pure-tone average. DATA COLLECTION AND ANALYSIS: The order of measurement method for both experiments was counterbalanced. In Experiment 1, thresholds obtained via the Widex Sensogram were compared to thresholds obtained for each participant using a clinical audiometer and ER-3A insert ear phones. In Experiment 2, RECD values obtained via the Starkey IREMS were compared to RECD values obtained via the Audioscan Verifit™. A repeated-measures analysis of variance (ANOVA) was used for statistical analysis, and a Fisher's LSD (least significant difference) was used as a post hoc analysis tool. RESULTS: A significant difference between Sensogram thresholds and conventional audiometric thresholds was found with the Sensogram method resulting in better threshold values at 0.5, 1.0, and 2.0 kHz for both groups. In Experiment 2, a significant difference between RECD values obtained by the Starkey IREMS and the Audioscan Verifit system was found with significant differences in RECD values found at 0.25, 0.5, 0.75, 1.5, 2.0, and 6.0 kHz. CONCLUSIONS: The Sensogram data differ significantly from traditional audiometry at several frequencies important for speech intelligibility. Real-ear measures are still required for verification of prescribed gain, however, calling into question any claims of shortened fitting time. The Starkey IREMS does perform real-ear measurements that vary significantly from benchmark equipment. These technologies represent a positive direction in prescribing accurate gain during hearing-aid fittings, but a stand-alone system is still the preferred method for real-ear measurements in hearing-aid fittings.

Methyl-beta-cyclodextrin restores the structure and function of pulmonary surfactant films impaired by cholesterol.

Pulmonary surfactant, a defined mixture of lipids and proteins, imparts very low surface tension to the lung-air interface by forming an incompressible film. In acute respiratory distress syndrome and other respiratory conditions, this function is impaired by a number of factors, among which is an increase of cholesterol in surfactant. The current study shows in vitro that cholesterol can be extracted from surfactant and function subsequently restored to dysfunctional surfactant films in a dose-dependent manner by methyl-beta-cyclodextrin (MbetaCD). Bovine lipid extract surfactant was supplemented with cholesterol to serve as a model of dysfunctional surfactant. Likewise, when cholesterol in a complex with MbetaCD ("water-soluble cholesterol") was added in aqueous solution, surfactant films were rendered dysfunctional. Atomic force microscopy showed recovery of function by MbetaCD is accompanied by the re-establishment of the native film structure of a lipid monolayer with scattered areas of lipid bilayer stacks, whereas dysfunctional films lacked bilayers. The current study expands upon a recent perspective of surfactant inactivation in disease and suggests a potential treatment.