Some Refinements of a Methodology for Examining the Influence of Overt and Covert Self-Rules on Task Completion

The purpose of this study was to evaluate the role of overt and covert self-rule statements on the execution of a chained task by participants with developmental disabilities. A multiple baseline design across participants with multi-element phases embedded was used to evaluate the effects of overt and covert self-rules, alternating with blocking and nonblocking phases, on skill acquisition, generalization, and maintenance, in the absence of explicit reinforcement contingencies for accurate performance. All three participants demonstrated acquisition of the chained task and generalization to novel stimuli. Performance was shown to be only moderately disrupted for some participants during conditions in which the emission of overt and covert self-rules were blocked, raising questions regarding the degree to which a functional relationship between task completion and self-rule statements was obtained. Results are discussed in terms of the practical utility of teaching individuals to respond as listeners to their own emission of overt and covert self-rules as speakers.     

External self-representations improve self-awareness in a child with autism

We have previously suggested that the social symptoms of autism spectrum disorder (ASD) could be caused in part by a dysfunctional mirror neuron system (MNS). Since the recursive activity of a functioning MNS might enable the brain to integrate visual and motor sensations into a coherent body schema, the deficits in self-awareness often seen in ASD might be caused by the same mirror neuron dysfunction. CL is an autistic adolescent who is profoundly fascinated with his reflection, looking in mirrors at every opportunity. We demonstrate that CL’s abnormal gait improves significantly when using a mirror for visual feedback. We also show that both the fascination and the happiness that CL derives from looking at a computer-generated reflection diminish when a delay is introduced between the camera input and screen output. We believe that immediate, real-time visual feedback allows CL to integrate motor sensations with external visual ones into a coherent body schema that he cannot internally generate, perhaps due to a dysfunctional MNS.     

The King laryngeal tube: a mimic of esophageal intubation in the emergency department

The King Airway is a temporary airway device used primarily in the pre-hospital setting and typically exchanged for an endotracheal tube upon arrival to the emergency department. Since this usually occurs before imaging, many radiologists are unfamiliar with the King Airway. This lack of familiarity can have important consequences for the patient and treating team. The purpose of this article is to raise awareness of the King Airway among radiologists, emphasize appropriate positioning, and review the imaging complications of incorrect positioning.     

Capitellum excision: Mechanical implications and clinical consequences

Controversy exists regarding the optimal treatment of isolated fractures of the capitellum that are not amenable to open reduction and internal fixation. Excision of the capitellum could result in instability of the elbow, though only limited the clinical or laboratory evidence exists to support this outcome. The aim of our study was to determine if capitellum excision leads to significant instability by measuring the relative change in varus–valgus displacement of the elbow. The varus–valgus displacement was recorded in 11 cadaveric elbows before and after isolated excision of the capitellum. Specimens were testing in varus‐loaded and valgus‐loaded positions with and without a 1 kg weight on the forearm. The varus–valgus displacement at the elbow was measured using a 3D motion capture system. Capitellum excision did not significantly change varus–valgus displacements in either the adducted, varus, or valgus position of the elbow (p = 0.80, p = 0.28, p = 0.51). Furthermore, the addition of the 1 kg external functional load to the forearm did not produce a significant change in the varus and valgus loaded positions (p = 0.16, p = 0.36). Our results demonstrate that excision of the capitellum in the setting of intact ligamentous structures does not result in significant instability in either the adducted varus loaded or valgus loaded positions of the elbow. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:346–350, 2014.     

West Nile virus associations in wild mammals: a synthesis

Exposures to West Nile virus (WNV) have been documented in a variety of wild mammals in both the New and Old Worlds. This review tabulates at least 100 mammal species with evidence of WNV exposure. Many of these exposures were detected in free-ranging mammals, while several were noted in captive individuals. In addition to exposures, this review discusses experimental infections in terms of the potential for reservoir competence of select wild mammal species. Overall, few experimental infections have been conducted on wild mammals. As such, the role of most wild mammals as potential amplifying hosts for WNV is, to date, uncertain. In most instances, experimental infections of wild mammals with WNV have resulted in no or low-level viremia. Some recent studies have indicated that certain species of tree squirrels (Sciurus spp.), eastern chipmunks (Tamias striatus), and eastern cottontail rabbits (Sylvilagus floridanus) develop viremia sufficient for infecting some mosquito species. Certain mammalian species, such as tree squirrels, mesopredators, and deer have been suggested as useful species for WNV surveillance. In this review article, the information pertaining to wild mammal associations with WNV is synthesized.     

Effect of estrogen on the growth hormone (GH) secretory response to GH-releasing factor in the castrate adult female rat in vivo

Five groups (n = 11) of 250-g female rats were oophorectomized and immediately thereafter received daily sc injections of estradiol benzoate (EB; 0.05, 0.5, 5.0, and 50.0 micrograms) or vehicle for 28 days. A sixth group underwent sham operation and received injections of vehicle. Somatomedin-C (SmC) concentrations were determined before EB administration. After 4 weeks of EB treatment, the GH response to human GH-releasing factor (1-44) (GRF; 5 micrograms/kg, iv) was determined under pentobarbital anesthesia in seven animals from each group. Serum PRL, LH, and estradiol and plasma SmC concentrations were also measured. The GH secretory response to GRF (delta GH) was greatest in castrated animals receiving vehicle (P less than 0.05) and was significantly blunted in animals receiving 5.0 and 50.0 micrograms EB (P less than 0.05) compared to that in sham-operated animals. A significant negative correlation was observed between delta GH and serum PRL concentrations (r = -0.53; P less than 0.0001). SmC concentrations after treatment were significantly lower in animals receiving 5.0 and 50.0 micrograms EB (P less than 0.01), than in sham-operated animals and were elevated compared to those in sham-operated controls in the group receiving the lowest dose of EB (0.05 microgram; P less than 0.01). Posttreatment SmC levels correlated positively with delta GH (r = 0.58; P less than 0.001) and negatively with serum estradiol concentrations (r = -0.47; P less than 0.01). Pituitary glands from the remaining animals in each group (n = 4) were weighed and assayed for GH, PRL, and LH content. Pituitary PRL content increased with increasing doses of EB replacement and correlated strongly (r = 0.82; P less than 0.0001) with pituitary weight. In the castrated adult female rat, high doses of estrogen inhibited the GH secretory response to GRF in vivo and decreased SmC concentrations. Low dose estrogen increased SmC concentrations, although the GH secretary response to GRF in this group was similar to that in sham-operated rats. The latter observation suggests that the rise in SmC levels associated with low dose estrogen may not be mediated through a change in GH secretion.     

Enterococcal meningitis: Combined vancomycin and rifampin therapy

Intrathecal vancomycin and oral rifampin have been used together to successfully treat a patient with enterococcal meningitis who was allergic to penicillin and who had failed a course of treatment with chloramphenicol. This therapy was tolerated very well and represents an alternate mode of therapy which should be considered in penicillin allergic patients with enterococcal meningitis.     

Endogenous peroxidase in the nuclear envelope and endoplasmic reticulum of human monocytes in vitro: association with arachidonic acid metabolism

The development of peroxidase (PO) reaction in the nuclear envelope (NE) and endoplasmic reticulum (ER) of monocytes differentiating in vitro and its relationship with arachidonic acid metabolism were studied. The PO, as visualized by the diaminobenzidine (DAB) technique, appeared in the NE and ER of the majority of monocytes within 24 hours of culture, with a substantial decrease thereafter. The influence of three major groups of agents--inhibitors of PO, of prostanoids, and of protein biosynthesis--upon the development of the PO reaction was examined. When aminotriazole, a PO inhibitor, was added to the culture medium, the appearance of PO was suppressed in the monocytes. The cyclooxygenase blocker, indomethacin, however, did not influence the development of PO. Also the blockers of protein synthesis, puromycin, cycloheximide, and actinomycin D, did not affect the appearance of PO. The prostanoids released from the monocytes, ie, prostaglandin E and thromboxane B2, were determined by radioimmunoassay and showed a time sequence of secretion that corresponded to the appearance of PO in the cells: a marked increase within the first 24 hours with a substantial decrease thereafter. The presence of the PO inhibitors aminotriazole and sodium azide in the culture medium produced a suppression of prostanoid release from the monocytes comparable with that of indomethacin. The data suggest that the PO in the NE and ER of differentiating monocytes in vitro (1) is associated with arachidonic acid metabolism, and (2) is not formed by de novo protein synthesis but rather by an activation process.     

Genetic modifiers of EGFR dependence in non-small cell lung cancer

Lung adenocarcinomas harboring activating mutations in the epidermal growth factor receptor (EGFR) represent a common molecular subset of non-small cell lung cancer (NSCLC) cases. EGFR mutations predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs) and thus represent a dependency in NSCLCs harboring these alterations, but the genetic basis of EGFR dependence is not fully understood. Here, we applied an unbiased, ORF-based screen to identify genetic modifiers of EGFR dependence in EGFR-mutant NSCLC cells. This approach identified 18 kinase and kinase-related genes whose overexpression can substitute for EGFR in EGFR-dependent PC9 cells, and these genes include seven of nine Src family kinase genes, FGFR1, FGFR2, ITK, NTRK1, NTRK2, MOS, MST1R, and RAF1. A subset of these genes can complement loss of EGFR activity across multiple EGFR-dependent models. Unbiased gene-expression profiling of cells overexpressing EGFR bypass genes, together with targeted validation studies, reveals EGFR-independent activation of the MEK-ERK and phosphoinositide 3-kinase (PI3K)-AKT pathways. Combined inhibition of PI3K-mTOR and MEK restores EGFR dependence in cells expressing each of the 18 EGFR bypass genes. Together, these data uncover a broad spectrum of kinases capable of overcoming dependence on EGFR and underscore their convergence on the PI3K-AKT and MEK-ERK signaling axes in sustaining EGFR-independent survival.The term “oncogene addiction” has been used to describe the phenomenon whereby tumor cells exhibit singular reliance on an oncogene or oncogenic pathway for their survival, despite the accumulation of multiple genetic lesions (1). In non-small cell lung cancer (NSCLC), this principle is perhaps best exemplified with the finding that epidermal growth factor receptor (EGFR) mutations predict response to EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, and thus represent a dependency in the subset of tumors harboring these alterations (2–6). However, though EGFR-mutant NSCLCs typically respond dramatically to EGFR TKIs, clinical responses are not universal, even within this genetically defined cohort, with the rate of objective response estimated to be ∼71% (5, 6). Furthermore, the overwhelming majority of patients who initially respond to EGFR inhibitors ultimately develop resistance to therapy (7). A deeper understanding of the genetic underpinnings of EGFR addiction, and how EGFR-mutant cells can overcome reliance on EGFR, may improve clinical outcomes.Here, we have applied an unbiased screening approach to identify genetic modifiers of EGFR dependence in NSCLC. Mounting evidence supports the existence of several genetic modifiers of EGFR dependence in EGFR-mutant NSCLC, which can reduce the degree to which these tumors rely on EGFR and thereby contribute to EGFR TKI resistance (8). Examples include amplification of the MET receptor tyrosine kinase (RTK) (9), activation of the NF-κB pathway (8), amplification of the HER2 (ERBB2) RTK (10), amplification of the CRKL gene (11), and activation of the AXL kinase (12). Notably, MET bypass can be reciprocally achieved via EGFR activation in MET-dependent cells (13), and analogous examples of reciprocal kinase switching have been reported in other kinase-driven cancer models (14, 15). These and other findings suggest that compensatory kinase switching may be a more general way in which oncogene-dependent cancers overcome reliance on their primary driver kinase (14, 16), but the full-range of kinases capable of mediating EGFR bypass has not been systematically studied.Recent advances in large-scale functional genetic libraries have made it possible to query a wide range of genetic perturbations for their ability to modulate specific cellular phenotypes in mammalian systems (17, 18). Using the model of EGFR-mutant, erlotinib-sensitive NSCLC cells, we have performed a systematic ORF-based screen to identify kinase and kinase-related genes whose overexpression can complement loss of EGFR activity in an EGFR-dependent context. Our findings indicate broad potential for EGFR substitution in the setting of EGFR dependence, with compensatory mechanisms commonly conferring EGFR-independent activation of the PI3K-AKT and MEK-ERK signaling pathways. Importantly, this approach has recovered known mechanisms of erlotinib resistance as well as identified novel mediators of EGFR bypass in EGFR-mutant NSCLC. These data support the idea that the EGFR-dependent state can be redundantly driven by diverse genetic inputs that commonly converge on shared downstream signaling nodes.