Variation in Generic Drug Manufacturers' Product Characteristics.

Objectives: Studies suggest appearance may be an important factor in medication nonadherence. This study was undertaken to characterize the range of appearances and costs of 16 oral solid generic medications in four major chronic diseases/conditions.

Methods: We identified frequently prescribed medications in four therapeutic classes-antidiabetics, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins), beta blockers, and heart failure drugs-and verified that each had at least three generic manufacturer sources in 2016.

Effect of Budesonide Added to Large-Volume, Low-pressure Saline Sinus Irrigation for Chronic Rhinosinusitis: A Randomized Clinical Trial.

Importance: Recent studies suggest that budesonide added to saline nasal lavage can be an effective treatment for patients with chronic rhinosinusitis (CRS).

Objective: To evaluate the incremental effect of adding budesonide to large-volume, low-pressure saline sinus irrigation.

Design, Setting, And Participants: This double-blind, placebo-controlled, randomized clinical trial was conducted at a quaternary care academic medical center between January 1, 2016, and February 16, 2017.

Reporting of Effect Size and Confidence Intervals in JAMA Otolaryngology-Head & Neck Surgery.

Importance: Effect sizes and confidence intervals (CIs) are critical for the interpretation of the results for any outcome of interest.

Objective: To evaluate the frequency of reporting effect sizes and CIs in the results of analytical studies.

Design, Setting, And Participants: Descriptive review of analytical studies published from January 2012 to December 2015 in JAMA Otolaryngology-Head & Neck Surgery.

Transoral Resection of Human Papillomavirus (HPV)-Positive Squamous Cell Carcinoma of the Oropharynx: Outcomes with and Without Adjuvant Therapy.

Background: With the rise of oropharyngeal squamous cell carcinoma associated with human papillomavirus (HPV), appropriate treatment strategies continue to be tailored toward minimizing treatment while preserving oncologic outcomes. This study aimed to compare the outcomes for those undergoing transoral resection with or without adjuvant therapy for HPV-related oropharyngeal carcinoma.

Methods: A case-match cohort analysis was performed at two institutions on patients with HPV-related oropharyngeal squamous cell carcinoma.

Postoperative hemorrhage and hospital revisit after transoral robotic surgery.

Objectives/hypothesis: To investigate the incidence and complications related to postoperative hemorrhage (POH) after transoral robotic surgery (TORS).

Study Design: Retrospective review of the State Inpatient Database (SID), the State Ambulatory Surgery Database (SASD), and the State Emergency Department Database (SEDD) from the Healthcare Cost and Utilization Project.

Methods: Patients were identified from the SID, SASD, and SEDD for the states of Florida, New York, and California from 2005 to 2013 who had an International Classification of Diseases, Ninth Edition code for a surgical procedure on the upper aerodigestive tract associated with a code for robotic-assisted surgery.

Nicotinic acid-adenine dinucleotide phosphate activates the skeletal muscle ryanodine receptor.

Calcium is a universal second messenger. The temporal and spatial information that is encoded in Ca(2+)-transients drives processes as diverse as neurotransmitter secretion, axonal outgrowth, immune responses and muscle contraction. Ca(2+)-release from intracellular Ca(2+) stores can be triggered by diffusible second messengers like Ins P (3), cyclic ADP-ribose or nicotinic acid-adenine dinucleotide phosphate (NAADP).

Short- and long-term functional alterations of the skeletal muscle calcium release channel (Ryanodine receptor) by Suramin: apparent dissociation of single channel current recording and [3H]ryanodine binding.

The present study demonstrates the following characteristic suramin actions on the purified skeletal muscle calcium release channel in single-channel current recordings and [(3)H]ryanodine binding to HSR: 1) Suramin (0.3-0.9 mM) induced a concentration-dependent increase in the open probability (P(o) congruent with 0.

Modulation of the calmodulin-induced inhibition of sarcoplasmic reticulum calcium release channel (ryanodine receptor) by sulfhydryl oxidation in single channel current recordings and [(3)H]ryanodine binding.

The modulation of the calmodulin-induced inhibition of the calcium release channel (ryanodine receptor) by two sulfhydryl oxidizing compounds, 4-(chloromercuri)phenyl-sulfonic acid (4-CMPS) and 4, 4'-dithiodipyridine (4,4'-DTDP) was determined by single channel current recordings with the purified and reconstituted calcium release channel from rabbit skeletal muscle sarcoplasmic reticulum (HSR) and [(3)H]ryanodine binding to HSR vesicles. 0.1 microm CaM reduced the open probability (P(o)) of the calcium release channel at maximally activating calcium concentrations (50-100 microm) from 0.

Activation and inhibition of purified skeletal muscle calcium release channel by NO donors in single channel current recordings.

The actions of the nitric oxide (NO) donors 1-hydroxy-2-oxo-3-(N-methyl-3-aminopropyl)-3 methyl-1-triazine (NOC-7), S-nitrosoacetylcysteine (CySNO) and S-nitrosoglutathione (GSNO) on the purified calcium release channel (ryanodine receptor) of rabbit skeletal muscle were determined by single channel current recordings. In addition, the activation of the NO donor modulated calcium release channel by the sulfhydryl oxidizing organic mercurial compound 4-(chloromercuri)phenylsulfonic acid (4-CMPS) was investigated. NOC-7 (0.

Suramin and suramin analogs activate skeletal muscle ryanodine receptor via a calmodulin binding site.

Contraction of skeletal muscle is triggered by the rapid release of Ca2+ from the sarcoplasmic reticulum via the ryanodine receptor/calcium-release channel. The trypanocidal drug suramin is an efficient activator of the ryanodine receptor. Here, we used high-affinity [3H]ryanodine binding to sarcoplasmic reticulum from rabbit skeletal muscle to screen for more potent analogs of suramin.

Modification of sulfhydryls of the skeletal muscle calcium release channel by organic mercurial compounds alters Ca2+ affinity of regulatory Ca2+ sites in single channel recordings and [3H]ryanodine binding.

The actions of two organic mercurial compounds, 4-(chloromercuri)phenyl-sulfonic acid (4-CMPS) and p-chloromercuribenzoic acid (p-CMB) on the calcium release channel (ryanodine receptor) from rabbit skeletal muscle were determined by single channel recordings with the purified calcium release channel, radioligand binding to sarcoplasmic reticulum vesicles (HSR) and calcium release from HSR. p-CMB or 4-CMPS (20-100 microM) increased the mean open probability (Po) of the calcium channel at subactivating (20 nM), maximally activating (20-100 microM and inhibitory (1-4 mM) Ca2+ concentrations, with no effect on unitary conductance. This activation was partly reversed by 2 mM DTT.

Phosphorylation of the purified cardiac ryanodine receptor by exogenous and endogenous protein kinases.

The ryanodine receptor is the main Ca(2+)-release structure in skeletal and cardiac sarcoplasmic reticulum. In both tissues, phosphorylation of the ryanodine receptor has been proposed to be involved in the regulation of Ca2+ release. In the present study, we have examined the ability of the purified cardiac ryanodine receptor to serve as a substrate for phosphorylation by exogenously added catalytic subunit of the cyclic AMP (cAMP)-dependent protein kinase (PK-A), cyclic GMP (cGMP)-dependent protein kinase (PK-G), or calmodulin-dependent protein kinase (PK-CaM).

Phosphorylation of serine 2843 in ryanodine receptor-calcium release channel of skeletal muscle by cAMP-, cGMP- and CaM-dependent protein kinase.

The aim of the present study was to determine the phosphorylation of the purified ryanodine receptor-calcium release channel (RyR) of rabbit skeletal muscle sarcoplasmic reticulum by the cAMP-dependent protein kinase (PK-A), cGMP-dependent protein kinase (PK-G) and Ca(2+)-, CaM-dependent protein kinase (PK-CaM) and the localization of phosphorylation sites. Phosphorylation was highest with PK-A (about 0.9 mol phosphate/mol receptor subunit), between one-half to two-thirds with PK-G and between one-third and more than two-thirds with PK-CaM.

Activation and inhibition of the calcium-release channel of isolated skeletal muscle heavy sarcoplasmic reticulum. Models of the calcium-release channel.

Calcium-independent calcium efflux from heavy sarcoplasmic reticulum (HSR) of skeletal muscle was found to be biphasic, with half-times of 2-6 s and 200-400 s for the first and second phase, respectively. Calcium-, AMP- and caffeine-induced calcium efflux was triphasic, with half-times of 0.05-0.

[Calcium channel mediated calcium release from the rabbit skeletal muscle sarcoplasmic reticulum vesicle].

Activation and inhibition of the calcium release channel of rabbit skeletal muscle heavy sarcoplasmic reticulum (HSR) was investigated by various methods. The calcium release channel is activated by binding of calcium in the micromolar range and by binding of adenine nucleotides in the millimolar range. Ruthenium red and neomycin are potent inhibitors of the channel at nanomolar to micromolar concentrations.

Drug-induced calcium release from heavy sarcoplasmic reticulum of skeletal muscle.

Calcium release from isolated heavy sarcoplasmic reticulum of rabbit skeletal muscle by several calmodulin antagonistic drugs was measured spectrophotometrically with arsenazo III and compared with the properties of the caffeine-induced calcium release. Trifluoperazine and W7 (about 500 microM) released all actively accumulated calcium (half-maximum release at 129 microM and 98 microM, respectively) in the presence 0.5 mM MgCl2 and 1 mg/ml sarcoplasmic reticulum protein; calmidazolium (100 microM) and compound 48/80 (70 micrograms/ml) released maximally 30-40% calcium, whilst bepridil (100 microM) and felodipin (50 microM) with calmodulin antagonistic strength similar to trifluoperazine (determined by inhibition of the calcium, calmodulin-dependent protein kinase of cardiac sarcoplasmic reticulum) did not cause a detectable calcium release, indicating that this drug-induced calcium release is not due to the calmodulin antagonistic properties of the tested drugs.

Inhibition of calcium release from skeletal muscle sarcoplasmic reticulum by calmodulin.

The effect of calmodulin on calcium release from heavy sarcoplasmic reticulum isolated from rabbit skeletal muscle was investigated with actively and passively calcium loaded sarcoplasmic reticulum vesicles and measured either spectrophotometrically with arsenazo III or by Millipore filtration technique. The transient calcium-, caffeine- and AMP-induced calcium release from actively loaded sarcoplasmic reticulum vesicles was reduced to 29%, 51% and 59% of the respective control value by 1 microM exogenous calmodulin. Stopped-flow measurements demonstrate that calmodulin reduces the apparent rate of caffeine-induced calcium release from actively loaded sarcoplasmic reticulum.

Calcium release from calmodulin and its C-terminal or N-terminal halves in the presence of the calmodulin antagonists phenoxybenzamine and melittin measured by stopped-flow fluorescence with Quin 2 and intrinsic tyrosine. Inhibition of calmodulin-dependent protein kinase of cardiac sarcoplasmic reticulum.

Calcium dissociation from the C-terminal and N-terminal halves of calmodulin, intact bovine brain calmodulin and the respective phenoxybenzamine complexes or melittin complexes was measured directly by stopped-flow fluorescence with the calcium chelator Quin 2 and, when possible, also by protein fluorescence using endogenous tyrosine fluorescence by mixing with EGTA. Calcium dissociation from the C-terminal half of calmodulin, which contains only the two high-affinity calcium-binding sites, and from intact calmodulin was monophasic, with good correlation of the rates of calcium dissociation obtained by the two methods. The apparent rates with Quin 2 and endogenous tyrosine fluorescence were 13.

Calcium release from intact calmodulin and calmodulin fragment 78-148 measured by stopped-flow fluorescence with 2-p-toluidinylnaphthalene sulfonate. Effect of calmodulin fragments on cardiac sarcoplasmic reticulum.

Calcium release from high and low-affinity calcium-binding sites of intact bovine brain calmodulin (CaM) and from the tryptic fragment 78-148, purified by high-pressure liquid chromatography, containing only the high-affinity calcium-binding sites, was determined by fluorescence stopped-flow with 2-p-toluidinylnaphthalene sulfonate (TNS). The tryptic fragments 1-77 and 78-148 each contain a calcium-dependent TNS-binding site, as shown by the calcium-dependent increase in TNS fluorescence. The rate of the monophasic fluorescence decrease in endogenous tyrosine on calcium dissociation from intact calcium-saturated calmodulin (kobs 10.

Calmodulin X (Ca2+)4 is the active calmodulin-calcium species activating the calcium-, calmodulin-dependent protein kinase of cardiac sarcoplasmic reticulum in the regulation of the calcium pump.

Calcium-, calmodulin-dependent phosphorylation of cardiac sarcoplasmic reticulum increases the rate of calcium transport. The complex dependence of calmodulin-dependent phosphoester formation on free calcium and total calmodulin concentrations can be satisfactorily explained by assuming that CaM X (Ca2+)4 is the sole calmodulin-calcium species which activates the calcium-, calmodulin-dependent, membrane-bound protein kinase. The apparent dissociation constant of the E X CaM X (Ca2+)4 complex determined from the calcium dependence of calmodulin-dependent phosphoester formation over a 100-fold range of total calmodulin concentrations (0.