Citations

Without adequate safety measures, oral chemotherapy can lead to undetected dosing errors. The Mayo Clinic launched a project to ensure that all capecitabine and temozolomide prescriptions receive an independent double check.

Exosomes are small extracellular vesicles that are thought to participate in intercellular communication. Recent work from our laboratory suggests that, in normal and cystic liver, exosome-like vesicles accumulate in the lumen of intrahepatic bile ducts, presumably interacting with cholangiocyte cilia. However, direct evidence for exosome-ciliary interaction is limited and the physiological relevance of such interaction remains unknown. Thus, in this study, we tested the hypothesis that biliary exosomes are involved in intercellular communication by interacting with cholangiocyte cilia and inducing intracellular signaling and functional responses. Exosomes were isolated from rat bile by differential ultracentrifugation and characterized by scanning, transmission, and immunoelectron microscopy. The exosome-ciliary interaction and its effects on ERK1/2 signaling, expression of the microRNA, miR-15A, and cholangiocyte proliferation were studied on ciliated and deciliated cultured normal rat cholangiocytes. Our results show that bile contains vesicles identified as exosomes by their size, characteristic “saucer-shaped” morphology, and specific markers, CD63 and Tsg101. When NRCs were exposed to isolated biliary exosomes, the exosomes attached to cilia, inducing a decrease of the phosphorylated-to-total ERK1/2 ratio, an increase of miR-15A expression, and a decrease of cholangiocyte proliferation. All these effects of biliary exosomes were abolished by the pharmacological removal of cholangiocyte cilia. Our findings suggest that bile contains exosomes functioning as signaling nanovesicles and influencing intracellular regulatory mechanisms and cholangiocyte proliferation through interaction with primary cilia.

This paper concerns the ultrasonic characterization of air-saturated double-layered porous materials by solving the inverse problem using experimental reflected signals at normal incidence. The double-layered porous media consist of two slabs of homogeneous isotropic porous materials with a rigid frame. The ultrasonic propagation in double-layered porous material is modeled using a temporal model in which the inertial effects are described by the tortuosity. The viscous and thermal losses of the medium are described by two susceptibility kernels which depend on the viscous and thermal characteristic lengths. The sensitivity of porosity, tortuosity, and viscous characteristic length of each layer is studied showing their effect on the reflected interface waveforms. The inverse problem is solved numerically by the least-squares method. Five parameters are inverted: porosity and tortuosity of the two layers and the viscous characteristic length of the first layer. The minimization of the discrepancy between experimental and theoretical data is made in the time domain. The inverse problem is shown to be well posed and its solution to be unique. Experimental results for waves reflected by the interfaces of the double-layered porous material are given and compared with theoretical predictions.

AbstractPurposeThe purpose of this study was (1) to describe a staged protocol for management of the dislocated knee and (2) to describe clinical and functional outcomes for patients who received initial spanning external fixation as part of this protocol.MethodNine knees in 9 patients, consisting of 6 males and 3 females, mean age 30.4 (range 19–44) years with diagnosis or presumption of knee dislocation were treated with a protocol of stabilization with external fixator. Mean follow‐up was 24 (range 13–42) months. Indications for spanning external fixation included significant vascular injury, gross instability on examination with failure to maintain joint reduction, open knee dislocation, inability to tolerate mobilization in a brace. The standard protocol involved vascular examination including ankle‐brachial index, ligamentous examination (under anesthesia when applicable), stabilization with temporary joint spanning external fixator, thromboprophylaxis, reconstructive knee surgery, and standard rehabilitation.ResultsMean range of motion (ROM) was 97.4° (range 80°–150°, SD 20.75, median 127.5). Median IKDC score was 80 (range 30–95), and mean Lysholm score was 76.7 (range 46–95). Heterotopic ossification (HO) was noted in 4 knees (44%).ConclusionThe treatment algorithm utilized in this series for management of the dislocated knee demonstrated satisfactory clinical and functional outcomes. This staged protocol provides a management option for those patients who may be best served with initial spanning joint external fixation. Larger prospective studies are needed to fully understand the merit of staged protocols in this setting.

Context: Intermittent PTH treatment stimulates bone formation, but the mechanism(s) of this effect remain unclear. Sclerostin is an inhibitor of Wnt signaling, and animal studies have demonstrated that PTH suppresses sclerostin production. Objective: The objective of the study was to test whether intermittent PTH treatment of postmenopausal women alters circulating sclerostin levels. Design: Prospective study. Setting: The study was conducted at a clinical research unit. Participants and Interventions: Participants included 27 postmenopausal women treated with PTH (1-34) for 14 d and 28 control women. Main Outcome Measures: Serum sclerostin levels were measured. Results: Circulating sclerostin levels decreased significantly in the PTH-treated subjects, from (mean ± SEM) 551 ± 32 to 482 ± 31 pg/ml (−12.7%, P < 0.0001) but did not change in the control women (baseline, 559 ± 34 pg/ml; end point, 537 ± 40 pg/ml, P = 0.207; P = 0.017 for difference in changes between groups). Bone marrow plasma was obtained in a subset of the control and PTH-treated subjects (n = 19 each) at the end of the treatment period, and marrow plasma and peripheral serum sclerostin levels were significantly correlated (R = 0.64, P < 0.0001). Marrow plasma sclerostin levels were 24% lower in PTH-treated compared with control women, but perhaps due to the smaller sample size, this difference was not statistically significant (P = 0.173). Conclusions: Circulating sclerostin levels correlate with bone marrow plasma levels and are reduced by intermittent PTH therapy in postmenopausal women. Further studies are needed to assess the extent to which decreases in sclerostin production contribute to the anabolic skeletal response to PTH.

Paraneoplastic opsoclonus is well described in neuroblastoma. In the adult oncologic population, opsoclonus is seen usually within the context of opsoclonus-myoclonus ataxia and is associated most strongly with small-cell lung cancer. Patients with paraneoplastic opsoclonus are often seronegative. Patients with gynecologic malignancies are known to be predisposed to paraneoplastic syndromes; however, we describe the first case of paraneoplastic opsoclonus in association with endometrial cancer.

PurposeFatigue is one of the most common symptoms experienced by patients with cancer. This trial was developed to evaluate the efficacy of long-acting methylphenidate for improving cancer-related fatigue and to assess its toxicities.Patients and MethodsAdults with cancer were randomly assigned in a double-blinded manner to receive methylphenidate (target dose, 54 mg/d) or placebo for 4 weeks. The Brief Fatigue Inventory was the primary outcome measure, while secondary outcome measures included a Symptom Experience Diary (SED), the Short Form-36 (SF-36) Vitality Subscale, a linear analog self-assessment, the Pittsburgh Sleep Quality Index, and the Subject Global Impression of Change.ResultsIn total, 148 patients were enrolled. Using an area under the serum concentration-time curve analysis, there was no evidence that methylphenidate, as compared with placebo, improved the primary end point of cancer-related fatigue in this patient population (P = .35). Comparisons of secondary end points, including clinically significant changes in quality-of-life variables and cancer-related fatigue change from baseline, were similarly negative. However, a subset analysis suggested that patients with more severe fatigue and/or with more advanced disease did have some fatigue improvement with methylphenidate (eg, in patients with stage III or IV disease, the mean improvement in usual fatigue was 19.7 with methylphenidate v 2.1 with placebo; P = .02). There was a significant difference in self-reported toxicities (SED), with increased levels of nervousness and appetite loss in the methylphenidate arm.ConclusionThis clinical trial was unable to support the primary prestudy hypothesis that the chosen long-acting methylphenidate product would decrease cancer-related fatigue.

Background— Mechanisms promoting the transition from hypertensive heart disease to heart failure with preserved ejection fraction are poorly understood. When inappropriate for salt status, mineralocorticoid (deoxycorticosterone acetate) excess causes hypertrophy, fibrosis, and diastolic dysfunction. Because cardiac mineralocorticoid receptors are protected from mineralocorticoid binding by the absence of 11-β hydroxysteroid dehydrogenase, salt-mineralocorticoid–induced inflammation is postulated to cause oxidative stress and to mediate cardiac effects. Although previous studies have focused on salt/nephrectomy in accelerating mineralocorticoid-induced cardiac effects, we hypothesized that hypertensive heart disease is associated with oxidative stress and sensitizes the heart to mineralocorticoid, accelerating hypertrophy, fibrosis, and diastolic dysfunction. Methods and Results— Cardiac structure and function, oxidative stress, and mineralocorticoid receptor–dependent gene transcription were measured in sham-operated and transverse aortic constriction (studied 2 weeks later) mice without and with deoxycorticosterone acetate administration, all in the setting of normal-salt diet. Compared with sham mice, sham plus deoxycorticosterone acetate mice had mild hypertrophy without fibrosis or diastolic dysfunction. Transverse aortic constriction mice displayed compensated hypertensive heart disease with hypertrophy, increased oxidative stress (osteopontin and NOX4 gene expression), and normal systolic function, filling pressures, and diastolic stiffness. Compared with transverse aortic constriction mice, transverse aortic constriction plus deoxycorticosterone acetate mice had similar left ventricular systolic pressure and fractional shortening but more hypertrophy, fibrosis, and diastolic dysfunction with increased lung weights, consistent with heart failure with preserved ejection fraction. There was progressive activation of markers of oxidative stress across the groups but no evidence of classic mineralocorticoid receptor–dependent gene transcription. Conclusions— Pressure-overload hypertrophy sensitizes the heart to mineralocorticoid excess, which promotes the transition to heart failure with preserved ejection fraction independently of classic mineralocorticoid receptor–dependent gene transcription.

External qigong as a pharmacotherapy adjunct was investigated in 50 subjects with chronic pain (pain lasting > 3 months with pain score of ≥ 3 on 0–10 numeric analog scale) who presented to a qigong healing center. Participants were randomized to receive either external qigong treatment (EQT) or equivalent attention time (EAT) in weekly 30-min sessions for four consecutive weeks. Outcomes were assessed before and after sessions. The primary outcome measure was intensity of pain by a 10-cm visual analog scale used to rate all pain severity measurements. At 8-week follow-up, participants were contacted by telephone and mailed a questionnaire. Most had experienced pain for > 5 years (66%); the rest, for > 3 to 5 years (8%), 1 to 3 years (10%), or < 1 year but > 3 months (10%). The most frequent concomitant diagnoses were multifactorial (26%), osteoarthritis (18%), and low back pain (12%). Most patients were also receiving other treatments (74%); none previously had EQT. Participants were randomly assigned to EQT ( n = 26) or EAT ( n = 24). These groups had no significant differences at baseline except for prior awareness of qigong (EQT 31% vs. EAT 63%; p = 0.025). Compared to the EAT group, EQT participants had a significant decrease in pain intensity in the 2nd ( p = 0.003), 3rd ( p < 0.001), and 4th weeks of treatment ( p = 0.003). At week 8, these differences in overall decreased pain intensity persisted but were not statistically significant.