Has Choosing Wisely® affected rates of dual-energy X-ray absorptiometry use?

UNLABELLED: Reducing overuse of tests such as dual-energy X-ray absorptiometry (DXA) scans in younger women is an important quality issue. We evaluated trends in DXA ordering before and after Choosing Wisely recommendations were released. We found no significant difference in ordering trends suggesting that other initiatives are needed to change behavior. INTRODUCTION: Reducing overuse of tests such as dual-energy X-ray absorptiometry (DXA) scans in younger women is an important quality issue, but trends in care are difficult to change. We evaluated (1) trends in DXA ordering before and after the Choosing Wisely recommendation release and (2) patterns of key characteristics that indicate a potentially appropriate DXA scan order. METHODS: We performed a retrospective longitudinal analysis of electronic health record data at a multi-specialty, ambulatory care network of 34 practices across Maryland and Washington, DC. Since the Choosing Wisely DXA recommendation was released April 2012, the study periods were April-December 2011 (pre-initiative) and April-December 2012 (post-initiative). Women between 50 and 64 years with primary care encounters, and primary care providers who saw ten or more women in the study population in both pre and post periods were included. RESULTS: For 42,320 eligible patients, the mean provider ordering rate was 2.6 % pre-initiative and 2.0 % post-initiative; there was no significant difference in trend over time. Over 70 % of the population had no characteristics associated with potentially appropriate DXA ordering. Low body mass index, current smoker status, and osteopenia were the most common characteristics indicating potentially appropriate DXA orders. Patients with any of these three characteristics had DXA ordering rates between 3-20 %. CONCLUSIONS: The trend in provider ordering rates of DXA scans did not decrease after the release of the DXA Choosing Wisely recommendation. Targeted initiatives addressing providers with high ordering rates will be needed to change behavior.

Pharmacology and therapeutic role of inorganic nitrite and nitrate in vasodilatation.

Nitrite has emerged as an important bioactive molecule that can be biotransformed to nitric oxide (NO) related metabolites in normoxia and reduced to NO under hypoxic and acidic conditions to exert vasodilatory effects and confer a variety of other benefits to the cardiovascular system. Abundant research is currently underway to understand the mechanisms involved and define the role of nitrite in health and disease. In this review we discuss the impact of nitrite and dietary nitrate on vascular function and the potential therapeutic role of nitrite in acute heart failure.

Vascular tone pathway polymorphisms in relation to primary open-angle glaucoma.

AIMS: Vascular perfusion may be impaired in primary open-angle glaucoma (POAG); thus, we evaluated a panel of markers in vascular tone-regulating genes in relation to POAG. METHODS: We used Illumina 660W-Quad array genotype data and pooled P-values from 3108 POAG cases and 3430 controls from the combined National Eye Institute Glaucoma Human Genetics Collaboration consortium and Glaucoma Genes and Environment studies. Using information from previous literature and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, we compiled single-nucleotide polymorphisms (SNPs) in 186 vascular tone-regulating genes. We used the 'Pathway Analysis by Randomization Incorporating Structure' analysis software, which performed 1000 permutations to compare the overall pathway and selected genes with comparable randomly generated pathways and genes in their association with POAG. RESULTS: The vascular tone pathway was not associated with POAG overall or POAG subtypes, defined by the type of visual field loss (early paracentral loss (n=224 cases) or only peripheral loss (n=993 cases)) (permuted P≥0.20). In gene-based analyses, eight were associated with POAG overall at permuted P<0.001: PRKAA1, CAV1, ITPR3, EDNRB, GNB2, DNM2, HFE, and MYL9. Notably, six of these eight (the first six listed) code for factors involved in the endothelial nitric oxide synthase activity, and three of these six (CAV1, ITPR3, and EDNRB) were also associated with early paracentral loss at P<0.001, whereas none of the six genes reached P<0.001 for peripheral loss only. DISCUSSION: Although the assembled vascular tone SNP set was not associated with POAG, genes that code for local factors involved in setting vascular tone were associated with POAG.

Relationships between postweaning residual feed intake in heifers and forage use, body composition, feeding behavior, physical activity, and heart rate of pregnant beef females.

The objectives of this study were to determine if residual feed intake (RFI) classification of beef heifers affected efficiency of forage utilization, body composition, feeding behavior, heart rate, and physical activity of pregnant females. Residual feed intake was measured in growing Bonsmara heifers for 2 yr (n=62 and 53/yr), and heifers with the lowest (n=12/yr) and highest (n=12/yr) RFI were retained for breeding. Of the 48 heifers identified as having divergent RFI, 19 second-parity and 23 first-parity females were used in the subsequent pregnant-female trial. Pregnant females were fed a chopped hay diet (ME=2.11 Mcal kg(-1) DM) in separate pens equipped with GrowSafe bunks to measure individual intake and feeding behavior. Body weights were measured at 7-d intervals and BCS and ultrasound measurements of 12th-rib fat depth, rump fat depth, and LM area obtained on d 0 and 77. Heart rate and physical activity were measured for 7 consecutive d. First-parity females had lower (P<0.05) initial BW, BW gain, and initial hip height and tended (P=0.07) to have lower DMI compared to second-parity females. Females with low RFI as heifers consumed 17% less (P<0.01) forage compared to females with high RFI as heifers but maintained the same BW, BW gain, and body composition. Likewise, RFI classification did not affect calving date. An interaction (P=0.04) between heifer RFI classification and parity was found for calf birth weight. Calves from first-parity low-RFI females were lighter at birth (P<0.01) than calves from high-RFI females, but RFI classification did not affect BW of calves born to second-parity females. Residual feed intake classification did not affect bunk visit frequency, but low-RFI females spent 26% less time (P<0.01) at the bunk compared to high-RFI females. First-parity females had more (P<0.05) daily step counts and greater lying-bout frequencies compared to second-parity females, but physical activity was not affected by RFI classification. Heart rates of females classified as low RFI were 7% lower (P=0.03) compared to high-RFI females. Heifer postweaning RFI but not G:F or residual gain were positively correlated with forage intake (r=0.38) and RFI (r=0.42) of pregnant females. Results indicate that heifers identified as having low postweaning RFI have greater efficiency of forage utilization as pregnant females, with minimal impacts on growth, body composition, calving date, and calf birth BW, compared to their high-RFI counterparts.

Technical note: Evaluation of bimodal distribution models to determine meal criterion in heifers fed a high-grain diet.

Meals are clusters of feedbunk visit (BV) events that are differentiated from the next meal by a nonfeeding interval that is longer compared with the nonfeeding intervals within a meal. The longest nonfeeding interval considered to be part of a meal is defined as the meal criterion. The objective of this study was to determine which combination of 2 probability density functions [(PDF): Gaussian normal (G), Weibull (W), Log-Normal, Gamma, and Gumbel] used in a bimodal distribution model had the best fit of nonfeeding interval data collected in beef heifers. Feeding behavior traits (572,627 total BV events) were measured in 119 heifers fed a high-grain diet (3.08 Mcal ME/kg DM), using a GrowSafe system for 66 d. The frequency and duration of BV events averaged 75 ± 15 events/d and 73.0 ± 22.3 min/d, respectively. The bimodal PDF combinations were fitted to the log(10)-transformed interval lengths between BV events for each animal, using R mixdist package (2.13). The Akaike Information Criterion (AIC) was used to assess goodness of fit of the 25 bimodal PDF combinations. The PDF model with the least AIC value was selected as the best fit for each individual. A χ(2) analysis of the selected best PDF distribution across individuals revealed that 78.2% of the heifers best fit were G-W or W-W PDF models. The likelihood probability estimates were calculated from the average AIC deviation of each model from the standard G-G model. The G-W likelihood probability estimate was greater (P = 0.001) than the W-W combination (0.997 vs. 0.727). Our analysis indicated the G-W model had a statistically better fit and is most likely the best approach to define meal criterion in beef heifers fed high-grain diets.

Repression of the prolactin promoter: a functional consequence of the heterodimerization between Pit-1 and Pit-1 beta.

The POU-homeodomain transcription factor Pit-1 is required for the differentiation of the anterior pituitary cells and the expression of their hormone products. Pit-1beta, an alternate splicing isoform, has diametrically different outcomes when it is expressed in different cell types. Pit-1beta acts as a transcriptional repressor of prolactin (PRL) and growth hormone genes in pituitary cells, and as a transcriptional activator in non-pituitary cells. In order to explore these differences, we: (1) identified the transcriptional cofactors necessary for reconstitution of repression in non-pituitary cells; (2) tested the effect of the beta-domain on heterodimerization with Pit-1 and physical interaction with the co-activator CREB binding protein (CBP); and (3) determined the beta-domain sidechain chemistry requirements for repression. Co-expression of both Pit-1 isoforms reconstituted the repression of the PRL promoter in non-pituitary cells. The beta-domain allowed heterodimerization with Pit-1 but blocked physical interaction with CBP, and specific chemical properties of the beta-domain beyond hydrophobicity were dispensable. These data strongly suggest that Pit-1beta represses hormone gene expression by heterodimerizing with Pit-1 and interfering with the assembly of the Pit-1-CBP complex required for PRL promoter activity in pituitary cells.

Pit-1beta reduces transcription and CREB-binding protein recruitment in a DNA context-dependent manner.

Many transcription factors are expressed as multiple isoforms with distinct effects on the regulation of gene expression, and the functional consequences of structural differences between transcription factor isoforms may allow for precise control of gene expression. The pituitary transcription factor isoforms Pit-1 and Pit-1beta differentially regulate anterior pituitary hormone gene expression. Pit-1 is required for the development of and appropriate hormone expression by anterior pituitary somatotrophs and lactotrophs. Pit-1beta differs structurally from Pit-1 by the splice-insertion of the 26-residue beta-domain in the trans-activation domain, and it differs functionally from Pit-1 in that it represses expression of the prolactin promoter in a cell-type specific manner. In order to identify signal and promoter context requirements for repression by Pit-1beta, we examined its function in the presence of physiological regulatory signals as well as wild-type and mutant Pit-1-dependent target promoters. Here, we demonstrate that Pit-1beta impairs recruitment of cAMP response element-binding protein (CREB)-binding protein to the promoters that it represses. In addition, we show that repression of target promoter activity, reduction in promoter histone acetylation, and decrease of CREB-binding protein recruitment all depend on promoter context. These findings provide a mechanism for promoter-specific repression by Pit-1beta.

Early versus delayed surgery for acute cervical spinal cord injury.

The optimal timing of surgical intervention in cervical spinal cord injuries has not been defined. The goals of the study were to investigate changes in neurologic status, length of hospitalization, and acute complications associated with surgery within 3 days of injury versus surgery more than 3 days after the injury. All patients undergoing surgical treatment for an acute cervical spinal injury with neurologic deficit at two institutions between March 1989 and May 1991 were reviewed retrospectively. Forty-three patients initially were evaluated. At one institution, patients with neurologic spinal injuries had surgical intervention within 72 hours of injury. At the other institution, patients underwent immediate closed reduction with subsequent observation of neurologic status for 10 to 14 days before undergoing surgical stabilization. This study indicates that patients who sustain acute traumatic injuries of the cervical spine with associated neurologic deficit may benefit from surgical decompression and stabilization within 72 hours of injury. Surgery within 72 hours of injury in patients sustaining acute cervical spinal injuries with neurologic involvement is not associated with a higher complication rate. Early surgery may improve neurologic recovery and decrease hospitalization time in patients with cervical spinal cord injuries.

Partial purification and characterization of the DNA polymerase from the cyanelles of Cyanophora paradoxa.

A DNA polymerase was partially purified and characterized from the photosynthetic organelles (cyanelles) of the protist, Cyanophora paradoxa. While cyanelles have several cyanobacterial features, such as a lysozyme-sensitive cell wall, unstacked thylakoids and light harvesting phycobilisomes, their genome size and structure resemble those of chloroplasts, suggesting that cyanelles occupy a unique intermediate position between chloroplasts and their phylogenetic ancestors, the cyanobacteria. When comparing the biochemical characteristics of the cyanelle DNA polymerase to those of its counterparts from higher plant chloroplasts and from a cyanobacterium, it is clear that the cyanelle enzyme resembles chloroplast DNA polymerases which are eukaryotic gamma-type enzymes.

Detection of human IL-2 in normal and inflamed dental pulps.

Irreversible pulpitis has been associated with an increase in the number of pulpal T-cells. Interleukin-2 (IL-2) stimulates T-cell proliferation and signals the release of other proinflammatory mediators associated with connective tissue degradation. IL-2 has been suggested to be a useful marker of pathologic inflammatory activity in periodontal and systemic disease conditions. The purpose of this study was to analyze normal and inflamed dental pulps for the presence of immunoreactive IL-2 (iIL-2). Normal healthy pulpal tissue was obtained from 17 impacted third molars and inflamed samples were obtained from 12 symptomatic carious molars clinically diagnosed with irreversible pulpitis. Pulpal tissues were collected, prepared, and analyzed for histological status and iIL-2 concentration by a modified ELISA technique. iIL-2 was detected in all vital pulpal tissues. A t-test revealed significant differences in iIL-2 concentrations when inflamed pulpal tissues were compared to normal healthy samples (T = -2.75, p < 0.05). These results suggest that iIL-2 may serve as a marker of pathologic inflammatory activity in irreversible pulpitis.

Prevention of postoperative pericardial adhesions using tissue-protective solutions.

Repeat cardiac surgical procedures are associated with increased technical difficulty and risk because of the previous formation of dense adhesions between the heart and the surrounding tissues. Dilute solutions of sodium hyaluronic acid (NaHA) and carboxymethyl cellulose (CMC) have been shown to prevent postoperative abdominal and pelvic adhesions and could therefore potentially inhibit adhesion formation following cardiac surgery. Adhesion prevention using 0.1% NaHA, 0.4% NaHA, or 0.1% CMC solutions was examined in a canine abrasion/desiccation pericardial adhesion model (5 animals/group) and compared to 10 animals treated with Ringer's lactate (RL) solution alone. The pericardium and heart were coated with 25 ml of test or control solution prior to and after pericardiotomy, after controlled gauze abrasion, after 30 min of desiccation, and prior to closure. At 6 weeks, animals were reexplored and adhesions were scored in a blinded manner by three to four surgeons using a 0-4 scale. Scores of 2 or greater were considered clinically significant. Mean adhesion scores from the left epicardium were 0.0 in animals treated with 0.1% NaHA, 0.6 in animals treated with 0.4% NaHA or 1% CMC, and 2.3 in animals treated with RL (P < 0.05 Duncan's ANOVA). In addition, none of the animals treated with 0.1% NaHA, 20% of the animals treated with 0.4% NaHA, and 20% of the animals treated with 1% CMC had clinically significant adhesions, whereas 80% of animals treated with RL had such adhesions. Sodium hyaluronic acid and CMC solutions, used as tissue coatings during cardiac surgery, inhibit the formation of undesired postoperative adhesions. Application of these biocompatible polymer solutions during surgery could reduce the technical difficulty and risk of repeat cardiac surgical procedures.

Accuracy of Deoxynucleotide Incorporation by Soybean Chloroplast DNA Polymerases Is Independent of the Presence of a 3[prime] to 5[prime] Exonuclease.

DNA polymerase was purified from soybean (Glycine max) chloroplasts that were actively replicating DNA. The main form (form I) of the enzyme was associated with a low level of 3[prime] to 5[prime] exonuclease activity throughout purification, although the ratio of exonuclease to polymerase activity decreased with each successive purification step. A second form (form II) of DNA polymerase, which elutes from DEAE-cellulose at a higher salt concentration than form I, was devoid of any exonuclease activity. To assess the potential function of the 3[prime] to 5[prime] exonuclease in proofreading, the fidelity of deoxynucleotide incorporation was measured for form I DNA polymerase throughout purification. Despite the steadily decreasing ratio of 3[prime] to 5[prime] exonuclease to polymerase activity, the extent of misincorporation by form I enzyme remained unchanged during the final purification steps, suggesting that the exonuclease did not contribute to the accuracy of DNA synthesis by this polymerase. Fidelity of form I DNA polymerase, when compared with that of form II, revealed a higher level of misincorporation for form I enzyme, a finding that is consistent with the exonuclease playing little or no role in exonucleolytic proofreading.

Action potential duration alternans in dog Purkinje and ventricular muscle fibers. Further evidence in support of two different mechanisms.

An abrupt shortening of cycle length causes action potential duration (APD) alternation in both canine Purkinje (P) and ventricular (V) muscle fibers. Our recent study suggested that APD alternans is determined by the process controlling APD during electrical restitution in P but not in V fibers. In the latter, alternans was attributed to changes in the availability of intracellular calcium [Ca2+]i. We examined this hypothesis further with the following pharmacologic probes known to alter restitution or action of [Ca2+]i: tetradotoxin (0.5-3.0 microM), lidocaine HCl (2.0-12.0 micrograms/ml), sotalol (10 microM), nicorandil (10-20 microM), 4-amino-pyridine (0.5 microM), ryanodine (10 microM), caffeine (2 mM), and ARL 115 BS (100 microM). Alternans in P fibers persisted under all studied conditions but varied in magnitude depending on the time constant and amplitude of restitution. In V fibers, the magnitude of alternans did not correlate with APD changes during restitution, and APD alternans was associated with the alternans of action potential shape and alternans of developed tension. Alternans in V was suppressed by caffeine at 2.0 mM [Ca2+]o when tension was increased and by ryanodine at 1.0 mM [Ca2+]o when tension was decreased. Alternans in V was not altered by changes in [Ca2+]o within the range of 1.0-4.0 mM; by ARL 115 BS, a compound that increases myofibrillar sensitivity to calcium; or by any other pharmacologic probes. We concluded that in P fibers, APD alternans was determined by the factors controlling APD in the absence of alternans; V fibers posses an independent mechanism of alternans linked to alternans of tension and controlled by [Ca2+]i; in V fibers, alternans could be suppressed by both positive and negative inotropic interventions; and calcium released from sarcoplasmic reticulum plays an important role in the V alternans.

Lipid risk factors in patients requiring arterial reconstruction.

Progressive peripheral atherosclerosis commonly leads to failure of a bypass graft. Lowering blood cholesterol retards coronary atherosclerosis and similar treatment might limit peripheral atherosclerosis. To identify lipid risk factors for peripheral atherosclerosis, 144 patients with peripheral atherosclerosis (98 with severe disease and 46 with stable claudication) and 61 age-matched control subjects were studied. Fasting lipid (cholesterol and triglycerides) and lipoprotein (high-density lipoprotein [HDL], low-density lipoprotein [LDL], and very-low-density lipoprotein [VLDL] cholesterol [C]) levels were measured. The incidence of hypertension and diabetes mellitus, amount of previous tobacco use, and location and severity of the peripheral atherosclerosis were also determined. Patients with peripheral atherosclerosis had higher VLDL-C and lower HDL-C levels than controls had, but serum cholesterol and plasma LDL-C levels were similar. Patients with peripheral atherosclerosis also had a higher incidence of diabetes mellitus and hypertension. Predictors of peripheral atherosclerosis by regression analysis were diabetes mellitus, low HDL-C levels, and tobacco use, with diabetes mellitus being the strongest variable. Peripheral atherosclerosis below the inguinal ligament was strongly predicted by low HDL-C and increased VLDL-C levels but not by increased cholesterol or LDL-C levels. Thus lipid risk factors for peripheral atherosclerosis are different, and attempts at limiting late graft failure by lowering lipid levels should be directed toward these lipoproteins.

Selective parasympathectomy increases the quantity of inhibitory guanine nucleotide-binding proteins in canine cardiac ventricle.

In mammalian heart, vagal stimulation or the direct application of acetylcholine produces profound direct effects on the electro-physiologic characteristics of atrial myocytes. At the tissue level, these effects are observed as shortening of atrial action potential duration. Despite anatomic, biochemical, and physiologic evidence for significant vagal input to the mammalian ventricle, similar direct effects of acetylcholine on the ventricular action potential have been difficult to demonstrate. Chronic denervation via cervical vagotomy is one method that has been shown to render previously unresponsive ventricular myocytes sensitive to acetylcholine, but the molecular mechanism has not been defined. In the experiments described, selective cardiac para-sympathectomy was performed on mongrel dogs. Five to seven days after parasympathectomy, the dogs were sacrificed, electrophysiologic responses to acetylcholine were measured, and sarcolemmal vesicles were prepared. After parasympathectomy, ventricular myocytes were responsive to the effects of acetylcholine, manifested as shortening of the action potential duration. A quantitative and functional assessment of the transmembrane signalling mechanisms of the muscarinic receptor was carried out. After parasympathectomy, the density of muscarinic receptors in the sarcolemma was increased, compared with control ventricles. After parasympathectomy, ventricular sarcolemma displayed significant increases in both basal and oxotremorine-stimulated GTPase activity. ADP-ribosylation revealed significantly increased quantities of the pertussis toxin substrates Gi and Go. The quantity of ADP ribose incorporated was correlated with the increased level of GTPase activity in control and oxotremorine-stimulated membranes. Quantitation of the alpha and beta gamma subunits of the guanine nucleotide-binding proteins by immunoblot confirmed the increase in density of inhibitory guanine nucleotide-binding proteins following parasympathectomy. The results offer new insights into possible mechanisms of altered electrophysiologic responsiveness to acetylcholine following cardiac parasympathectomy.

Alternans of action potential duration after abrupt shortening of cycle length: differences between dog Purkinje and ventricular muscle fibers.

The purpose of this study was to determine whether the alternans of action potential duration (APD) occurring in Purkinje and ventricular muscle fibers after an abrupt shortening of cycle length can be explained by the two factors controlling the cycle length-dependent APD changes (i.e., restitution and memory effect). Action potentials were recorded simultaneously from dog Purkinje fibers and ventricular muscle fibers using conventional microelectrode techniques. APD change during alternans was dependent on the preceding diastolic interval in the same manner as during restitution in Purkinje fibers but not in ventricular muscle fibers. The course of memory change was not affected by the presence of alternans in either fiber type. In Purkinje fibers, APD alternans was attenuated by a Ca2+ channel blocker, nisoldipine (2 X 10(-6) M), and augmented by a Ca2+ channel agonist, Bay K 8644 (3 X 10(-8) M). These effects were attributed to the changes in the kinetics and the amplitude of restitution. In ventricular muscle fibers, APD alternans was always preceded and accompanied by alternans of action potential shape. Alternans of both action potential shape and APD was suppressed by nisoldipine (2 X 10(-6) M) and attenuated by Bay K 8644 (3 X 10(-8) M). These results show that in Purkinje fibers, APD during alternans can be explained by restitution and memory effect. However, in ventricular muscle fibers, the mechanism of APD alternans is linked to factors controlling action potential shape. These findings are compatible with the hypothesis that APD alternans in Purkinje fibers depends on the differences in the recovery of membrane currents generated by the preceding action potential and in ventricular muscle fibers on the differences in the concentration and/or handling of intracellular calcium.