Publications by authors named "Caleb Davis"

21 Publications

  • Page 1 of 1

Noncontingent reinforcement: Arbitrary versus maintaining reinforcers for escape-maintained problem behavior.

J Appl Behav Anal 2021 Mar 5. Epub 2021 Mar 5.

Perkins School for the Blind.

Noncontingent reinforcement (NCR) involves the delivery of maintaining reinforcers on a time-dependent schedule and often includes extinction. However, arbitrary reinforcers may be equally efficacious during NCR without extinction for treating escape-maintained problem behavior. The purpose of this study was to extend previous research on NCR by evaluating the relative efficacy of NCR without extinction and comparing maintaining versus arbitrary reinforcers for 4 individuals with escape-maintained problem behavior. Two different NCR conditions, NCR using the maintaining reinforcer (escape) and NCR using an arbitrary reinforcer (an edible), were evaluated using multielement and reversal designs. Treatment effects varied across participants. Results for 2 participants showed a reduction in problem behavior during NCR without extinction with both the arbitrary and maintaining reinforcers. For 1 participant, results showed a reduction in problem behavior with both the arbitrary and maintaining reinforcers only when extinction was added to NCR. For the 4th participant, the maintaining reinforcer was effective during NCR without extinction, but the arbitrary reinforcer was ineffective.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jaba.821DOI Listing
March 2021

Intra-articular Fracture Pattern in Intercondylar Distal Femur Fractures: An Analysis of Frequency and Major Fracture Fragments.

Injury 2021 Apr 28;52(4):967-970. Epub 2020 Nov 28.

University Of Louisville Department of Orthopaedic Surgery 550 S. Jackson St., 1st Floor ACB building Louisville, KY 40202. Electronic address:

Introduction: The treatment of intercondylar distal femur fractures requires anatomic reduction of intra-articular fragments and absolute fixation. Preoperative planning is necessary to understand fracture morphology. All fracture lines need to be recognized as the primary implant may not capture all articular fragments, mainly when coronal plane fractures are present. Oftentimes, independent interfragmentary compression screws are necessary. No recent studies have visually mapped out the distal femur articular fracture fragments necessary for absolute fixation. The objectives of this study are to determine the frequency of coronal plane fractures in intercondylar distal femur fractures and describe the pattern of intra-articular fracture fragments.

Materials And Methods: The hospital's trauma registry was queried for distal femur ORIF CPT codes logged in the past four years. A retrospective chart review was performed using the EMR and CT scans. Demographics and mechanisms of injury were analyzed. Fracture fragments were surveyed and drawn out by hand on a template for easy organization. Patients' fractures were categorized into the following groups: fractures with no intra-articular coronal plane fractures, those with medial coronal fractures, those with lateral coronal fractures, or those with both medial and lateral coronal fractures. Major fracture fragments were identified.

Results: A total of 55 patients were included. 26 patients (47%) were found to have no intra-articular coronal plane fractures; 6 patients (11%) were found to have medial coronal plane fractures; 15 patients (27%) were found to have lateral coronal plane fractures, and 8 patients (15%) had medial and lateral coronal plane fractures. Collectively, intra-articular coronal plane fractures were identified in 29 patients (53%) with intercondylar distal femur fractures. Four major fracture fragments along with intercondylar and condylar comminution sites were identified.

Discussion: Distal femur intra-articular coronal plane fractures can yield large anterior and posterior condylar fracture fragments of either the medial condyle, lateral condyle, or both condyles. Coronal plane fracture fragments must be identified to obtain absolute fixation. Our study found a higher coronal plane fracture line frequency (52.7%) than prior commonly cited studies. Surgeons must be on the lookout for anterior fracture fragments, posterior fracture fragments, and articular comminution when treating intercondylar femur fractures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.injury.2020.11.061DOI Listing
April 2021

Surgical Options and Approaches for Septic Arthritis of the Native Hip and Knee Joint.

J Arthroplasty 2020 03;35(3S):S14-S18

Department of Orthopedic Surgery, University of Louisville, Louisville, Kentucky 40292.

Septic arthritis (SA) of the adult knee and hip is a constantly evolving and urgent surgical issue. The epidemiology has shifted over the last few decades as have the most popular antibiotics and surgical treatments. SA of all types is increasing in the United States. There remains a high variability in the conservative and surgical management options available. This review will outline the most current understanding of the etiology and epidemiology of SA and will also discuss the distribution of causative organisms and appropriate treatments for each. A summary of evidence for different debridement and reconstructive techniques will also be presented in addition to novel areas of research to decrease the morbidity of this constantly growing problem.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.arth.2019.10.062DOI Listing
March 2020

Flexor Tenosynovectomy for Recurrent Carpal Tunnel Syndrome: A Retrospective Case Series of 108 Hands.

Hand (N Y) 2021 Jan 2;16(1):18-24. Epub 2019 Apr 2.

The University of Tennessee College of Medicine, Chattanooga, USA.

The etiology of recurrent carpal tunnel syndrome (CTS) is unclear, and outcomes following secondary surgery in this demographic have been poorer than primary surgery. Fibrosis and hypertrophy have been identified in the flexor tenosynovium in these patients. The authors use flexor tenosynovectomy (FTS) for recurrent CTS after primary carpal tunnel release and present a review of these patients. A retrospective chart review was performed of 108 cases of FTS for recurrent CTS from 1995 to 2015 by 4 attending surgeons at one institution. Demographic information, symptoms, and outcomes were among the data recorded. A phone survey was conducted on available patients where the shortened version of the Disabilities of the Arm, Shoulder and Hand Questionnaire (QuickDASH) and satisfaction were assessed. Average office follow-up was 12 months. Average age was 57.5 years. A total of 104 (96%) reported symptom improvement and 48 (44%) reported complete symptom resolution. Forty patients were available for long-term follow-up at an average 6.75 years postoperatively via phone interview. Average QuickDASH score was 31.2 in these patients. Thirty-six (90%) of 40 patients were initially satisfied at last office visit, and 31 (78%) of 40 were satisfied at average 6.9 years, a maintenance of satisfaction of 86%. Satisfied patients were older (58 years) than unsatisfied patients (51 years). Both long-term satisfaction and QuickDASH scores in our cohort are consistent with or better than published results from nerve-shielding procedures. The authors believe a decrease in both carpal tunnel volume and potential adhesions of fibrotic or inflammatory synovium contributes to the benefits of this procedure. This remains our procedure of choice for recurrent CTS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1558944719840735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818022PMC
January 2021

Trampoline-Related Injuries: A Comparison of Injuries Sustained at Commercial Jump Parks Versus Domestic Home Trampolines.

J Am Acad Orthop Surg 2019 Jan;27(1):23-31

From the Department of Orthopaedic Surgery, University of Tennessee College of Medicine Chattanooga, Chattanooga, TN (Dr. Doty, Dr. Voskuil, Ms. Swafford, Dr. Gardner, Dr. Kiner, and Dr. Nowotarski), and University of Tennessee Health Science Center, Memphis, TN (Dr. Davis).

Introduction: The nature of trampoline injuries may have changed with the increasing popularity of recreational jump parks.

Methods: A retrospective review was performed evaluating domestic trampoline and commercial jump park injuries over a 2-year period.

Results: There were 439 trampoline injuries: 150 (34%) at jump parks versus 289 (66%) on home trampolines. Fractures and dislocations accounted for 55% of jump park injuries versus 44% of home trampoline injuries. In adults, fractures and dislocations accounted for 45% of jump park injuries versus 17% of home trampoline injuries. More lower extremity fractures were seen at jump parks versus home trampolines in both children and adults. Adults had a 23% surgical rate with jump park injuries versus a 10% surgical rate on home trampolines.

Discussion: Trampoline-related injury distribution included a higher percentage of fractures/dislocations, lower extremity fractures, fractures in adults, and surgical interventions associated with jump parks versus home trampolines.

Level Of Evidence: Level III.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5435/JAAOS-D-17-00470DOI Listing
January 2019

Somatic cancer variant curation and harmonization through consensus minimum variant level data.

Genome Med 2016 11 4;8(1):117. Epub 2016 Nov 4.

Innovation Center for Biomedical Informatics and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.

Background: To truly achieve personalized medicine in oncology, it is critical to catalog and curate cancer sequence variants for their clinical relevance. The Somatic Working Group (WG) of the Clinical Genome Resource (ClinGen), in cooperation with ClinVar and multiple cancer variant curation stakeholders, has developed a consensus set of minimal variant level data (MVLD). MVLD is a framework of standardized data elements to curate cancer variants for clinical utility. With implementation of MVLD standards, and in a working partnership with ClinVar, we aim to streamline the somatic variant curation efforts in the community and reduce redundancy and time burden for the interpretation of cancer variants in clinical practice.

Methods: We developed MVLD through a consensus approach by i) reviewing clinical actionability interpretations from institutions participating in the WG, ii) conducting extensive literature search of clinical somatic interpretation schemas, and iii) survey of cancer variant web portals. A forthcoming guideline on cancer variant interpretation, from the Association of Molecular Pathology (AMP), can be incorporated into MVLD.

Results: Along with harmonizing standardized terminology for allele interpretive and descriptive fields that are collected by many databases, the MVLD includes unique fields for cancer variants such as Biomarker Class, Therapeutic Context and Effect. In addition, MVLD includes recommendations for controlled semantics and ontologies. The Somatic WG is collaborating with ClinVar to evaluate MVLD use for somatic variant submissions. ClinVar is an open and centralized repository where sequencing laboratories can report summary-level variant data with clinical significance, and ClinVar accepts cancer variant data.

Conclusions: We expect the use of the MVLD to streamline clinical interpretation of cancer variants, enhance interoperability among multiple redundant curation efforts, and increase submission of somatic variants to ClinVar, all of which will enhance translation to clinical oncology practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13073-016-0367-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5095986PMC
November 2016

SV-STAT accurately detects structural variation via alignment to reference-based assemblies.

Source Code Biol Med 2016 18;11. Epub 2016 Jun 18.

Structural and Computational Biology and Molecular Biophysics (SCBMB) Program, Baylor College of Medicine, Houston, TX 77030 USA ; Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX 77030 USA ; W. M. Keck Center for Interdisciplinary Bioscience Training, Houston, TX 77005 USA.

Background: Genomic deletions, inversions, and other rearrangements known collectively as structural variations (SVs) are implicated in many human disorders. Technologies for sequencing DNA provide a potentially rich source of information in which to detect breakpoints of structural variations at base-pair resolution. However, accurate prediction of SVs remains challenging, and existing informatics tools predict rearrangements with significant rates of false positives or negatives.

Results: To address this challenge, we developed 'Structural Variation detection by STAck and Tail' (SV-STAT) which implements a novel scoring metric. The software uses this statistic to quantify evidence for structural variation in genomic regions suspected of harboring rearrangements. To demonstrate SV-STAT, we used targeted and genome-wide approaches. First, we applied a custom capture array followed by Roche/454 and SV-STAT to three pediatric B-lineage acute lymphoblastic leukemias, identifying five structural variations joining known and novel breakpoint regions. Next, we detected SVs genome-wide in paired-end Illumina data collected from additional tumor samples. SV-STAT showed predictive accuracy as high as or higher than leading alternatives. The software is freely available under the terms of the GNU General Public License version 3 at https://gitorious.org/svstat/svstat.

Conclusions: SV-STAT works across multiple sequencing chemistries, paired and single-end technologies, targeted or whole-genome strategies, and it complements existing SV-detection software. The method is a significant advance towards accurate detection and genotyping of genomic rearrangements from DNA sequencing data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13029-016-0051-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4913042PMC
June 2016

Focused Analysis of Exome Sequencing Data for Rare Germline Mutations in Familial and Sporadic Lung Cancer.

J Thorac Oncol 2016 Jan;11(1):52-61

Baylor College of Medicine, Houston, TX, USA. Electronic address:

Introduction: The association between smoking-induced chronic obstructive pulmonary disease (COPD) and lung cancer (LC) is well documented. Recent genome-wide association studies (GWAS) have identified 28 susceptibility loci for LC, 10 for COPD, 32 for smoking behavior, and 63 for pulmonary function, totaling 107 nonoverlapping loci. Given that common variants have been found to be associated with LC in genome-wide association studies, exome sequencing of these high-priority regions has great potential to identify novel rare causal variants.

Methods: To search for disease-causing rare germline mutations, we used a variation of the extreme phenotype approach to select 48 patients with sporadic LC who reported histories of heavy smoking-37 of whom also exhibited carefully documented severe COPD (in whom smoking is considered the overwhelming determinant)-and 54 unique familial LC cases from families with at least three first-degree relatives with LC (who are likely enriched for genomic effects).

Results: By focusing on exome profiles of the 107 target loci, we identified two key rare mutations. A heterozygous p.Arg696Cys variant in the coiled-coil domain containing 147 (CCDC147) gene at 10q25.1 was identified in one sporadic and two familial cases. The minor allele frequency (MAF) of this variant in the 1000 Genomes database is 0.0026. The p.Val26Met variant in the dopamine β-hydroxylase (DBH) gene at 9q34.2 was identified in two sporadic cases; the minor allele frequency of this mutation is 0.0034 according to the 1000 Genomes database. We also observed three suggestive rare mutations on 15q25.1: iron-responsive element binding protein neuronal 2 (IREB2); cholinergic receptor, nicotinic, alpha 5 (neuronal) (CHRNA5); and cholinergic receptor, nicotinic, beta 4 (CHRNB4).

Conclusions: Our results demonstrated highly disruptive risk-conferring CCDC147 and DBH mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtho.2015.09.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4714038PMC
January 2016

Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma.

N Engl J Med 2016 Jan 4;374(2):135-45. Epub 2015 Nov 4.

Background: Papillary renal-cell carcinoma, which accounts for 15 to 20% of renal-cell carcinomas, is a heterogeneous disease that consists of various types of renal cancer, including tumors with indolent, multifocal presentation and solitary tumors with an aggressive, highly lethal phenotype. Little is known about the genetic basis of sporadic papillary renal-cell carcinoma, and no effective forms of therapy for advanced disease exist.

Methods: We performed comprehensive molecular characterization of 161 primary papillary renal-cell carcinomas, using whole-exome sequencing, copy-number analysis, messenger RNA and microRNA sequencing, DNA-methylation analysis, and proteomic analysis.

Results: Type 1 and type 2 papillary renal-cell carcinomas were shown to be different types of renal cancer characterized by specific genetic alterations, with type 2 further classified into three individual subgroups on the basis of molecular differences associated with patient survival. Type 1 tumors were associated with MET alterations, whereas type 2 tumors were characterized by CDKN2A silencing, SETD2 mutations, TFE3 fusions, and increased expression of the NRF2-antioxidant response element (ARE) pathway. A CpG island methylator phenotype (CIMP) was observed in a distinct subgroup of type 2 papillary renal-cell carcinomas that was characterized by poor survival and mutation of the gene encoding fumarate hydratase (FH).

Conclusions: Type 1 and type 2 papillary renal-cell carcinomas were shown to be clinically and biologically distinct. Alterations in the MET pathway were associated with type 1, and activation of the NRF2-ARE pathway was associated with type 2; CDKN2A loss and CIMP in type 2 conveyed a poor prognosis. Furthermore, type 2 papillary renal-cell carcinoma consisted of at least three subtypes based on molecular and phenotypic features. (Funded by the National Institutes of Health.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa1505917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4775252PMC
January 2016

Assessing structural variation in a personal genome-towards a human reference diploid genome.

BMC Genomics 2015 Apr 11;16:286. Epub 2015 Apr 11.

Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA.

Background: Characterizing large genomic variants is essential to expanding the research and clinical applications of genome sequencing. While multiple data types and methods are available to detect these structural variants (SVs), they remain less characterized than smaller variants because of SV diversity, complexity, and size. These challenges are exacerbated by the experimental and computational demands of SV analysis. Here, we characterize the SV content of a personal genome with Parliament, a publicly available consensus SV-calling infrastructure that merges multiple data types and SV detection methods.

Results: We demonstrate Parliament's efficacy via integrated analyses of data from whole-genome array comparative genomic hybridization, short-read next-generation sequencing, long-read (Pacific BioSciences RSII), long-insert (Illumina Nextera), and whole-genome architecture (BioNano Irys) data from the personal genome of a single subject (HS1011). From this genome, Parliament identified 31,007 genomic loci between 100 bp and 1 Mbp that are inconsistent with the hg19 reference assembly. Of these loci, 9,777 are supported as putative SVs by hybrid local assembly, long-read PacBio data, or multi-source heuristics. These SVs span 59 Mbp of the reference genome (1.8%) and include 3,801 events identified only with long-read data. The HS1011 data and complete Parliament infrastructure, including a BAM-to-SV workflow, are available on the cloud-based service DNAnexus.

Conclusions: HS1011 SV analysis reveals the limits and advantages of multiple sequencing technologies, specifically the impact of long-read SV discovery. With the full Parliament infrastructure, the HS1011 data constitute a public resource for novel SV discovery, software calibration, and personal genome structural variation analysis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12864-015-1479-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4490614PMC
April 2015

Identifying gene disruptions in novel balanced de novo constitutional translocations in childhood cancer patients by whole-genome sequencing.

Genet Med 2015 Oct 8;17(10):831-5. Epub 2015 Jan 8.

Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.

Purpose: We applied whole-genome sequencing (WGS) to children diagnosed with neoplasms and found to carry apparently balanced constitutional translocations to discover novel genic disruptions.

Methods: We applied the structural variation (SV) calling programs CREST, BreakDancer, SV-STAT, and CGAP-CNV, and we developed an annotative filtering strategy to achieve nucleotide resolution at the translocations.

Results: We identified the breakpoints for t(6;12)(p21.1;q24.31), disrupting HNF1A in a patient diagnosed with hepatic adenomas and maturity-onset diabetes of the young (MODY). Translocation as the disruptive event of HNF1A, a gene known to be involved in MODY3, has not been previously reported. In a subject with Hodgkin lymphoma and subsequent low-grade glioma, we identified t(5;18)(q35.1;q21.2), disrupting both SLIT3 and DCC, genes previously implicated in both glioma and lymphoma.

Conclusion: These examples suggest that implementing clinical WGS in the diagnostic workup of patients with novel but apparently balanced translocations may reveal unanticipated disruption of disease-associated genes and aid in prediction of the clinical phenotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/gim.2014.189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496310PMC
October 2015

Device-based in vitro techniques for mechanical stimulation of vascular cells: a review.

J Biomech Eng 2015 Apr 5;137(4):040801. Epub 2015 Feb 5.

The most common cause of death in the developed world is cardiovascular disease. For decades, this has provided a powerful motivation to study the effects of mechanical forces on vascular cells in a controlled setting, since these cells have been implicated in the development of disease. Early efforts in the 1970 s included the first use of a parallel-plate flow system to apply shear stress to endothelial cells (ECs) and the development of uniaxial substrate stretching techniques (Krueger et al., 1971, "An in Vitro Study of Flow Response by Cells," J. Biomech., 4(1), pp. 31-36 and Meikle et al., 1979, "Rabbit Cranial Sutures in Vitro: A New Experimental Model for Studying the Response of Fibrous Joints to Mechanical Stress," Calcif. Tissue Int., 28(2), pp. 13-144). Since then, a multitude of in vitro devices have been designed and developed for mechanical stimulation of vascular cells and tissues in an effort to better understand their response to in vivo physiologic mechanical conditions. This article reviews the functional attributes of mechanical bioreactors developed in the 21st century, including their major advantages and disadvantages. Each of these systems has been categorized in terms of their primary loading modality: fluid shear stress (FSS), substrate distention, combined distention and fluid shear, or other applied forces. The goal of this article is to provide researchers with a survey of useful methodologies that can be adapted to studies in this area, and to clarify future possibilities for improved research methods.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1115/1.4029016DOI Listing
April 2015

The somatic genomic landscape of chromophobe renal cell carcinoma.

Cancer Cell 2014 Sep 21;26(3):319-330. Epub 2014 Aug 21.

Department of Surgery, Urology Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.

We describe the landscape of somatic genomic alterations of 66 chromophobe renal cell carcinomas (ChRCCs) on the basis of multidimensional and comprehensive characterization, including mtDNA and whole-genome sequencing. The result is consistent that ChRCC originates from the distal nephron compared with other kidney cancers with more proximal origins. Combined mtDNA and gene expression analysis implicates changes in mitochondrial function as a component of the disease biology, while suggesting alternative roles for mtDNA mutations in cancers relying on oxidative phosphorylation. Genomic rearrangements lead to recurrent structural breakpoints within TERT promoter region, which correlates with highly elevated TERT expression and manifestation of kataegis, representing a mechanism of TERT upregulation in cancer distinct from previously observed amplifications and point mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccr.2014.07.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4160352PMC
September 2014

In vitro biomechanical comparison of 3.5 mm LC-DCP/intramedullary rod and 5 mm clamp-rod internal fixator (CRIF)/intramedullary rod fixation in a canine femoral gap model.

Vet Surg 2014 Oct 31;43(7):860-8. Epub 2014 Jan 31.

Department of Veterinary Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas.

Objective: To compare the biomechanical properties of clamp rod internal fixation (CRIF)/rod and LC-DCP/rod constructs in a canine femoral gap model.

Study Design: Cadaveric biomechanical study.

Sample Population: Canine femora (n = 10 pair).

Methods: Femora with 40 mm ostectomies were assigned to LC-DCP/rod or CRIF/rod treatment groups. Five construct pairs had 4-point bending and 5 pairs had torsional loading. Construct stiffness, strength, and bending angle at failure or permanent angular deformation (torsional loading) were determined. Statistical comparisons were performed using Student t tests; significance was set at P ≤ .05.

Results: There was significantly greater permanent angular deformation, or residual twist, in the CRIF/rod constructs (23.1 ± 0.89°) compared with LC-DCP/rod constructs (7.47 ± 2.08°). Whereas there was no significant difference in torsional stiffness of these constructs at torsional loads <4.92 N m (P = .819), LC-DCP/rod constructs had significantly greater torsional stiffness (0.303 ± 0.079 N m/°) and strength (11.546 ± 2.79 N m) than CRIF/rod construct stiffness (0.06 ± 0.013 N m/°) and strength (6.078 ± 0.527 N m) at torsional loads >4.92 N m. Differences in stiffness and strength in 4-point bending were not statistically significant.

Conclusions: LC-DCP/rod constructs had significantly less permanent angular deformation than CRIF/rod constructs. CRIF/rod constructs became less stiff as torsional load was increased, thus the LC-DCP/rod constructs had significantly greater torsional stiffness and strength under high torsional loads. LC-DCP/rod and CRIF/rod constructs performed similarly under 4-point bend loading conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1532-950X.2014.12130.xDOI Listing
October 2014

Unusual presentation of toxoplasma gondii encephalitis.

West J Emerg Med 2012 Dec;13(6):488-90

Henry Ford Hospital, Department of Emergency Medicine, Detroit, Michigan.

We report a case of altered mental status secondary to acute Toxoplasma Gondii encephalitis. The patient had no medical or surgical history and presented with acute onset of lethargy with no clear precipitant. A physical exam revealed no focal neurological deficits and a subsequent medical workup revealed multiple intracranial lesions with a biopsy confirming the diagnosis of Toxoplasma Gondii encephalitis in the setting of newly diagnosed human immunodeficiency virus (HIV). A literature review revealed that this is a unique case of toxoplasmic encephalopathy in the United States in a previously undiagnosed HIV positive patient presenting to an emergency department.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5811/westjem.2012.4.12178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3555586PMC
December 2012

Genome-wide high-density SNP linkage search for glioma susceptibility loci: results from the Gliogene Consortium.

Cancer Res 2011 Dec 28;71(24):7568-75. Epub 2011 Oct 28.

Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

Gliomas, which generally have a poor prognosis, are the most common primary malignant brain tumors in adults. Recent genome-wide association studies have shown that inherited susceptibility plays a role in the development of glioma. Although first-degree relatives of patients exhibit a two-fold increased risk of glioma, the search for susceptibility loci in familial forms of the disease has been challenging because the disease is relatively rare, fatal, and heterogeneous, making it difficult to collect sufficient biosamples from families for statistical power. To address this challenge, the Genetic Epidemiology of Glioma International Consortium (Gliogene) was formed to collect DNA samples from families with two or more cases of histologically confirmed glioma. In this study, we present results obtained from 46 U.S. families in which multipoint linkage analyses were undertaken using nonparametric (model-free) methods. After removal of high linkage disequilibrium single-nucleotide polymorphism, we obtained a maximum nonparametric linkage score (NPL) of 3.39 (P = 0.0005) at 17q12-21.32 and the Z-score of 4.20 (P = 0.000007). To replicate our findings, we genotyped 29 independent U.S. families and obtained a maximum NPL score of 1.26 (P = 0.008) and the Z-score of 1.47 (P = 0.035). Accounting for the genetic heterogeneity using the ordered subset analysis approach, the combined analyses of 75 families resulted in a maximum NPL score of 3.81 (P = 0.00001). The genomic regions we have implicated in this study may offer novel insights into glioma susceptibility, focusing future work to identify genes that cause familial glioma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-11-0013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3242820PMC
December 2011

Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy.

Cell 2011 Jun;145(7):1036-48

Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA.

Ion channel mutations are an important cause of rare Mendelian disorders affecting brain, heart, and other tissues. We performed parallel exome sequencing of 237 channel genes in a well-characterized human sample, comparing variant profiles of unaffected individuals to those with the most common neuronal excitability disorder, sporadic idiopathic epilepsy. Rare missense variation in known Mendelian disease genes is prevalent in both groups at similar complexity, revealing that even deleterious ion channel mutations confer uncertain risk to an individual depending on the other variants with which they are combined. Our findings indicate that variant discovery via large scale sequencing efforts is only a first step in illuminating the complex allelic architecture underlying personal disease risk. We propose that in silico modeling of channel variation in realistic cell and network models will be crucial to future strategies assessing mutation profile pathogenicity and drug response in individuals with a broad spectrum of excitability disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2011.05.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3131217PMC
June 2011

Bayesian estimation of genomic copy number with single nucleotide polymorphism genotyping arrays.

BMC Res Notes 2010 Dec 30;3:350. Epub 2010 Dec 30.

Department of Statistics, Rice University, 6100 Main, Houston, TX 77005-1827, USA.

Background: The identification of copy number aberration in the human genome is an important area in cancer research. We develop a model for determining genomic copy numbers using high-density single nucleotide polymorphism genotyping microarrays. The method is based on a Bayesian spatial normal mixture model with an unknown number of components corresponding to true copy numbers. A reversible jump Markov chain Monte Carlo algorithm is used to implement the model and perform posterior inference.

Results: The performance of the algorithm is examined on both simulated and real cancer data, and it is compared with the popular CNAG algorithm for copy number detection.

Conclusions: We demonstrate that our Bayesian mixture model performs at least as well as the hidden Markov model based CNAG algorithm and in certain cases does better. One of the added advantages of our method is the flexibility of modeling normal cell contamination in tumor samples.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1756-0500-3-350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3023756PMC
December 2010

Stargazin and other transmembrane AMPA receptor regulating proteins interact with synaptic scaffolding protein MAGI-2 in brain.

J Neurosci 2006 Jul;26(30):7875-84

Department of Neurology, Baylor College of Medicine, Houston, Texas 77030, USA.

The spatial coordination of neurotransmitter receptors with other postsynaptic signaling and structural molecules is regulated by a diverse array of cell-specific scaffolding proteins. The synaptic trafficking of AMPA receptors by the stargazin protein in some neurons, for example, depends on specific interactions between the C terminus of stargazin and the PDZ [postsynaptic density-95 (PSD-95)/Discs large/zona occludens-1] domains of membrane-associated guanylate kinase scaffolding proteins PSD-93 or PSD-95. Stargazin [Cacng2 (Ca2+ channel gamma2 subunit)] is one of four closely related proteins recently categorized as transmembrane AMPA receptor regulating proteins (TARPs) that appear to share similar functions but exhibit distinct expression patterns in the CNS. We used yeast two-hybrid screening to identify MAGI-2 (membrane associated guanylate kinase, WW and PDZ domain containing 2) as a novel candidate interactor with the cytoplasmic C termini of the TARPs. MAGI-2 [also known as S-SCAM (synaptic scaffolding molecule)] is a multi-PDZ domain scaffolding protein that interacts with several different ligands in brain, including PTEN (phosphatase and tensin homolog), dasm1 (dendrite arborization and synapse maturation 1), dendrin, axin, beta- and delta-catenin, neuroligin, hyperpolarization-activated cation channels, beta1-adrenergic receptors, and NMDA receptors. We confirmed that MAGI-2 coimmunoprecipitated with stargazin in vivo from mouse cerebral cortex and used in vitro assays to localize the interaction to the C-terminal -TTPV amino acid motif of stargazin and the PDZ1, PDZ3, and PDZ5 domains of MAGI-2. Expression of stargazin recruited MAGI-2 to cell membranes and cell-cell contact sites in transfected HEK-293T cells dependent on the presence of the stargazin -TTPV motif. These experiments identify MAGI-2 as a strong candidate for linking TARP/AMPA receptor complexes to a wide range of other postsynaptic molecules and pathways and advance our knowledge of protein interactions at mammalian CNS synapses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/JNEUROSCI.1851-06.2006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6674230PMC
July 2006

The alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate receptor trafficking regulator "stargazin" is related to the claudin family of proteins by Its ability to mediate cell-cell adhesion.

J Biol Chem 2005 May 10;280(20):19711-20. Epub 2005 Mar 10.

Department of Neurology, Baylor College of Medicine, Houston, Texas 77030, USA.

Mutations in the Cacng2 gene encoding the neuronal transmembrane protein stargazin result in recessively inherited epilepsy and ataxia in "stargazer" mice. Functional studies suggest a dual role for stargazin, both as a modulatory gamma subunit for voltage-dependent calcium channels and as a regulator of post-synaptic membrane targeting for alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate (AMPA)-type glutamate receptors. Co-immunoprecipitation experiments demonstrate that stargazin can bind proteins of either complex in vivo, but it remains unclear whether it can associate with both complexes simultaneously. Cacng2 is one of eight closely related genes (Cacng1-8) encoding proteins with four transmembrane segments, cytoplasmic termini, and molecular masses between 25 and 44 kDa. This group of Cacng genes constitutes only one branch of a larger monophyletic assembly dominated by over 20 genes encoding proteins known as claudins. Claudins regulate cell adhesion and paracellular permeability as fundamental components of non-neuronal tight junctions. Because stargazin is structurally similar to claudins, we hypothesized that it might also have retained claudin-like functions inherited from a common ancestor. Here, we report that expression of stargazin in mouse L-fibroblasts results in cell aggregation comparable with that produced by claudins, and present evidence that the interaction is heterotypic and calcium dependent. The data suggest that the cell adhesion function of stargazin preceded its current role in neurons as a regulator of either voltage-dependent calcium channels or AMPA receptors. We speculate these complexes may have co-opted the established presence of stargazin at sites of close cell-cell contact to facilitate their own evolving intercellular signaling functions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1074/jbc.M500623200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1255971PMC
May 2005

Genetic disruption of cortical interneuron development causes region- and GABA cell type-specific deficits, epilepsy, and behavioral dysfunction.

J Neurosci 2003 Jan;23(2):622-31

Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.

The generation of properly functioning circuits during brain development requires precise timing of cell migration and differentiation. Disruptions in the developmental plan may lead to neurological and psychiatric disorders. Neocortical circuits rely on inhibitory GABAergic interneurons, the majority of which migrate from subcortical sources. We have shown that the pleiotropic molecule hepatocyte growth factor/scatter factor (HGF/SF) mediates interneuron migration. Mice with a targeted mutation of the gene encoding urokinase plasminogen activator receptor (uPAR), a key component in HGF/SF activation and function, have decreased levels of HGF/SF and a 50% reduction in neocortical GABAergic interneurons at embryonic and perinatal ages. Disruption of interneuron development leads to early lethality in most models. Thus, the long-term consequences of such perturbations are unknown. Mice of the uPAR-/- strain survive until adulthood, and behavior testing demonstrates that they have an increased anxiety state. The uPAR-/- strain also exhibits spontaneous seizure activity and higher susceptibility to pharmacologically induced convulsions. The neocortex of the adult uPAR-/- mouse exhibits a dramatic region- and subtype-specific decrease in GABA-immunoreactive interneurons. Anterior cingulate and parietal cortical areas contain 50% fewer GABAergic interneurons compared with wild-type littermates. However, interneuron numbers in piriform and visual cortical areas do not differ from those of normal mice. Characterization of interneuron subpopulations reveals a near complete loss of the parvalbumin subtype, with other subclasses remaining intact. These data demonstrate that a single gene mutation can selectively alter the development of cortical interneurons in a region- and cell subtype-specific manner, with deficits leading to long-lasting changes in circuit organization and behavior.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6741866PMC
January 2003