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Brain metastases are a challenging manifestation of renal cell carcinoma. We have a limited understanding of brain metastasis tumor and immune biology, drivers of resistance to systemic treatment, and their overall poor prognosis. Current data support a multimodal treatment strategy with radiation treatment and/or surgery. Nonetheless, the optimal approach for the management of brain metastases from renal cell carcinoma remains unclear. To improve patient care, the authors sought to standardize practical management strategies. They performed an unstructured literature review and elaborated on the current management strategies through an international group of experts from different disciplines assembled via the network of the International Kidney Cancer Coalition. Experts from different disciplines were administered a survey to answer questions related to current challenges and unmet patient needs. On the basis of the integrated approach of literature review and survey study results, the authors built algorithms for the management of single and multiple brain metastases in patients with renal cell carcinoma. The literature review, consensus statements, and algorithms presented in this report can serve as a framework guiding treatment decisions for patients. CA Cancer J Clin. 2022;72:454-489.

We examine how social status-the amount of respect and admiration conferred by others-is related to leader ratings of team member voice. In a field study using 373 West Point cadets nested in 60 squads, we find that there are two countervailing pathways linking social status to leader voice ratings: A positive structural path via instrumental network centrality and a negative psychological path via perceived image risk. In addition, we show that these relationships are contingent upon a relational moderator, such that high-quality team interpersonal relationships weakened the positive indirect effect via instrumental network centrality but strengthened the negative indirect effect via image risk. Two post hoc experiments provided preliminary support for our arguments that perceived image risk causes people to deliver their voice in a manner that is more acceptable to recipients and ruled out several alternative explanations. The results of our multilevel analyses shed new light on how, why, and when social status impacts leader ratings of voice. In doing so, we challenge assumptions in the extant voice research and open avenues for future research. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Objectives To compare the treatment and posttreatment effects of Invisalign aligners that incorporated SmartForce features and attachments to traditional fixed appliances. Materials and Methods This randomized controlled trial included 66 patients, 32 aligners, and 34 fixed-appliance patients. The median ages of the aligner and braces patients were 26.7 (interquartile range [IQR]: 9.8) and 25.9 (IQR: 16.6) years, respectively. Pretreatment occlusion was assessed using the ABO Discrepancy Index. Posttreatment (T1) and 6-month retention (T2) occlusions were quantified using the ABO Objective Grading System (OGS) scores. Results The braces group finished treatment significantly (P < .001) earlier (0.4 years) than the aligner group. The median DI scores for the aligner and braces groups were 4.5 and 7.0, respectively, which was a statistically significant (P = .015), but clinically insignificant, difference. There were no statistically significant between-group differences for the total OGS scores or any of the individual component scores at debond (T1) or after 6 months of retention (T2). During the posttreatment period, alignment and overjet worsened significantly in the aligner group, while buccolingual inclinations and occlusal relations improved. Over the same period, alignment worsened in the braces group and buccolingual inclinations improved. There was no statistically significant between-group difference in posttreatment changes of the total OGS scores. Conclusions While patients with simple malocclusions require 4.8 months longer treatment times with aligners than traditional braces, the treatment and 6-month posttreatment occlusal outcomes are similar.

Undergraduate students participating in the UCLA Undergraduate Research Consortium for Functional Genomics (URCFG) have conducted a two-phased screen using RNA interference (RNAi) in combination with fluorescent reporter proteins to identify genes important for hematopoiesis in Drosophila. This screen disrupted the function of approximately 3500 genes and identified 137 candidate genes for which loss of function leads to observable changes in the hematopoietic development. Targeting RNAi to maturing, progenitor, and regulatory cell types identified key subsets that either limit or promote blood cell maturation. Bioinformatic analysis reveals gene enrichment in several previously uncharacterized areas, including RNA processing and export and vesicular trafficking. Lastly, the participation of students in this course-based undergraduate research experience (CURE) correlated with increased learning gains across several areas, as well as increased STEM retention, indicating that authentic, student-driven research in the form of a CURE represents an impactful and enriching pedagogical approach.

Current drug development efforts for the treatment of atrial fibrillation are hampered by the fact that many preclinical models have been unsuccessful in reproducing human cardiac physiology and its response to medications. In this study, we demonstrated an approach using human induced pluripotent stem cell‐derived atrial and ventricular cardiomyocytes (hiPSC‐aCMs and hiPSC‐vCMs, respectively) coupled with a sophisticated optical mapping system for drug screening of atrial‐selective compounds in vitro. We optimized differentiation of hiPSC‐aCMs by modulating the WNT and retinoid signaling pathways. Characterization of the transcriptome and proteome revealed that retinoic acid pushes the differentiation process into the atrial lineage and generated hiPSC‐aCMs. Functional characterization using optical mapping showed that hiPSC‐aCMs have shorter action potential durations and faster Ca2+ handling dynamics compared with hiPSC‐vCMs. Furthermore, pharmacological investigation of hiPSC‐aCMs captured atrial‐selective effects by displaying greater sensitivity to atrial‐selective compounds 4‐aminopyridine, AVE0118, UCL1684, and vernakalant when compared with hiPSC‐vCMs. These results established that a model system incorporating hiPSC‐aCMs combined with optical mapping is well‐suited for preclinical drug screening of novel and targeted atrial selective compounds., Chamber‐specific differentiation of hiPSC‐derived cardiomyocytes allowed for the development of an atrial cardiomyocyte‐based drug screening platform. In‐depth characterization of hiPSC‐derived atrial and ventricular cardiomyocytes revealed chamber‐specific phenotypes in molecular signatures and functional profiles. Drug screening with high‐content optical mapping system captured atrial‐selective pharmacology which demonstrated the utility of hiPSC‐derived atrial cardiomyocytes as an in vitro drug screening model.

Laminopathies are rare diseases associated with mutations in LMNA, which encodes nuclear lamin A/C. LMNA variants lead to diverse tissue-specific phenotypes including cardiomyopathy, lipodystrophy, myopathy, neuropathy, progeria, bone/skin disorders, and overlap syndromes. The mechanisms underlying these heterogeneous phenotypes remain poorly understood, although post-translational modifications, including phosphorylation, are postulated as regulators of lamin function. We catalogued all known lamin A/C human mutations and their associated phenotypes, and systematically examined the putative role of phosphorylation in laminopathies. In silico prediction of specific LMNA mutant-driven changes to lamin A phosphorylation and protein structure was performed using machine learning methods. Some of the predictions we generated were validated via assessment of ectopically expressed wild-type and mutant LMNA. Our findings indicate phenotype- and mutant-specific alterations in lamin phosphorylation, and that some changes in phosphorylation may occur independently of predicted changes in lamin protein structure. Therefore, therapeutic targeting of phosphorylation in the context of laminopathies will likely require mutant- and kinase-specific approaches.

The authors sought to identify factors that affect hospital staff's decision to pursue criminal charges against patients who assault staff on inpatient psychiatric units.Data on assaults occurring on inpatient psychiatric units in one hospital system were collected over 32 months, from November 1, 2016, to July 1, 2019. The events were grouped by whether staff pursued criminal charges after the incident. Descriptive statistics and regression models were used to describe the data and identify predictive variables.Data were reviewed from 9,654 admissions, of which 124 patient encounters involved assaults on staff. Overall, 27 (22%) of 124 assaults on staff resulted in staff pursuing criminal charges. Regression models indicated that criminal history (odds ratio [OR]=2.18, 95% CI=1.26-3.78, p=0.006), age (OR=0.92, 95% CI=0.91-0.94, p0.001), and diagnosis of chronic mental illness with psychotic symptoms (OR=7.23, 95% CI=1.49-35.04, p=0.01) predicted patient assaults resulting in contact with law enforcement. Several variables were not statistically significantly associated with filing of criminal charges, including race, gender, degree of injury from the assault, number of instances of restraint, and number of as-needed medications.This is the largest quantitative study to examine the demographic and clinical factors that may play a role in whether staff pursue criminal charges against patients on inpatient psychiatric units. The results suggest that certain patients are more likely to be reported to law enforcement. Institutions should monitor factors that increase the likelihood of assaults on staff resulting in criminal charges and create policies that mitigate discrepancies in criminal justice involvement.

Hepatocellular Carcinoma (HCC) is one of the most lethal cancers with a high mortality and recurrence rate. Circulating tumor cell (CTC) detection offers various opportunities to advance early detection and monitoring of HCC tumors which is crucial for improving patient outcome. We developed and optimized a novel Labyrinth microfluidic device to efficiently isolate CTCs from peripheral blood of HCC patients. CTCs were identified in 88.1% of the HCC patients over different tumor stages. The CTC positivity rate was significantly higher in patients with more advanced HCC stages. In addition, 71.4% of the HCC patients demonstrated CTCs positive for cancer stem cell marker, CD44, suggesting that the major population of CTCs could possess stemness properties to facilitate tumor cell survival and dissemination. Furthermore, 55% of the patients had the presence of circulating tumor microemboli (CTM) which also correlated with advanced HCC stage, indicating the association of CTM with tumor progression. Our results show effective CTC capture from HCC patients, presenting a new method for future noninvasive screening and surveillance strategies. Importantly, the detection of CTCs with stemness markers and CTM provides unique insights into the biology of CTCs and their mechanisms influencing metastasis, recurrence and therapeutic resistance.

Fundamental to the functional behavior of cardiac muscle is that the cardiomyocytes are integrated as a functional syncytium. Disrupted electrical activity in the cardiac tissue can lead to serious complications including cardiac arrhythmias. Therefore, it is important to study electrophysiological properties of the cardiac tissue. With advancements in stem cell research, protocols for the production of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been established, providing great potential in modelling cardiac arrhythmias and drug testing. The hiPSC-CM model can be used in conjunction with electrophysiology-based platforms to examine the electrical activity of the cardiac tissue. Techniques for determining the myocardial electrical activity include multielectrode arrays (MEAs), optical mapping (OM), and patch clamping. These techniques provide critical approaches to investigate cardiac electrical abnormalities that underlie arrhythmias.

Caspase-8 (CASP8) is one of the most frequently mutated genes in head and neck squamous carcinomas (HNSCCs), and CASP8 mutations are associated with poor survival. The distribution of these mutations in HNSCCs suggests that they are likely to be inactivating. Inhibition of CASP8 has been reported to sensitize cancer cells to necroptosis, a regulated cell death mechanism. Here, we show that knockdown of CASP8 renders HNSCCs susceptible to necroptosis by a second mitochondria-derived activator of caspase (SMAC) mimetic, birinapant, in combination with pan-caspase inhibitors Z-VAD-FMK or emricasan and radiation. In a syngeneic mouse model of oral cancer, birinapant, particularly when combined with radiation, delayed tumor growth and enhanced survival under CASP8 loss. Exploration of molecular underpinnings of necroptosis sensitivity confirmed that the level of functional receptor-interacting serine/threonine protein kinase 3 (RIP3) determines susceptibility to this mode of death. Although an in vitro screen revealed that low RIP3 levels rendered many HNSCC cell lines resistant to necroptosis, patient tumors maintained RIP3 expression and should therefore remain sensitive. Collectively, these results suggest that targeting the necroptosis pathway with SMAC mimetics, especially in combination with radiation, may be relevant therapeutically in HNSCC with compromised CASP8 status, provided that RIP3 function is maintained., Caspase-8 status sensitizes a murine model of head and neck squamous carcinoma to the combination of radiation and SMAC mimetic treatment through increased necroptosis.

Doxorubicin is a potent anticancer drug used to treat a variety of cancer types. However, its use is limited by doxorubicin-induced cardiotoxicity (DIC). A missense variant in the RARG gene (S427L; rs2229774) has been implicated in susceptibility to DIC in a genome wide association study. The goal of this study was to investigate the functional role of this RARG variant in DIC. We used induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) from patients treated with doxorubicin. iPSC-CMs from individuals who experienced DIC (cases) showed significantly greater sensitivity to doxorubicin compared to iPSC-CMs from doxorubicin-treated individuals who did not develop DIC (controls) in cell viability and optical mapping experiments. Using CRISPR/Cas9, we generated isogenic cell lines that differed only at the RARG locus. Genetic correction of RARG-S427L to wild type resulted in reduced doxorubicin-induced double stranded DNA breaks, reactive oxygen species production, and cell death. Conversely, introduction of RARG-S427L increased susceptibility to doxorubicin. Finally, genetic disruption of the RARG gene resulted in protection from cell death due to doxorubicin treatment. Our findings suggest that the presence of RARG-S427L increases sensitivity to DIC, establishing a direct, causal role for this variant in DIC.

Background Proton radiotherapy (PRT) may be a less toxic alternative to photon radiotherapy (XRT) for patients with head and neck squamous cell carcinoma (HNSCC). However, the molecular responses of HNSCC cells to PRT vs XRT are unclear. Methods Proteomics analyses of protein expression profiles by reverse-phase protein arrays were done for two human papillomavirus [HPV]-negative and two HPV+ cell lines. Expression patterns of 175 proteins involved in several signaling pathways were tested. Results Compared with PRT, XRT tended to induce lower expression of DNA damage repair-and cell cycle arrest-related proteins and higher expression of cell survival- and proliferation-related proteins. Conclusions Under these experimental conditions, PRT and XRT induced different protein expression and activation profiles. Further preclinical verification is needed, as are studies of tumor pathway mutations as biomarkers for choice of treatment or as radiosensitization targets to improve the response of HNSCC to PRT or XRT.

Summary: Ibrutinib (IB) is an oral Bruton's tyrosine kinase (BTK) inhibitor that has demonstrated benefit in B cell cancers, but is associated with a dramatic increase in atrial fibrillation (AF). We employed cell-specific differentiation protocols and optical mapping to investigate the effects of IB and other tyrosine kinase inhibitors (TKIs) on the voltage and calcium transients of atrial and ventricular human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs). IB demonstrated direct cell-specific effects on atrial hPSC-CMs that would be predicted to predispose to AF. Second-generation BTK inhibitors did not have the same effect. Furthermore, IB exposure was associated with differential chamber-specific regulation of a number of regulatory pathways including the receptor tyrosine kinase pathway, which may be implicated in the pathogenesis of AF. Our study is the first to demonstrate cell-type-specific toxicity in hPSC-derived atrial and ventricular cardiomyocytes, which reliably reproduces the clinical cardiotoxicity observed. : The authors employ cell-specific cardiac differentiation protocols, RNA-seq, and optical mapping to demonstrate atrial-specific toxicity of ibrutinib, a first-in-class BTK inhibitor. Other tyrosine kinase inhibitors (TKIs) with the same drug target do not affect atrial electrophysiology. Nilotinib and vandetanib, two TKIs known to be associated with QT prolongation and risk of sudden death, demonstrated ventricular-specific electrophysiologic dysregulation. Keywords: cardiac electrophysiology, tyrosine kinase inhibitors, atrial fibrillation, drug screening, optical mapping, RNA-seq

Sudden unexpected death of an infant (SUDI) is a devastating occurrence for families. To investigate the genetic pathogenesis of SUDI, we sequenced >70 genes from 191 autopsy-negative SUDI victims. Ten infants sharing a previously unknown variant in troponin I (TnI) were identified. The mutation (TNNI1 R37C/) is in the fetal/neonatal paralog of TnI, a gene thought to be expressed in the heart up to the first 24 months of life. Using phylogenetic analysis and molecular dynamics simulations, it was determined that arginine at residue 37 in TNNI1 may play a critical functional role, suggesting that the variant may be pathogenic. We investigated the biophysical properties of the TNNI1 R37C mutation in human reconstituted thin filaments (RTFs) using fluorometry. RTFs reconstituted with the mutant R37C TnI exhibited reduced Ca-binding sensitivity due to an increased Ca off-rate constant. Furthermore, we generated TNNI1 R37C/ mutants in human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) using CRISPR-Cas9. In monolayers of hiPSC-CMs, we simultaneously monitored voltage and Ca transients through optical mapping and compared them to their isogenic controls. We observed normal intrinsic beating patterns under control conditions in TNNI1 R37C/− at stimulation frequencies of 55 beats/min (bpm), but these cells showed no restitution with increased stimulation frequency to 65 bpm and exhibited alternans at >75 bpm. The WT hiPSC-CMs did not exhibit any sign of arrhythmogenicity even at stimulation frequencies of 120 bpm. The approach used in this study provides critical physiological and mechanistic bases to investigate sarcomeric mutations in the pathogenesis of SUDI., The generous support of the Canadian Institutes of Health Research (CIHR) to G.F.T. (Grant PJT-148964) and D.P.T. (Project Program FRN-CIHR: 156236) is gratefully acknowledged. The Stem Cell Network also made a significant contribution (to G.F.T.) to support this work (Grant SCN FY19CTA15). This work was undertaken, in part, thanks to funding from the Canada Research Chairs program for Tier 1 Chairs (G.F.T. and D.P.T.). D.P.T. holds the Alberta Innovates Technology Futures Strategic Chair in (Bio) Molecular Simulation. A.Y.L. holds a doctoral fellowship from the Natural Sciences and Engineering Research Council of Canada.

Metastasis contributes to poor prognosis in many types of cancer and is the leading cause of cancer-related deaths. Tumor cells metastasize to distant sites via the circulatory and lymphatic systems. In this review, we discuss the potential of circulating tumor cells for diagnosis and describe the experimental therapeutics that aim to target these disseminating cancer cells. We discuss the advantages and limitations of such strategies and how they may lead to the development of the next generation of antimetastasis treatments.

Background Photon (X-ray) radiotherapy (XRT) kills cells via DNA damage, however, how proton radiotherapy (PRT) causes cell death in head and neck squamous cell carcinoma (HNSCC) is unclear. We investigated mechanisms of HNSCC cell death after XRT versus PRT. Methods We assessed type of death in 2 human papillomavirus (HPV)-positive and two HPV-negative cell lines: necrosis and apoptosis (Annexin-V fluorescein isothiocyanate [FITC]); senescence (β-galactosidase); and mitotic catastrophe (γ-tubulin and diamidino-phenylindole [DAPI]). Results The XRT-induced or PRT-induced cellular senescence and mitotic catastrophe in all cell lines studied suggested that PRT caused cell death to a greater extent than XRT. After PRT, mitotic catastrophe peaked in HPV-negative and HPV-positive cells at 48 and 72 hours, respectively. No obvious differences were noted in the extent of cell necrosis or apoptosis after XRT versus PRT. Conclusion Under the conditions and in the cell lines reported here, mitotic catastrophe and senescence were the major types of cell death induced by XRT and PRT, and PRT may be more effective.

Since current experimental models of Atrial Fibrillation (AF) have significant limitations, we used human embryonic stem cells (hESCs) to generate an atrial-specific tissue model of AF for pharmacologic testing. We generated atrial-like cardiomyocytes (CMs) from hESCs which preferentially expressed atrial-specific genes, and had shorter action potential (AP) durations compared to ventricular-like CMs. We then generated confluent atrial-like CM sheets and interrogated them using optical mapping techniques. Atrial-like CM sheets (~1 cm in diameter) showed uniform AP propagation, and rapid re-entrant rotor patterns, as seen in AF could be induced. Anti-arrhythmic drugs were tested on single atrial-like CMs and cell sheets. Flecainide profoundly slowed upstroke velocity without affecting AP duration, leading to reduced conduction velocities (CVs), curvatures and cycle lengths of rotors, consistent with increased rotor organization and expansion. By contrast, consistent with block of rapid delayed rectifier K+ currents (Ikr) and AP prolongation in isolated atrial-like CMs, dofetilide prolonged APs and reduced cycle lengths of rotors in cell sheets without affecting CV. In conclusion, using our hESC-derived atrial CM preparations, we demonstrate that flecainide and dofetilide modulate reentrant arrhythmogenic rotor activation patterns in a manner that helps explain their efficacy in treating and preventing AF.

Summary We present "Labyrinth," a label-free microfluidic device to isolate circulating tumor cells (CTCs) using the combination of long loops and sharp corners to focus both CTCs and white blood cells (WBCs) at a high throughput of 2.5 mL/min. The high yield (>90%) and purity (600 WBCs/mL) of Labyrinth enabled us to profile gene expression in CTCs. As proof of principle, we used previously established cancer stem cell gene signatures to profile single cells isolated from the blood of breast cancer patients. We observed heterogeneous subpopulations of CTCs expressing genes for stem cells, epithelial cells, mesenchymal cells, and cells transitioning between epithelial and mesenchymal. Labyrinth offers a cell-surface marker-independent single-cell isolation platform to study heterogeneous CTC subpopulations.

Zebrafish (Danio rerio) are widely used as vertebrate model in developmental genetics and functional genomics as well as in cardiac structure-function studies. The zebrafish heart has been increasingly used as a model of human cardiac function, in part, due to the similarities in heart rate and action potential duration and morphology with respect to humans. The teleostian zebrafish is in many ways a compelling model of human cardiac function due to the clarity afforded by its ease of genetic manipulation, the wealth of developmental biological information, and inherent suitability to a variety of experimental techniques. However, in addition to the numerous advantages of the zebrafish system are also caveats related to gene duplication (resulting in paralogs not present in human or other mammals) and fundamental differences in how zebrafish hearts function. In this review, we discuss the use of zebrafish as a cardiac function model through the use of techniques such as echocardiography, optical mapping, electrocardiography, molecular investigations of excitation-contraction coupling, and their physiological implications relative to that of the human heart. While some of these techniques (e.g., echocardiography) are particularly challenging in the zebrafish because of diminutive size of the heart (~1.5 mm in diameter) critical information can be derived from these approaches and are discussed in detail in this article.

Study Design. Prospective, randomized trial. Objective. To assess the in vivo kinematics of the cervical spine after cervical fusion and arthroplasty. Summary of Background Data. Compared with spinal fusion, disc replacement may impede the development of adjacent segment disease. To achieve this goal, any arthroplasty device should achieve desired spinal alignment while maintaining physiologic spinal motion at both the operated and surrounding motion segments. Methods. As part of a multicenter, prospective, randomized Food and Drug Administration IDE clinical evaluation of the porous coated motion artificial cervical disc, patients underwent either a single-level total disc replacement (TDR; 272 patients) or anterior cervical discectomy and fusion (ACDF; 182 patients) for treatment of cervical radiculopathy or myelopathy. Neutral, flexion, and extension radiographs of the cervical spine obtained before surgery, and at 3, 6, and 12 months after surgery were assessed. Quantitative assessments and comparisons of motion patterns were produced using validated computer-assisted methods. Kinematic parameters, including segmental rotation, translation, center of rotation (COR), disc height, and disc angle were calculated. Results. Cervical TDR preserved angular motion at the operated level, although the range was reduced from 8.0° before surgery to 6.2° at 12 months after surgery (P < 0.001). Significantly after TDR, adjacent-level angular motion was unchanged. In patients treated with fusion, angular motion at the superior adjacent level increased from 9.6° before surgery to 11.0° (P = 0.003) at 12 months, with a trend toward increased postoperative translation (P = 0.07). For the TDR group, the horizontal COR averaged 0.8 mm posterior to the disc center before surgery and 0.2 mm anterior to the center at 12 months after TDR (P < 0.001), and the vertical COR averaged 2.5 mm below the endplate before surgery and 4.0 mm below at 12 months (P = 0.001). COR at the adjacent levels was unaltered by fusion or TDR. Lordotic alignment and disc height at the index level increased after intervention in both groups. Conclusion.TDR with the porous coated motion implant is able to restore and maintain lordotic alignment and disc height and maintain angular motion while allowing for similar translation to that seen before surgery. In contrast, after ACDF, the superior adjacent level developed increased angular motion compared with preoperative range of motion. This study provides in vivo data regarding the functioning of TDR and ACDF and their impact on adjacent-level kinematics.

A cadaveric study.To define the relationship of the lumbar exiting nerve root and trunks within the psoas muscle with reference to the radiographic center of the intervertebral disc, the recommended disc access point for the minimally invasive lateral transpsoas approach.The transpsoas approach to the lumbar intervertebral body disc is a minimally invasive approach used for interbody fusion. This approach carries the potential risk of injury to the intrapsoas nerves. There are no published studies investigating the locations of the intrapsoas neural elements with reference to the transpsoas access corridor developed during minimally invasive lateral approaches to the disc.Ten human cadaveric specimens were analyzed. A guide wire was placed in each disc space center under lateral fluoroscopic guidance as has been recommended for disc access in the transpsoas fusion technique. Using calipers, the distances from the exiting nerve and trunk to the wire were measured.In general, the nerve trunk was a mean of 14 mm posterior to the center of the disc and was a mean of 5 mm closer to the center of the disc than the exited nerve. The trunks were closer to the center of the disc caudally in the lumbar spine, with the distance ranging from a mean of 16.4 mm at L2-3 to 10.6 mm at the L4-5 level. The intrapsoas location of the exited nerve was less variable and was greater than 15 mm from the projected center of the disc. At L4-5, the trunk approximated the center of the disc in 15% of specimens.This study suggests that the intrapsoas nerves are a safe distance from the radiographic center of the intervertebral disc in a majority of cases; however, anatomic variations in the location of these nerves place them at injury risk in a small number of cases. These results suggest that neural monitoring whereas traversing the psoas may be important to enhance the safety of the transpsoas approach. Care is particularly warranted at the L4-5 level.

Highly rearranged and mutated cancer genomes present major challenges in the identification of pathogenetic events driving the neoplastic transformation process. Here we engineered lymphoma-prone mice with chromosomal instability to assess the usefulness of mouse models in cancer gene discovery and the extent of cross-species overlap in cancer-associated copy number aberrations. Along with targeted re-sequencing, our comparative oncogenomic studies identified FBXW7 and PTEN to be commonly deleted both in murine lymphomas and in human T-cell acute lymphoblastic leukaemia/lymphoma (T-ALL). The murine cancers acquire widespread recurrent amplifications and deletions targeting loci syntenic to those not only in human T-ALL but also in diverse human haematopoietic, mesenchymal and epithelial tumours. These results indicate that murine and human tumours experience common biological processes driven by orthologous genetic events in their malignant evolution. The highly concordant nature of genomic events encourages the use of genomically unstable murine cancer models in the discovery of biological driver events in the human oncogenome.

Many neurons in the dorsal and ventral visual stream have the property that after a brief visual stimulus presentation in their receptive field, the spiking activity in these neurons persists above their baseline levels for several seconds. This maintained activity is not always correlated with the monkey’s task and its origin is unknown. We have previously proposed a simple neural network model, based on shape selective neurons in monkey lateral intraparietal cortex, which predicts the valence and time course of reflexive (bottom-up) spatial attention. In the same simple model, we demonstrate here that passive maintained activity or short-term memory of specific visual events can result without need for an external or top-down modulatory signal. Mutual inhibition and neuronal adaptation play distinct roles in reflexive attention and memory. This modest 4-cell model provides the first simple and unified physiologically plausible mechanism of reflexive spatial attention and passive short-term memory processes.

Background context Several methods to sterilize allograft bone exist, including gamma irradiation and freeze-drying, which can alter the mechanical properties of the graft. Efforts are under way to develop a method for processing osseous allograft that maintains structural integrity. Herein is presented one such method. Purpose To analyze the mechanical properties, compared with nontreated controls, of a novel sterilization process for allograft cortical bone. Study design/setting A controlled biomechanical evaluation of allograft bone under various types of loading after a novel sterilization treatment. Patient sample Not applicable; basic science. Outcome measures The load to failure was recorded for both the study and control groups, and statistical analysis of these results was performed. Significance level (α) and power (β) were set to 0.05 and 0.90, respectively. Single-factor analysis of variance (ANOVA) was used to detect significant differences between the treated and untreated groups. A post-experimental power analysis was performed for each of the response variables. Methods Cortical tibia and femur samples from seven cadaveric donors (mean age 68.7 years) were treated with Biocleanse and compared with untreated samples with regard to density and strength. All samples were loaded to failure under diametral and biaxial compression, shear, and three-point bending. Results Statistical analysis was done on the density and failure stress for all modes of loading. ANOVA did not indicate a significant (p>.05) effect of treatment on the density except for the axial and biaxial specimens (p .05) between cortical bone treated with Biocleanse and untreated specimens under all four types of mechanical loading. Post-experimental power analysis revealed power to be greater than 0.9 for each test. Conclusions Sterilization of allograft bone with Biocleanse does not significantly alter the mechanical properties when compared with untreated samples. The effect of this sterilization process on the osteoconductive and osteoinductive properties of allograft bone must be determined.

Event-related brain potentials (ERPs) were elicited with auditory stimuli from normal subjects every 10 min. for 10 successive trial blocks to assess ultradian influences on the P300 component. Based on a theoretical analysis of the underlying relationship between background EEG activity and P300 variability, subjects were divided into two groups according to whether P300 amplitude increased or decreased initially over trial blocks. P300 amplitude habituated across trial blocks. P300 latency produced systematic cyclical variation with approximately a 90-min period that was opposite in phase for the different subject groups. The findings suggest that ultradian rhythms contribute to P300 latency variability. The implications o the results for P300 in applied settings are discussed.

Acute lung injury and acute respiratory distress syndrome have been reported in a significant proportion of patients with critical neurologic illness. Our aim was to identify risk factors for acute lung injury/acute respiratory distress syndrome in this population.Prospective, observational study.A 22-bed, adult neurosciences critical care unit at a tertiary care hospital.Primary neurologic disorder, mechanical ventilation48 hrs.None.A total of 192 patients were enrolled with a range of neurologic disorders. Among these, 68 (35%) were diagnosed with acute lung injury/acute respiratory distress syndrome. In a multivariate logistic regression analysis, independent risk factors for acute lung injury/acute respiratory distress syndrome were pneumonia (odds ratio [95% confidence interval] 3.12 [1.5-6.0], p = .002), circulatory shock (2.2 [1.07-4.57], p = .03), and absence of a gag or cough reflex (3.41 [1.34-8.68], p = .01). Neither neurologic diagnosis nor neurologic severity, assessed with the Glasgow Coma Scale, was significantly associated with the development of acute lung injury/acute respiratory distress syndrome.Acute lung injury/acute respiratory distress syndrome occurred in more than one third of mechanically ventilated neurosciences critical care unit patients. Loss of the cough or gag reflex is strongly predictive of acute lung injury/acute respiratory distress syndrome, while neurologic diagnosis and Glasgow Coma Scale are not. Lower brainstem dysfunction, a clinical marker of neurologic injury not captured by the Glasgow Coma Scale, is a risk factor for acute lung injury/acute respiratory distress syndrome and could inform decisions regarding airway protection and mechanical ventilation.

The Na+/Ca2+ exchanger (NCX) is increasingly recognized as a physiological mediator of Ca2+ influx and significantly contributes to salt-sensitive hypertension. We recently reported that Ca2+ influx by the NCX (1) is the primary mechanism of Ca2+ entry in purinergically stimulated rat aorta smooth muscle cells and (2) requires functional coupling with transient receptor potential channel 6 nonselective cation channels. Using the Na+ indicator CoroNa Green, we now directly observed and characterized the localized cytosolic [Na+] ([Na+]i) elevations that have long been hypothesized to underlie physiological NCX reversal but that have never been directly shown. Stimulation of rat aorta smooth muscle cells caused both global and monotonic [Na+]i elevations and localized [Na+]i transients (LNats) at the cell periphery. Inhibition of nonselective cation channels with SKF-96365 (50 micromol/L) and 2-amino-4-phosphonobutyrate (75 micromol/L) reduced both global and localized [Na+]i elevations in response to ATP (1 mmol/L). This effect was mimicked by expression of a dominant negative construct of transient receptor potential channel 6. Selective inhibition of NCX-mediated Ca2+ entry with KB-R7943 (10 micromol/L) enhanced the LNats, whereas the global cytosolic [Na+] signal was unaffected. Inhibition of mitochondrial Na+ uptake with CGP-37157 (10 micromol/L) increased both LNats and global cytosolic [Na+] elevations. These findings directly demonstrate NCX regulation by LNats, which are restricted to subsarcolemmal, cytoplasmic microdomains. Analysis of the LNats, which facilitate Ca2+ entry via NCX, suggests that mitochondria limit the cytosolic diffusion of LNats generated by agonist-mediated activation of transient receptor potential channel 6-containing channels.

Animal studies suggest that increased circulating estrogen and progesterone, and activation of the endorphin system cause prenancy-induced antinociceptive effects. Human studies have provided inconsistent results and have often lacked a nonpregnant control group. In this study, we compared sensitivity to experimental heat and cold pain in pregnant and nonpregnant women. Nineteen healthy nonpregnant female volunteers and 20 pregnant women at term were enrolled. Pain threshold and tolerance were examined using experimental heat-induced pain and cold pressor pain models. Subjects were evaluated pre- and 1-2 days post-delivery (pregnant), or on consecutive days (nonpregnant). Heat pain tolerance was significantly increased in the pregnant women during pre and postdelivery when compared with nonpregnant controls (50.0 +/- 1.0 vs 49.0 +/- 1.2 and 50.1 +/- 0.7 vs 49.2 +/- 1.2 degrees C; mean +/- sd). However, pain induced by the cold pressor test was endured for a similar amount of time by both study groups. Pregnancy-induced analgesic effects at term can be detected in a model of experimental heat pain. These effects persist during the first 24-48 h after delivery. Experimental heat pain is a suitable modality for further characterizing the phenomenon of pregnancy-induced analgesia in humans.

Cervical disc herniations are a common cause of radicular pain from nerve root impingement and may necessitate surgical decompression to alleviate symptoms. The use of cervical epidural injections has not been studied in detail. The objective of this retrospective study was to examine the efficacy of cervical epidural steroid injections for the treatment of symptomatic herniated cervical discs.Patients with herniated cervical discs without myelopathy that had failed conservative management and were otherwise surgical candidates were offered a trial of cervical epidural injections. The results and benefits of the injections were examined as well as the incidence of proceeding to surgical intervention.Of the 70 treated patients, 44 (63%) had significant relief of their symptoms and did not wish to proceed with surgical treatment. Of the 26 patients who underwent surgical decompression, 92% had successful resolution of their symptoms. The nonsurgical and surgical groups were similar in terms of gender, preinjection symptoms, or number of injections. However, significant differences between the two groups were found with regard to age (P0.05) and time from initial consultation to initial injection (P0.05). With an average of 13-month follow-up, 45 (65.3%) patients reported a good/excellent result per Odom criteria. In addition, 53 (75%) would attempt cervical epidural steroid injections again in the future. No complications were noted in our series.Cervical epidural injections are a reasonable part of the nonoperative treatment of patients with symptomatic cervical disc herniations. The success rates appear to be very similar to prior studies of lumbar epidural injections for symptomatic lumbar disc herniations. It appears that a large percentage of the patients may obtain relief from radicular symptoms and avoid surgery for the follow-up period up to 1 year. In addition, patients older than 50 years and those who received the injections earlier, less than 100 days from diagnosis, seemed to have a more favorable outcome.

Epidural steroid injections are widely used as part of the conservative care for symptomatic herniated lumbar discs. There are studies showing their effectiveness, and some studies demonstrating no clinical benefits. The purpose of this study was to evaluate the effectiveness of epidural steroid injections for patients with symptomatic lumbar disc herniations who were surgical candidates. Sixty-nine patients were diagnosed with a herniated disc in the lumbar spine and remained symptomatic despite conservative care, and were treated with an epidural injection in an attempt to avoid surgical discectomy. Of the total group of 69 patients (average age = 44.8 years, range 19-77 years, average follow-up = 1.5 years), 53 (77%) had successful resolution or significant decrease of their symptoms and were able to avoid surgery. Only 16 (23%) patients failed to have significant relief of their symptoms and required surgical treatment of their herniated disc. Epidural steroid injections have a reasonable success rate for the alleviation of radicular symptoms from lumbar herniated discs for up to twelve to twenty-seven months. Patients treated with injections may be able to avoid surgical treatment up to this period and perhaps even longer.

A method for target sequence enrichment from the human genome is described. This hybridization-based approach using oligonucleotide probes in solution has excellent sensitivity and accuracy for calling SNPs, To exploit fully the potential of current sequencing technologies for population-based studies, one must enrich for loci from the human genome. Here we evaluate the hybridization-based approach by using oligonucleotide capture probes in solution to enrich for approximately 3.9 Mb of sequence target. We demonstrate that the tiling probe frequency is important for generating sequence data with high uniform coverage of targets. We obtained 93% sensitivity to detect SNPs, with a calling accuracy greater than 99%.