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Pace LA, Plate JF, Smith TL, Van Dyke ME.
Biomaterials. 2013 Aug ;34(24):5907-5914.
PMID: 23680369
Peripheral nerve injuries requiring surgery can be repaired by autograft, the clinical "gold standard", allograft, or nerve conduits. Most published clinical studies show the effectiveness of nerve conduits in small size defects in sensory nerves. Many preclinical studies suggest that peripheral nerve regeneration through conduits can be enhanced and repair lengths increased with the use of a biomaterial filler in the conduit lumen. We have previously shown that a luminal hydrogel filler derived from human hair keratin (HHK) can improve electrophysiological and histological outcomes in mouse, rabbit, and non-human primate nerve injury models, but insight into potential mechanisms has been lacking. Based on the premise that a keratin biomaterial (KOS) hydrogel provides an instantaneous structural matrix within the lumen, the current study compares the cellular behavior elicited by KOS hydrogel to Matrigel (MAT) and saline (SAL) conduit fillers in a 1 cm rat sciatic nerve injury model at early stages of regeneration. While there was little difference in initial cellular influx, the KOS group showed earlier migration of dedifferentiated Schwann cells (SC) from the proximal nerve end compared to the other groups. The KOS group also showed faster SC dedifferentiation and myelin debris clearance, and decreased macrophage infiltration during Wallerian degeneration of the distal nerve tissue.
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Orlando G, Booth C, Wang Z, Totonelli G, Ross CL, Moran E, Salvatori M, Maghsoudlou P, Turmaine M, Delario G, Al-Shraideh Y, Farooq U, Farney AC, Rogers J, Iskandar SS, Burns A, Marini FC, De Coppi P, Stratta RJ, Soker S.
Biomaterials. 2013 Aug ;34(24):5915-5925.
PMID: 23680364
In the United States, more than 2600 kidneys are discarded annually, from the total number of kidneys procured for transplant. We hypothesized that this organ pool may be used as a platform for renal bioengineering and regeneration research. We previously showed that decellularization of porcine kidneys yields renal extracellular matrix (ECM) scaffolds that maintain their basic components, support cell growth and welfare in vitro and in vivo, and show an intact vasculature that, when such scaffolds are implanted in vivo, is able to sustain physiological blood pressure. The purpose of the current study was to test if the same strategy can be applied to discarded human kidneys in order to obtain human renal ECM scaffolds. The results show that the sodium dodecylsulfate-based decellularization protocol completely cleared the cellular compartment in these kidneys, while the innate ECM framework retained its architecture and biochemical properties. Samples of human renal ECM scaffolds stimulated angiogenesis in a chick chorioallantoic membrane assay. Importantly, the innate vascular network in the human renal ECM scaffolds retained its compliance. Collectively, these results indicate that discarded human kidneys are a suitable source of renal scaffolds and their use for tissue engineering applications may be more clinically applicable than kidneys derived from animals.
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Mirmalek-Sani SH, Orlando G, McQuilling JP, Pareta R, Mack DL, Salvatori M, Farney AC, Stratta RJ, Atala A, Opara EC, Soker S.
Biomaterials. 2013 Jul ;34(22):5488-95.
PMID: 23583038
Emergent technologies of regenerative medicine have the potential to overcome the limitations of organ transplantation by supplying tissues and organs bioengineered in the laboratory. Pancreas bioengineering requires a scaffold that approximates the biochemical, spatial and vascular relationships of the native extracellular matrix (ECM). We describe the generation of a whole organ, three-dimensional pancreas scaffold using acellular porcine pancreas. Imaging studies confirm that our protocol effectively removes cellular material while preserving ECM proteins and the native vascular tree. The scaffold was seeded with human stem cells and porcine pancreatic islets, demonstrating that the decellularized pancreas can support cellular adhesion and maintenance of cell functions. These findings advance the field of regenerative medicine towards the development of a fully functional, bioengineered pancreas capable of establishing and sustaining euglycemia and may be used for transplantation to cure diabetes mellitus.
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Sun X, Kang Y, Bao J, Zhang Y, Yang Y, Zhou X.
Biomaterials. 2013 Jul ;34(21):4971-81.
PMID: 23566802
Osteogenetic microenvironment is a complex constitution in which extracellular matrix (ECM) molecules, stem cells and growth factors each interact to direct the coordinate regulation of bone tissue development. Importantly, angiogenesis improvement and revascularization are critical for osteogenesis during bone tissue regeneration processes. In this study, we developed a three-dimensional (3D) multi-scale system model to study cell response to growth factors released from a 3D biodegradable porous calcium phosphate (CaP) scaffold. Our model reconstructed the 3D bone regeneration system and examined the effects of pore size and porosity on bone formation and angiogenesis. The results suggested that scaffold porosity played a more dominant role in affecting bone formation and angiogenesis compared with pore size, while the pore size could be controlled to tailor the growth factor release rate and release fraction. Furthermore, a combination of gradient VEGF with BMP2 and Wnt released from the multi-layer scaffold promoted angiogenesis and bone formation more readily than single growth factors. These results demonstrated that the developed model can be potentially applied to predict vascularized bone regeneration with specific scaffold and growth factors.
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Kokkonen EW, Davis SA, Lin HC, Dabade TS, Feldman SR, Fleischer AB.
J Am Med Inform Assoc. 2013 Jun ;20(e1):e33-8.
PMID: 23538721
To assess differences in the use of electronic medical records (EMRs) among medical specialties and practice settings.
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Bura KS, Lord C, Marshall S, McDaniel A, Thomas G, Warrier M, Zhang J, Davis MA, Sawyer JK, Shah R, Wilson MD, Dikkers A, Tietge UJ, Collet X, Rudel LL, Temel RE, Brown JM.
J Lipid Res. 2013 Jun ;54(6):1567-77.
PMID: 23564696
Reverse cholesterol transport (RCT) can proceed through the classic hepatobiliary route or through the nonbiliary transintestinal cholesterol efflux (TICE) pathway. Scavenger receptor class B type I (SR-BI) plays a critical role in the classic hepatobiliary route of RCT. However, the role of SR-BI in TICE has not been studied. To examine the role of intestinal SR-BI in TICE, sterol balance was measured in control mice and mice transgenically overexpressing SR-BI in the proximal small intestine (SR-BI(hApoCIII-ApoAIV-Tg)). SR-BI(hApoCIII-ApoAIV-Tg) mice had significantly lower plasma cholesterol levels compared with wild-type controls, yet SR-BI(hApoCIII-ApoAIV-Tg) mice had normal fractional cholesterol absorption and fecal neutral sterol excretion. Both in the absence or presence of ezetimibe, intestinal SR-BI overexpression had no impact on the amount of cholesterol excreted in the feces. To specifically study effects of intestinal SR-BI on TICE we crossed SR-BI(hApoCIII-ApoAIV-Tg) mice into a mouse model that preferentially utilized the TICE pathway for RCT (Niemann-Pick C1-like 1 liver transgenic), and likewise found no alterations in cholesterol absorption or fecal sterol excretion. Finally, mice lacking SR-BI in all tissues also exhibited normal cholesterol absorption and fecal cholesterol disposal. Collectively, these results suggest that SR-BI is not rate limiting for intestinal cholesterol absorption or for fecal neutral sterol loss through the TICE pathway.
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Chen R, Daining CP, Sun H, Fraser R, Stokes SL, Leitges M, Gnegy ME.
J Neurochem. 2013 Jun ;125(5):663-72.
PMID: 23458603
The strength and duration of extracellular dopamine concentrations are regulated by the presynaptic dopamine transporter (DAT) and dopamine D2 autoreceptors (D2autoRs). There is a functional interaction between these two proteins. Activation of D2autoRs increases DAT trafficking to the surface whereas disruption of this interaction compromises activities of both proteins and alters dopaminergic transmission. Previously we reported that DAT expression and activity are subject to modulation by protein kinase Cβ (PKCβ). Here, we further demonstrate that PKCβ is integral for the interaction between DAT and D2autoR. Inhibition or absence of PKCβ abolished the communication between DAT and D2autoR. In mouse striatal synaptosomes and transfected N2A cells, the D2autoR-stimulated membrane insertion of DAT was abolished by PKCβ inhibition. Moreover, D2autoR-stimulated DAT trafficking is mediated by a PKCβ-extracellular signal-regulated kinase signaling cascade where PKCβ is upstream of extracellular signal-regulated kinase. The increased surface DAT expression upon D2autoR activation resulted from enhanced DAT recycling as opposed to reduced internalization. Further, PKCβ promoted accelerated DAT recycling. Our study demonstrates that PKCβ critically regulates D2autoR-activated DAT trafficking and dopaminergic signaling. PKCβ is a potential drug target for correcting abnormal extracellular dopamine levels in diseases such as drug addiction and schizophrenia.
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Czoty PW, Martelle SE, Gould RW, Nader MA.
J Pharmacol Exp Ther. 2013 Jun ;345(3):374-82.
PMID: 23579044
It has been hypothesized that drugs that serve as substrates for dopamine (DA) and norepinephrine (NE) transporters may be more suitable medications for cocaine dependence than drugs that inhibit DA and NE uptake by binding to transporters. Previous studies have shown that the DA/NE releaser d-amphetamine can decrease cocaine self-administration in preclinical and clinical studies. The present study examined the effects of methylphenidate (MPD), a DA uptake inhibitor, for its ability to decrease cocaine self-administration under conditions designed to reflect clinically relevant regimens of cocaine exposure and pharmacotherapy. Each morning, rhesus monkeys pressed a lever to receive food pellets under a fixed-ratio 50 schedule of reinforcement; cocaine was self-administered under a progressive-ratio schedule of reinforcement in the evening. After cocaine (0.003-0.56 mg/kg per injection, i.v.) dose-response curves were determined, self-administration sessions were suspended and MPD (0.003-0.0056 mg/kg per hour, i.v.; or 1.0-9.0 mg/kg p.o., b.i.d.) was administered for several weeks. A cocaine self-administration session was conducted every 7 days. When a MPD dose was reached that either persistently decreased cocaine self-administration or produced disruptive effects, the cocaine dose-effect curve was re-determined. In most cases, MPD treatment either produced behaviorally disruptive effects or increased cocaine self-administration; it took several weeks for these effects to dissipate. These data are consistent with the largely negative results of clinical trials with MPD. In contrast to the positive effects with the monoamine releaser d-amphetamine under identical conditions, these results do not support use of monoamine uptake inhibitors like MPD as a medication for cocaine dependence.
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Cartwright MS, Mayans DR, Gillson NA, Griffin LP, Walker FO.
Muscle Nerve. 2013 Jun ;47(6):890-893.
PMID: 23670837
Introduction: Nerve cross-sectional area reference values have been reported for many nerves, but there have been few studies in pediatric and geriatric populations. This study was conducted to determine the influence of age on nerve cross-sectional area. Methods: Thirty-two children (3 months to 16 years) and 20 geriatric adults (67-92 years) without known neurologic conditions underwent bilateral ultrasound to measure the area of the following nerves: median at the wrist and forearm; ulnar at the wrist and elbow; radial in the spiral groove; sciatic in the distal thigh; fibular at the knee; tibial at the knee and ankle; and sural at the ankle. Results: In general, nerve cross-sectional area increased with age. Nerve size correlated most closely with age, but a correlation was also seen with body mass index. Conclusions: Nerve cross-sectional area increases with age, which is important to note when using ultrasound to evaluate children and geriatric patients. Muscle Nerve 47: 890-893, 2013.
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Yamaleyeva LM, Neves LA, Coveleskie K, Diz DI, Gallagher PE, Brosnihan KB.
Placenta. 2013 Jun ;34(6):497-502.
PMID: 23602334
We investigated the expression of angiotensin receptors in early pregnancy and established whether normal pregnancy or preeclampsia alters the expression and distribution of the uteroplacental AT1R, AT2R and mas/AT1-7R at late gestation.
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Bellavia L, Dumond JF, Perlegas A, Bruce King S, Kim-Shapiro DB.
Nitric Oxide. 2013 May 31;31():38-47.
PMID: 23545404
Angeli's salt (Na2N2O3) decomposes into nitroxyl (HNO) and nitrite (NO2(-)), compounds of physiological and therapeutic interest for their impact on biological signaling both through nitric oxide and nitric oxide independent pathways. Both nitrite and HNO oxidize oxygenated hemoglobin to methemoglobin. Earlier work has shown that HNO catalyzes the reduction of nitrite by deoxygenated hemoglobin. In this work, we have shown that HNO accelerates the oxidation of oxygenated hemoglobin by NO2(-). We have demonstrated this HNO mediated acceleration of the nitrite/oxygenated hemoglobin reaction with oxygenated hemoglobin being in excess to HNO and nitrite (as would be found under physiological conditions) by monitoring the formation of methemoglobin in the presence of Angeli's salt with and without added NO2(-). In addition, this acceleration has been demonstrated using the HNO donor 4-nitrosotetrahydro-2H-pyran-4-yl pivalate, a water-soluble acyloxy nitroso compound that does not release NO2(-) but generates HNO in the presence of esterase. This HNO donor was used both with and without NO2(-) and acceleration of the NO2(-) induced formation of methemoglobin was observed. We found that the acceleration was not substantially affected by catalase, superoxide dismutase, c-PTIO, or IHP, suggesting that it is not due to formation of extramolecular peroxide, NO2 or H2O2, or to modulation of allosteric properties. In addition, we found that the acceleration is not likely to be related to HNO binding to free reduced hemoglobin, as we found HNO binding to reduced hemoglobin to be much weaker than has previously been proposed. We suggest that the mechanism of the acceleration involves local propagation of autocatalysis in the nitrite-oxygenated Hb reaction. This acceleration of the nitrite oxyhemoglobin reaction could affect studies aimed at understanding physiological roles of HNO and perhaps nitrite and use of these agents in therapeutics such as hemolytic anemias, heart failure, and ischemia reperfusion injury.
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Klepin HD, Geiger AM, Tooze JA, Kritchevsky SB, Williamson JD, Pardee TS, Ellis LR, Powell BL.
Blood. 2013 May 23;121(21):4287-4294.
PMID: 23550038
We investigated the predictive value of geriatric assessment (GA) on overall survival (OS) for older adults with acute myelogenous leukemia (AML). Consecutive patients ≥ 60 years with newly diagnosed AML and planned intensive chemotherapy were enrolled at a single institution. Pretreatment GA included evaluation of cognition, depression, distress, physical function (PF) (self-reported and objectively measured), and comorbidity. Objective PF was assessed using the Short Physical Performance Battery (SPPB, timed 4-m walk, chair stands, standing balance) and grip strength. Cox proportional hazards models were fit for each GA measure as a predictor of OS. Among 74 patients, the mean age was 70 years, and 78.4% had an Eastern Cooperative Oncology Group (ECOG) score ≤ 1. OS was significantly shorter for participants who screened positive for impairment in cognition and objectively measured PF. Adjusting for age, gender, ECOG score, cytogenetic risk group, myelodysplastic syndrome, and hemoglobin, impaired cognition (Modified Mini-Mental State Exam < 77) and impaired objective PF (SPPB < 9) were associated with worse OS. GA methods, with a focus on cognitive and PF, improve risk stratification and may inform interventions to improve outcomes for older AML patients.
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Gibb AC, Ashley-Ross MA, Hsieh ST.
Integr Comp Biol. 2013 May 23. [Epub ahead of print]
PMID: 23704366
Moving on land versus in water imposes dramatically different requirements on the musculoskeletal system. Although many limbed vertebrates, such as salamanders and prehistoric tetrapodomorphs, have an axial system specialized for aquatic locomotion and an appendicular system adapted for terrestrial locomotion, diverse extant teleosts use the axial musculoskeletal system (body plus caudal fin) to move in these two physically disparate environments. In fact, teleost fishes living at the water's edge demonstrate diversity in natural history that is reflected in a variety of terrestrial behaviors: (1) species that have only incidental contact with land (such as largemouth bass, Micropterus) will repeatedly thrash, which can roll an individual downhill, but cannot produce effective overland movements, (2) species that have occasional contact with land (like Gambusia, the mosquitofish, which evade predators by stranding themselves) will produce directed terrestrial movement via a tail-flip jump, and (3) species that spend more than half of their lives on land (like the mudskipper, Periopthalmus) will produce a prone-jump, a behavior that allows the fish to anticipate where it will land at the end of the flight phase. Both tail-flip and prone jumps are characterized by a two-phase movement consisting of body flexion followed by extension-a movement pattern that is markedly similar to the aquatic fast-start. Convergence in kinematic pattern between effective terrestrial behaviors and aquatic fast starts suggests that jumps are an exaptation of a neuromuscular system that powers unsteady escape behaviors in the water. Despite such evidence that terrestrial behaviors evolved from an ancestral behavior that is ubiquitous among teleosts, some teleosts are unable to move effectively on land-possibly due to morphological trade-offs, wherein specialization for one environment comes at a cost to performance in the other. Indeed, upon emergence onto land, gravity places an increased mechanical load on the body, which may limit the maximum size of fish that can produce terrestrial locomotion via jumping. In addition, effective terrestrial locomotor performance may require a restructuring of the musculoskeletal system that directly conflicts with the low-drag, fusiform body shape that enhances steady swimming performance. Such biomechanical trade-offs may constrain which teleost species are able to make the evolutionary transition to life on land. Here, we synthesize the current knowledge of intermittent terrestrial locomotion in teleosts and demonstrate that extant fishes represent an important model system for elucidating fundamental evolutionary mechanisms and defining the physiological constraints that must be overcome to permit life in both the aquatic and terrestrial realms.
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Miller DP, Spangler JG, Vitolins MZ, Davis SW, Ip EH, Marion GS, Crandall SJ.
Acad Med. 2013 May 22. [Epub ahead of print]
PMID: 23702519
PURPOSE: Anti-obesity prejudices affect the quality of care obese individuals receive. The authors sought to determine the prevalence of weight-related biases among medical students and whether they were aware of their biases. METHOD: Between 2008 and 2011, the authors asked all third-year medical students at Wake Forest School of Medicine to complete the Weight Implicit Association Test (IAT), a validated measure of implicit preferences for "fat" or "thin" individuals. Students also answered a semantic differential item assessing their explicit weight-related preferences. The authors determined students' awareness of their biases by examining the correlation between students' explicit preferences and their IAT scores. RESULTS: Of 354 medical students, 310 (88%) completed valid surveys and consented to participate. Overall, 33% (101/310) self-reported a significant ("moderate" or "strong") explicit anti-fat bias. No students self-reported a significant explicit anti-thin bias. According to the IAT scores, over half of students had a significant implicit weight bias: 39% (121/310) had an anti-fat bias and 17% (52/310) an anti-thin bias. Two-thirds of students (67%, 81/121) were unaware of their implicit anti-fat bias. Only male gender predicted an explicit anti-fat bias (odds ratio 3.0, 95% confidence interval 1.8-5.3). No demographic factors were associated with an implicit anti-fat bias. Students' explicit and implicit biases were not correlated (Pearson r = 0.03, P = .58). CONCLUSIONS: Over one-third of medical students had a significant implicit anti-fat bias; few were aware of that bias. Accordingly, medical schools' obesity curricula should address weight-related biases and their potential impact on care.
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Ahn CS, Gustafson CJ, Sandoval LF, Davis SA, Feldman SR.
Am J Clin Dermatol. 2013 May 22. [Epub ahead of print]
PMID: 23696234
BACKGROUND: During the last decade, the implementation of biologic agents has changed the therapeutic management of severe psoriasis. Biologic agents have clinically proven efficacy, but their use is associated with a much higher cost compared with traditional treatment options. Therefore, when assessing the use of these drugs for the treatment of psoriasis, it is important to consider their cost effectiveness. OBJECTIVE: The objective of this study was to determine and compare the cost effectiveness of biologic agents with regard to the cost per patient achieving a minimally important difference (MID) in the Dermatology Life Quality Index (DLQI) and the cost per patient achieving a 75 % improvement in the Psoriasis Area Severity Index (PASI-75). METHODS: A PubMed literature search was conducted to identify studies describing the efficacy of all currently US FDA-approved biologic therapies. The cost effectiveness of each agent over a 12-week period was determined and a sensitivity analysis was performed. Based on clinical efficacy at 12 weeks, treatment paradigms were extrapolated to estimate cost-effectiveness ratios after 1 year of treatment. Pooled data on each biologic agent at different doses were compared in a one-way sensitivity analysis and in an extreme case scenario analysis. RESULTS: Twenty-seven studies were included in the analysis. Intravenous (IV) infliximab 3 mg/kg was the most cost-effective biologic agent with respect to both the cost per patient achieving PASI-75 and the cost per patient achieving a DLQI MID. The next most cost-effective agents in terms of cost per patient achieving PASI-75 were subcutaneous (SQ) adalimumab 40 mg administered every other week (eow) after an 80-mg loading dose, SQ adalimumab 40 mg eow, and IV infliximab 5 mg/kg. In terms of cost per patient achieving DLQI MID, IV infliximab 5 mg/kg, SQ etanercept 25 mg once weekly, SQ etanercept 50 mg once weekly, and SQ adalimumab 50 mg eow after an 80-mg loading dose were the next most cost-effective agents behind IV infliximab 3 mg/kg. For both costs per patient achieving DLQI MID and PASI-75, alefacept was the least cost-effective agent up to a 10 % level of variation at all doses except 0.025 mg/kg once weekly. LIMITATIONS: This study was limited by the use of efficacy data from 12-week clinical trials that did not compare treatments head to head to determine relative efficacy and may not be generalizable to longer treatment periods. Additionally, the estimated cost of treatment did not take into account indirect costs or variations in costs due to insurance company price contracting. CONCLUSIONS: Biologic treatments that were most cost effective were so in respect to both the cost per patient achieving DLQI MID and per patient achieving PASI-75. This suggests that the same agents that are effectively clearing the disease are also effective in improving the patients' subjective assessment of dermatology-related quality of life.
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Calipari ES, Ferris MJ.
J Neurosci. 2013 May 22;33(21):8923-5.
PMID: 23699503
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Schweppe ML, Seyler TM, Plate JF, Swenson RD, Lang JE.
Surg Technol Int. 2013 May 22;XXIII()[Epub ahead of print]
PMID: 23700180
There is a substantial preoccupation with different surgical approaches and minimally invasive techniques that may improve clinical outcomes for patients who undergo total hip arthroplasty. This study assessed the impact on hospital-related outcomes of the direct anterior approach (DAA) compared with the posterior approach (PA) performed by a single surgeon in 100 consecutive patients in each cohort. Patient age was similar in the DAA (61 ± 1.1 years) compared with the PA (62 ± 1.3, p = 0.733); however, BMI tended to be lower in DAA patients (29.1 ± 0.8) compared with PA patients (31.3 ± 0.7, p = 0.057). The DAA compared with the PA was associated with significantly less blood loss (285 ± 15 vs. 367 ± 21ml, p = 0.002) and transfusions (18 vs. 39 units, p = 0.009), less narcotic usage on postoperative days 1-3 (101 ± 12 vs. 146 ± 12 morphine equivalent dose, p = 0.010), a quicker hospital discharge (70 ± 3.3 vs. 97 ± 5.5 hours, p < 0.001), and a more favorable disposition (97% vs. 84% discharged home, p = 0.003). Thirty-day readmission rate was significantly higher with the PA (9%) compared with the DAA (1%, p = 0.030). The number of cups in the safe zone (5° to 25° anteversion and 30° to 50° inclination) was significantly higher with the DAA (92%) compared with the PA (75%, p = 0.002), possibly attributed to fluoroscopy used with the DAA. The DAA muscle-preservation technique may have led to the benefits observed in this study compared with the muscle-splitting technique associated with the PA.
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Aston ER, Neiberg RH, Liguori A.
Alcohol Alcohol. 2013 May 21. [Epub ahead of print]
PMID: 23695976
AIMS: Breath alcohol concentration (BrAC) estimation training has been effective in increasing estimation accuracy in social drinkers. Predictors of estimation accuracy may identify populations to target for training, yet potential predictors typically are not evaluated. In addition, the therapeutic efficacy of estimation training as a preventive strategy for problematic drinking is unknown. METHODS: Forty-six social drinkers with a recent binge history were randomly assigned to an intervention or control group (n = 23 per group). In each of three sessions (pretraining, training, testing), participants consumed alcohol (0.32, 0.24, 0.16 and 0.08 g/kg, in random order) every 30 min (total dose: 0.8 g/kg). Participants provided five BrAC estimates within 3 h of alcohol administration. The intervention group, but not control group, received internal and external training. During testing, participants provided BrAC estimates, but received no feedback. Participants returned for two follow-up visits to complete self-report measures. RESULTS: BrAC estimation training improved intervention group estimation accuracy within the laboratory. Together, training, low trait anxiety and low risk expectancy predicted high testing accuracy. There were no significant group differences in subsequent alcohol consumption, behavior under the influence or risk expectancy regarding potentially hazardous behaviors. CONCLUSION: BrAC estimation training is effective in the laboratory but may not translate into naturalistic settings.
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Jones TE, Ribas de Pouplana L, Alexander RW.
J Biol Chem. 2013 May 21. [Epub ahead of print]
PMID: 23696642
Recognition strategies for tRNA aminoacylation are ancient and highly conserved, having been selected very early in the evolution of the genetic code. In most cases, the trinucleotide anticodons of tRNA are important identity determinants for aminoacylation by cognate aminoacyl-tRNA synthetases (aaRSs). Yet a degree of ambiguity exists in the recognition of certain tRNA(Ile) isoacceptors that are initially transcribed with the methionine-specifying CAU anticodon. In most organisms, the C34 wobble position in these tRNA(Ile) precursors is rapidly modified to lysidine, to prevent recognition by methionyl-tRNA synthetase (MRS) and production of a chimeric Met-tRNA(Ile) that would compromise translational fidelity. In certain bacteria, however, lysidine modification is not required for MRS rejection, indicating that this recognition strategy is not universally conserved and may be relatively recent. To explore the actual distribution of lysidine-dependent tRNA(Ile) rejection by MRS, we have investigated the ability of bacterial MRSs from different clades to differentiate cognate tRNA(Met)CAU from near-cognate tRNA(Ile)CAU. Discrimination abilities vary greatly and appear unrelated to phylogenetic or structural features of the enzymes or sequence determinants of the tRNA. Our data indicates that tRNA(Ile) identity elements were established late and independently in different bacterial groups. We propose that the observed variation in MRS discrimination ability reflects differences in the evolution of the genetic code machineries of emerging bacterial clades.
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Richardson VN, Davis SA, Gustafson CJ, West CE, Feldman SR.
J Dermatolog Treat. 2013 May 21. [Epub ahead of print]
PMID: 23541214
Background: Cold sores are a common condition that can cause significant morbidity and mortality. Antivirals are the typical treatment for cold sores, but the ways in which these medications are used to treat cold sores are not well studied. Purpose: To determine the main treatments prescribed for cold sores and trends in their management over time. Methods: A retrospective analysis of the National Ambulatory Medical Care Survey database was used to analyze outpatient visits for cold sores from 1993 to 2009. Patients were included in the data analysis if they had one of the following three diagnoses reported for their reason-for-visit codes: cold sores (CS), herpes simplex (HS) or herpes simplex with cold sores (HS/CS). Results: There was a decreasing trend in the number of annual patient visits for cold sores. The majority of patients were mainly young to middle adulthood, white women. The top two most commonly prescribed medications were acyclovir followed by valacyclovir. Valacyclovir use increased in all three populations, while acyclovir use decreased. Conclusions: The trends observed may indicate that physicians are evolving their treatment strategies to implement newer antiviral medications. This may prove more efficacious for the treatment of cold sores.
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