Extreme chromosome 17 copy number instability is a prognostic factor in patients with gastroesophageal adenocarcinoma: A retrospective cohort study

Gastric and esophageal cancers frequently show genomic instability and aneuploidy. Chromosomal copy number instability (CIN) is a form of genomic instability that exerts pleiotropic effects on cellular biology and is a source of genetic heterogeneity in a population of cells. CIN results in cell‐to‐cell variation in chromosome copy number which can be detected and quantified by fluorescence in situ hybridization (FISH). CIN is a biomarker associated with differential response to a number of chemotherapy compounds. We quantified chromosome 17 copy number instability (CIN‐17) in 348 gastroesophageal adenocarcinomas by centromeric FISH in cases that were tested for HER2 amplification. We evaluated the association between CIN‐17 and clinical outcome after surgical and nonsurgical treatment. CIN‐17 was detected in 45.4% (158/348) and extreme CIN‐17 in 28.4% (99/348). Extreme CIN‐17 had no association with outcome in surgically treated patients. However, in patients treated with conventional radiation and/or chemotherapy, extreme CIN‐17 was associated with 55% reduction in overall mortality (hazard ratio, 0.448; 95% confidence interval, 0.263–0.763) after adjusting for age and clinical stage at diagnosis. Extreme CIN‐17 is detected in over a quarter of gastroesophageal adenocarcinomas and is a favorable prognostic marker in patients treated nonoperatively.     

Hand‐held Dynamometer Positioning Impacts Discomfort During Quadriceps Strength Testing: A Validity and Reliability Study

Purpose/Background

A belt‐stabilized hand‐held dynamometer (HHD) offers the ability to quantify quadriceps muscle strength in a clinical environment, but a limitation is participant discomfort at the interface between the HHD and the tibia. The purpose of this study was to quantify the level of discomfort associated with a modified belt‐stabilized HHD configuration compared to a standard belt‐stabilized configuration and an isokinetic dynamometer. The secondary purpose of this study was to determine the validity and reliability of a modified configuration used to measure quadriceps strength compared to the “gold‐standard” isokinetic dynamometer.

Methods

Twenty healthy participants (5 males, 15 females; age=24.7±2.2 years, height=171.1±8.8 cm, mass=72.0±18.7 kg) performed maximal knee extension isometric contractions during each of three testing conditions: isokinetic dynamometer, standard configuration with HHD placement on the tibia, and an alternative configuration with the HHD interfaced with the leg of a table. Discomfort was quantified using a Visual Analog Scale (VAS). Differences in discomfort and torque (N•m) associated with the testing positions were determined using Friedman test or repeated measures analysis of variance. Validity was quantified using Pearson correlations and within‐session intrarater reliability was determined using an intraclass correlation coefficient (ICC2,1) and associated confidence intervals (95% CI).

Results

The isokinetic dynamometer configuration resulted in the least discomfort (p< .01) and the modified configuration was more comfortable than the standard configuration (p= .003). There was a significant correlation between measures from the isokinetic dynamometer and the standard configuration (r=.87) and modified configuration (r=.93). Within‐session intrarater reliability was good for both the standard configuration (ICC_2,1=0.93) and modified configuration (ICC_2,1=0.93) conditions.

Conclusions

The use of the modified belt‐stabilized HHD configuration, where the HHD was interfaced with the leg of a table, offers a more comfortable alternative compared to the standard belt‐stabilized configuration to obtain isometric quadriceps strength measures in a clinical environment. This configuration is also a valid and reliable alternative to the “gold standard” isokinetic dynamometer when testing isometric quadriceps strength at 90° of knee flexion.

Level of Evidence

Diagnostic, Level 3     

Altered neuronal nitric oxide synthase in the aging vascular system: implications for estrogens therapy

Ovarian dysfunction at any age is associated with increased cardiovascular risk in women; however, therapeutic effects of exogenous estrogens are age dependent. Estradiol (E2) activates neuronal nitric oxide synthase (nNOS) in vascular cells. Because nNOS is prone to uncoupling under unfavorable biochemical conditions (as seen in aging), E2 stimulation of nNOS may lack vascular benefits in aging. Small mesenteric arteries were isolated from female Sprague Dawley rats, 3 or 12 months old, who were ovariectomized (Ovx) and treated with placebo or E2 for 4 wk. Vascular relaxation to exogenous E2 (0.001-100 μmol/liter) ± selective nNOS inhibitor (N-propyl-l-arginine, 2 μmol/liter) or pan-NOS inhibitor [Nω-nitro-l-arginine methyl ester (l-NAME), 100 μmol/liter] was examined on wire myograph. NOS expression was measured by Western blotting in thoracic aortas, in which superoxide generation was detected as dihydroethidium (DHE) fluorescence. E2 relaxations were impaired in Ovx conditions. E2 treatment (4 wk) normalized vascular function in young rats only. Both l-N-propyl-l-arginine and l-NAME blunted E2 relaxation in young controls, but only l-NAME did so in aging controls. NOS inhibition had no effect on acute E2 relaxation in Ovx rats, regardless of age or treatment. nNOS expression was similar in all animal groups. However, nNOS inhibition increased DHE fluorescence in young controls, whereas it reduced it in aging or Ovx animals. In E2-treated animals of either age, superoxide production was NOS independent. In conclusion, nNOS contributed to vascular relaxation in young, but not aging rats, where its enzymatic function shifted toward superoxide production. Thus, nNOS dysfunction may explain a mechanism of impaired E2 signaling in aging conditions.     

Central projections of lagenar primary neurons in the chick

Perception of linear acceleration and head position is the function of the utricle and saccule in mammals. Nonmammalian vertebrates possess a third otolith endorgan, the macula lagena. Different functions have been ascribed to the lagena in arboreal birds, including hearing, equilibrium, homing behavior, and magnetoreception. However, no conclusive evidence on the function of the lagena in birds is currently available. The present study is aimed at providing a neuroanatomical substrate for the function of the lagena in the chicken as an example of terrestrial birds. The afferents from the lagena of chick embryos (E19) to the brainstem and cerebellum were investigated by the sensitive lipophilic tracer Neuro Vue Red in postfixed ears. The results revealed that all the main vestibular nuclei, including the tangential nucleus, received lagenar projections. No lagenar terminals were found in auditory centers, including the cochlear nuclei. In the cerebellum, the labeled terminals were found variably in all of the cerebellar nuclei. In the cerebellar cortex, the labeled fibers were found mostly in the uvula, with fewer afferents in the flocculus and paraflocculus. None was seen in the nodulus. The absence of lagenar afferent projections in auditory nuclei and the presence of a projection pattern in the vestibular nuclei and cerebellum similar to that of the utricle and saccule suggest that the primary role of the lagena in the chick lies in the processing of vestibular information related to linear acceleration and static head position. J. Comp. Neurol. 521:3524‐3540, 2013. © 2013 Wiley Periodicals, Inc.     

Automated Continuous Acute Kidney Injury Prediction and Surveillance: A Random Forest Model

ObjectiveTo develop and validate a prediction model of acute kidney injury (AKI) of any severity that could be used for AKI surveillance and management to improve clinical outcomes.Patients and MethodsThis retrospective cohort study was conducted in medical, surgical, and mixed intensive care units (ICUs) at Mayo Clinic in Rochester, Minnesota, including adult (≥18 years of age) ICU-unique patients admitted between October 1, 2004, and April 30, 2011. Our primary objective was prediction of AKI using extant clinical data following ICU admission. We used random forest classification to provide continuous AKI risk score.ResultsWe included 4572 and 1958 patients in the training and validation mutually exclusive cohorts, respectively. Acute kidney injury occurred in 1355 patients (30%) in the training cohort and 580 (30%) in the validation cohort. We incorporated known AKI risk factors and routinely measured vital characteristics and laboratory results. The model was run throughout ICU admission every 15 minutes and achieved an area under the receiver operating characteristic curve of 0.88 on validation. It was 92% sensitive and 68% specific and detected 30% of AKI cases at least 6 hours before the criterion standard time (AKI stages 1-3). For discrimination of AKI stages 2 to 3, the model had 91% sensitivity, 71% specificity, and 53% detection of AKI cases at least 6 hours before AKI onset.ConclusionWe developed and validated an AKI prediction model using random forest for continuous monitoring of ICU patients. This model could be used to identify high-risk patients for preventive measures or identifying patients of prospective interventional trials.     

Malnourished Children in Refugee Camps and Lack of Connection with Services After US Resettlement

Identifying and addressing malnutrition among US-bound refugee children is an important human rights issue. Failure to address childhood malnutrition can impair cognitive development and productivity. The target population was children aged 6–59 months, originating from eight countries representing 51 % of US-resettled refugees for 2005–2011, living in 22 camps prior to potential US-resettlement. The corresponding camp-level nutritional survey data were evaluated. State Refugee Health Coordinators were surveyed on nutritional assessment, reporting and referrals for their US-refugee medical screenings. From 2004 to 2010, half of the camps (63 total surveys) had global acute malnutrition prevalence over 15 % at least once (surveys not done annually) and anemia prevalence greater than 40 %. The majority of US-refugee medical screenings included height and weight measurements but few used national or WHO standards to evaluate presence or level of malnutrition. Improve overseas camp monitoring and link these nutritional data to US-resettling refugee children to inform potential nutritional interventions. Domestically, use WHO or US growth standards for anthropometrics to determine presence of malnutrition and need for corrective action.