Citations

Precise measurement of low enrichment of stable isotope labeled amino‐acid tracers in tissue samples is a prerequisite in measuring tissue protein synthesis rates. The challenge of this analysis is augmented when small sample size is a critical factor. Muscle samples from human participants following an 8 h intravenous infusion of L‐[ring‐13C6]phenylalanine and a bolus dose of L‐[ring‐13C6]phenylalanine in a mouse were utilized. Liquid chromatography tandem mass spectrometry (LC/MS/MS), gas chromatography (GC) MS/MS and GC/MS were compared to the GC‐combustion‐isotope ratio MS (GC/C/IRMS), to measure mixed muscle protein enrichment of [ring‐13C6]phenylalanine enrichment. The sample isotope enrichment ranged from 0.0091 to 0.1312 molar percent excess. As compared with GC/C/IRMS, LC/MS/MS, GC/MS/MS and GC/MS showed coefficients of determination of R2 = 0.9962 and R2 = 0.9942, and 0.9217 respectively. However, the precision of measurements (coefficients of variation) for intra‐assay are 13.0%, 1.7%, 6.3% and 13.5% and for inter‐assay are 9.2%, 3.2%, 10.2% and 25% for GC/C/IRMS, LC/MS/MS, GC/MS/MS and GC/MS, respectively. The muscle sample sizes required to obtain these results were 8 µg, 0.8 µg, 3 µg and 3 µg for GC/C/IRMS, LC/MS/MS, GC/MS/MS and GC/MS, respectively. We conclude that LC/MS/MS is optimally suited for precise measurements of L‐[ring‐13C6]phenylalanine tracer enrichment in low abundance and in small quantity samples. Copyright © 2013 John Wiley & Sons, Ltd.

Analgetika sind die am häufigsten verschriebenen Medikamente. Neben ihrer analgetischen Wirksamkeit sind diese Arzneimittel mit einem erhöhten kardiovaskulären Risiko assoziiert, das nicht zuletzt auch auf eine durch die Wirksubstanzen selbst bedingte Erhöhung des Blutdrucks zurückzuführen ist. Epidemiologische und klinische Studien zeigten bereits, dass viele nicht-selektive nicht-steroidale-Antirheumatika und selektive Cyclooxygenase-2-Hemmer mit einer Erhöhung des Blutdrucks und einem erhöhten kardiovaskulären Ereignis einhergehen. Leider fehlten bislang Ergebnisse von prospektiven, randomisierten klinischen Studien mit klinisch relevanten Endpunkten, insbesondere bezüglich des möglichen Zusammenhangs zwischen kardiovaskulären Ereignissen und Analgetika zu eruieren. Dieses Review soll einen kurzen Überblick über klinische Daten bezüglich der Wirkung des Analgetikums Paracetamol auf den Blutdruck und die klinische Bedeutung verschaffen.

BackgroundAlcohol withdrawal accounts for a significant amount of hospital admissions and can quickly progress to the development of delirium tremens (DTs), seizures, and death. Rapid identification and management of alcohol withdrawal syndrome (AWS) is vital and can be managed with a number of different treatment strategies. Diazepam loading is a treatment strategy that utilizes the pharmacokinetics of this agent to achieve a rapid reduction in symptoms followed by sustained benefit over a period of days.ObjectiveThe purpose of this review is to evaluate the role of diazepam loading for AWS.MethodsA literature search of four databases—Pubmed, PsychInfo, Biosis, and Embase—was conducted to identify publications between 1960 and August 2011 that described the use of diazepam loading for the treatment of AWS. Eight trials, both open‐label and controlled trials were identified. Only four randomized controlled‐trials (RCTs) have been published and they are reviewed in this paper.ResultsIncluded trials of hospitalized inpatients found that diazepam loading provided rapid symptom relief as well as reduced the incidence of seizures and duration of DTs. In patients diagnosed with severe DTs, rapidly administered doses of diazepam produced a quick calming effect. While no adverse events resulting from diazepam loading were noted, no formal assessment tool was used to evaluate its safety. Larger randomized controlled‐trials are needed to better evaluate safety outcomes.ConclusionsDiazepam loading is an effective treatment option for hospitalized patients experiencing AWS. Diazepam loading uses the concept of symptom‐triggered therapy, a mainstay of current AWS treatment, while exploiting its prolonged elimination half‐life and eliminating the need for additional pharmacologic therapy. Studies reviewed found diazepam loading significantly improved a number of important outcomes in AWS, including time in DTs, compared to traditional treatment strategies. (Am J Addict 2013;22:113‐118)

Background One way to gain insight into the pathophysiology of chronic rhinosinusitis (CRS) is to study the immunologic changes that occur with exacerbation. This study describes the immunologic changes during CRS exacerbation Methods We performed a prospective study to investigate the immunologic changes seen during exacerbation of CRS with nasal polyposis. We recruited adult subjects who met clinical criteria for CRS with sinus CT scan within the past 5 years with Lund-Mackay score of >5 and nasal polyps. Subjects underwent a baseline visit with collection of nasal secretion and nasal wash. With acute worsening of symptoms, subjects underwent 6 near-consecutive-day collections and one follow-up collection 2 weeks later. IL-6, IL-33, eosinophil major basic protein (MBP), eosinophil-derived neurotoxin (EDN), myeloperoxidase (MPO), and uric acid were measured on the nasal samples from each visit. Results A total of 10 subjects were recruited and 9 had acute worsening of CRS during the study period. Eight of the nine subjects were women and ages ranged from 26 to 56 years. At baseline, most inflammatory parameters were low and eight of the nine subjects were on intranasal corticosteroids. Compared with baseline measurements, IL-6, MBP, MPO, EDN, and uric acid were significantly elevated during CRS exacerbation. Levels of IL-6 and MBP (r = 0.47) levels as well as IL-6 and MPO (r = 0.75) were both significantly correlated (p < 0.01). Conclusion Prospective study of CRS exacerbations is feasible and provides insights into the immunologic mechanisms of CRS.

Abstract Primary cilia are multisensory organelles recently found to be absent in some tumor cells, but the mechanisms of deciliation and the role of cilia in tumor biology remain unclear. Cholangiocytes, the epithelial cells lining the biliary tree, normally express primary cilia and their interaction with bile components regulates multiple processes, including proliferation and transport. Using cholangiocarcinoma as a model, we found that primary cilia are reduced in cholangiocarcinoma by a mechanism involving histone deacetylase 6 (HDAC6). The experimental deciliation of normal cholangiocyte cells increased the proliferation rate and induced anchorage-independent growth. Furthermore, deciliation induced the activation of mitogen-activated protein kinase and Hedgehog signaling, two important pathways involved in cholangiocarcinoma development. We found that HDAC6 is overexpressed in cholangiocarcinoma and overexpression of HDAC6 in normal cholangiocytes induced deciliation and increased both proliferation and anchorage-independent growth. To evaluate the effect of cilia restoration on tumor cells, we targeted HDAC6 by short hairpin RNA (shRNA) or by the pharmacologic inhibitor, tubastatin-A. Both approaches restored the expression of primary cilia in cholangiocarcinoma cell lines and decreased cell proliferation and anchorage-independent growth. The effects of tubastatin-A were abolished when cholangiocarcinoma cells were rendered unable to regenerate cilia by stable transfection of IFT88-shRNA. Finally, inhibition of HDAC6 by tubastatin-A also induced a significant decrease in tumor growth in a cholangiocarcinoma animal model. Our data support a key role for primary cilia in malignant transformation, provide a plausible mechanism for their involvement, and suggest that restoration of primary cilia in tumor cells by HDAC6 targeting may be a potential therapeutic approach for cholangiocarcinoma. Cancer Res; 73(7); 2259–70. ©2013 AACR.

PurposeTo investigate the feasibility of using MR elastography (MRE) for the evaluation of the stiffness of in vivo aortic wall.Materials and MethodsTo validate the experimental approach for imaging the aorta in vivo, a gel phantom with an embedded porcine aorta was imaged in the presence of fluid flow within the aorta. The potential changes in the elasticity of the vessel wall with changes in pressure were investigated. The feasibility of performing MRE of abdominal aorta was assessed in five volunteers (age, 22–40 years; body mass index, 21.5–25.2 kg/m2). The pulse‐gated cine MRE technique was used to study the wave propagation along the aorta throughout the cardiac cycle and provide estimates of aortic stiffness in diastole.ResultsIn the phantom study, the wave propagation was well visualized within the porcine aorta embedded in the gel phantom. An increase of the Young's modulus‐wall thickness (E*t) product with the increase in static pressure was observed. In the in vivo study, the waves were well visualized within the lumen of abdominal aorta in the five volunteers in diastolic phase, but they were not well visualized during systole.ConclusionMRE is feasible for noninvasively assessing the stiffness of the abdominal aorta and merits further investigation. J. Magn. Reson. Imaging 2013;38:1549–1553. © 2013 Wiley Periodicals, Inc.

Objectives/HypothesisAssess the role of retropharyngeal lymph node dissection in oropharyngeal squamous cell carcinoma treated with transoral robotic surgery (TORS).Study DesignProspective case series.MethodsRetrospective analysis of 72 patients with oropharyngeal squamous carcinoma treated with transoral oropharyngectomy, neck dissection, and retropharyngeal node dissection.ResultsEight of 55 (14.5%) patients with tonsil primaries had retropharyngeal metastases in contrast to none with tongue base primaries. The presence of pathologically positive retropharyngeal nodes was associated with clinical tumor (T) (P=.002) and node (N) stage (P=.007), preoperative computed tomography (CT) (P<.001), and positron emission tomography (PET)‐CT scan (P<.001). The negative predictive value of early T (Tx,1‐2) and N stage (N0‐N2a) was 91.7% and 100%, respectively. Preoperative CT and PET‐CT both yielded a positive predictive value of 100%, while the negative predictive value of imaging was optimized to 95.3% when these modalities were combined.ConclusionsIn patients with tonsil cancer the risk of retropharyngeal metastases is negligible in the presence of clinically T1‐2, N0‐N2a disease and negative CT and PET‐CT. We estimate that 40% of patients meet these criteria and may safely forego treatment of the retropharyngeal nodes. Approximately 10% of patients will have positive imaging and we recommend retropharyngeal node dissection at the time of surgery to treat macroscopic disease. In the remaining patients at risk for retropharyngeal node involvement, adjuvant radiotherapy is generally indicated based on other adverse features, and these nodes may be incorporated into the treatment field.Level of Evidence4. Laryngoscope, 2013

Objective. To examine the utility of the Framingham risk score (FRS) in estimating cardiovascular risk in psoriasis.Methods. We compared the predicted 10-year risk of cardiovascular events, namely, cardiovascular death, myocardial infarction, heart failure, percutaneous transluminal coronary angioplasty, and coronary artery bypass grafting using the FRS, to the observed risk of cardiovascular events in a population-based cohort of patients with psoriasis. Patients with incident or prevalent adult-onset psoriasis aged 30–79 years without prior history of cardiovascular disease were included.Results. Among the 1197 patients with predicted risk scores, the median FRS was 6.0%, while the observed 10-year cardiovascular risk was 6.9% (standardized incidence ratio (SIR): 1.14; 95% confidence interval (CI): 0.92–1.42). The SIR was not elevated for women nor for men. The differences between observed and predicted cardiovascular risks in patients <60 years (SIR: 1.01; 95% CI: 0.73–1.41) or ≥60 years (SIR: 1.26; 95% CI: 0.95–1.68) were not statistically significant.Conclusion. There was no apparent difference between observed and predicted cardiovascular risks in patients with psoriasis in our study. FRS reasonably estimated cardiovascular risk in both men and women as well as in younger and older psoriasis patients, suggesting that FRS can be used in risk stratification in psoriasis without further adjustment.