This is the fourth in a series of companion papers showing that when an efficient dynamo can be maintained by accretion disks around supermassive black holes in active galactic nuclei, it will lead ...to the formation of a powerful, magnetically collimated helix that could explain the observed jet/radiolobe structures on very large scales. Here, we present a hyper-resistive kinetic theory that shows how different instabilities can cause the slowly evolving magnetically collimated jets to accelerate ions and electrons in different regions of jets and lobes. In particular, we propose that the Drift Cyclotron Loss Cone instability at the ends of jets can accelerate ions up to the observed ultra-high-energy cosmic rays with energies 1020 eV. Based on this jet/lobe structure model and its associated acceleration processes, we estimate cosmic-ray intensities and likely radiative signatures and compare them with observations.
OBJECTIVES:To define the incidence of sacral U-type insufficiency fracture and describe management of a consecutive series of patients with this injury.
DESIGN:Retrospective analysis.
SETTING:Single ...Level II trauma center.
PATIENTS/PARTICIPANTS:Sixteen adult patients with sacral U-type insufficiency fractures treated over a 36-month period.
INTERVENTION:Patients were indicated for percutaneous screw fixation of the posterior pelvis if they had posterior pelvic pain that prohibited mobilization.
MAIN OUTCOME MEASUREMENTS:Visual analog scale for pain, distance ambulated on postoperative day 1, and change in sacral kyphosis.
RESULTS:The sacral U-type insufficiency fracture incidence was 16.7% (19/114); average patient age was 75 years. Delayed surgery was performed after primary nonoperative treatment had failed in 62.5% (10/16) at an average 83 days postinjury. Acute surgery was performed in 37.5% (6/16) at an average 5 days postinjury. Distance ambulated on postoperative day 1 was 114.4 feet 95% confidence interval (CI) (50.6, 178.2) and 88.7 feet 95% CI (2.8, 174.6) in the delayed and acute surgery groups, respectively, P = 0.18. Change in visual analog scale for pain was −3.2 95% CI (−5.0, −1.4) and −3.7 95% CI (−7.0, −0.4) in the delayed and acute surgery groups, respectively, P = 0.15. Change in sacral kyphosis from presentation to surgery was 12.3 degrees 95% CI (6.7, 17.9) and 0.3 degrees 95% CI (−0.2, 0.9) in the delayed and acute surgery groups, respectively, P < 0.01. Minimum follow-up was 12 months.
CONCLUSIONS:Treatment of sacral U-type insufficiency fractures by percutaneous screw fixation permits early mobilization, provides rapid pain relief, and prevents progressive deformity.
LEVEL OF EVIDENCE:Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.
Multiple surgeries are often required to manage segmental bone loss because of the complex mechanics and biology involved in reconstruction. These procedures can lead to prolonged recovery times, ...poor patient outcomes, and even delayed amputation. A two-stage technique uses induced biologic membranes with delayed placement of bone graft to manage this clinical challenge. In the first stage, a polymethyl methacrylate spacer is placed in the defect to produce a bioactive membrane, which appears to mature biochemically and physically 4 to 8 weeks after spacer placement. In the second, cancellous autograft is placed within this membrane and, via elution of several growth factors, the membrane appears to prevent graft resorption and promote revascularization and consolidation of new bone. Excellent clinical results have been reported, with successful reconstruction of segmental bone defects >20 cm.
Estimates of the incubation period for Q fever vary substantially between different reviews and expert advice documents. We systematically reviewed and quality appraised the literature to provide an ...evidence-based estimate of the incubation period of the Q fever by the aerosolised infection route. Medline (OVIDSP) and EMBASE were searched with the search limited to human studies and English language. Eligible studies included persons with symptomatic, acute Q fever, and defined exposure to Coxiella burnetti. After review of 7115 titles and abstracts, 320 records were screened at full-text level. Of these, 23 studies contained potentially useful data and were quality assessed, with eight studies (with 403 individual cases where the derivation of incubation period was possible) being of sufficient quality and providing individual-level data to produce a pooled summary. We found a median incubation period of 18 days, with 95% of cases expected to occur between 7 and 32 days after exposure.
Purpose We conducted this study to determine if preoperative magnetic resonance imaging (MRI) cross-sectional area measurements would correlate with intraoperative graft size in hamstring anterior ...cruciate ligament (ACL) reconstructions. Methods We retrospectively reviewed ACL reconstructions performed by a single surgeon using a quadruple-looped hamstring allograft. Preoperative MRI axial images were used to determine the combined cross-sectional area of the semitendinosis and gracilis tendons. These cross-sectional areas were correlated to the intraoperative graft size. Results We found a strong correlation between the MRI cross-sectional areas and graft size. If the combined cross-sectional areas were ≥18mm2 , there was an 88% probability of obtaining a graft of sufficient size at the time of surgery. Conclusions We conclude that our technique is a reliable option to assist the surgeon with preoperative determination of graft size. This is valuable to the orthopaedist to more accurately discuss graft options with the patient and improve preoperative preparation with respect to graft choice. Level of Evidence: Level II, development of diagnostic criteria on the basis of consecutive patients with universally applied gold standard.
Gliomas have displayed significant challenges in oncology due to their high degree of invasiveness, recurrence, and resistance to treatment strategies. In this work, the key hub genes mainly ...associated with different grades of glioma, which were represented by pilocytic astrocytoma (PA), oligodendroglioma (OG), anaplastic astrocytoma (AA), and glioblastoma multiforme (GBM), were identified through weighted gene co-expression network analysis (WGCNA) of microarray datasets retrieved from the Gene Expression Omnibus (GEO) database. Through this, four highly correlated modules were observed to be present across the PA (GSE50161), OG (GSE4290), AA (GSE43378), and GBM (GSE36245) datasets. The functional annotation and pathway enrichment analysis done through the Database for Annotation, Visualization, and Integrated Discovery (DAVID) showed that the modules and hub genes identified were mainly involved in signal transduction, transcription regulation, and protein binding, which collectively deregulate several signaling pathways, mainly PI3K/Akt and metabolic pathways. The involvement of several hub genes primarily linked to other signaling pathways, including the cAMP, MAPK/ERK, Wnt/β-catenin, and calcium signaling pathways, indicates potential interconnectivity and influence on the PI3K/Akt pathway and, subsequently, glioma severity. The Drug Repurposing Encyclopedia (DRE) was used to screen for potential drugs based on the up- and downregulated hub genes, wherein the synthetic progestin hormones norgestimate and ethisterone were the top drug candidates. This shows the potential neuroprotective effect of progesterone against glioma due to its influence on EGFR expression and other signaling pathways. Aside from these, several experimental and approved drug candidates were also identified, which include an adrenergic receptor antagonist, a PPAR-γ receptor agonist, a CDK inhibitor, a sodium channel blocker, a bradykinin receptor antagonist, and a dopamine receptor agonist, which further highlights the gene network as a potential therapeutic avenue for glioma.
The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how ...essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery.
A Common Nonsynonymous Single Nucleotide Polymorphism in the SLC30A8 Gene Determines ZnT8 Autoantibody Specificity in Type
1 Diabetes
Janet M. Wenzlau 1 ,
Yu Liu 2 ,
Liping Yu 1 ,
Ong Moua 1 ,
...Kimberly T. Fowler 1 ,
Sampathkumar Rangasamy 1 ,
Jay Walters 1 ,
George S. Eisenbarth 1 ,
Howard W. Davidson 1 and
John C. Hutton 1
1 Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado
2 Department of Endocrinology, Nanjing Medical University, First Affiliated Hospital, Nanjing, China
Corresponding author: John C. Hutton, john.hutton{at}uchsc.edu
Abstract
OBJECTIVE— Zinc transporter eight ( SLC30A8 ) is a major target of autoimmunity in human type 1A diabetes and is implicated in type 2 diabetes in genome-wide association
studies. The type 2 diabetes nonsynonymous single nucleotide polymorphism (SNP) affecting aa 325 lies within the region of highest ZnT8 autoantibody (ZnT8A) binding, prompting an investigation of its relationship to type
1 diabetes.
RESEARCH DESIGN AND METHODS— ZnT8A radioimmunoprecipitation assays were performed in 421 new-onset type 1 diabetic Caucasians using COOH-terminal constructs
incorporating the known human aa 325 variants (Trp, Arg, and Gln). Genotypes were determined by PCR-based SNP analysis.
RESULTS— Sera from 224 subjects (53%) were reactive to Arg 325 probes, from 185 (44%) to Trp 325 probes, and from 142 (34%) to Gln 325 probes. Sixty subjects reacted only with Arg 325 constructs, 31 with Trp 325 only, and 1 with Gln 325 only. The restriction to either Arg 325 or Trp 325 corresponded with inheritance of the respective C- or T-alleles. A strong gene dosage effect was also evident because both
Arg- and Trp-restricted ZnT8As were less prevalent in heterozygous than homozygous individuals. The SLC30A8 SNP allele frequency (75% C and 25% T) varied little with age of type 1 diabetes onset or the presence of other autoantibodies.
CONCLUSIONS— The finding that diabetes autoimmunity can be defined by a single polymorphic residue has not previously been documented.
It argues against ZnT8 autoimmunity arising from molecular mimicry and suggests a mechanistic link between the two major forms
of diabetes. It has implications for antigen-based therapeutic interventions because the response to ZnT8 administration could
be protective or immunogenic depending on an individual's genotype.
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 30 June 2008.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work
is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted June 24, 2008.
Received February 2, 2008.
DIABETES
In a good example of translational research, investigators who had initially demonstrated a role for insulin-like growth factor I in the pathogenesis of thyroid eye disease showed that an antibody to ...the receptor (teprotumumab) produced a meaningful improvement in 83% of patients.
In recent papers, we show how accretion disks around massive black holes could act as dynamos producing magnetic jets similar to the jets that create spheromaks in the laboratory. In this paper, we ...discuss how these magnetic astrophysical jets might naturally produce runaway ion beams accelerated to
$10^{20}$
eV or more, finally ejected as ultra high energy cosmic rays (UHECRs) long regarded as one of the mysteries of astrophysics. The acceleration is mainly due to the drift cyclotron loss cone kinetic instability known from plasma research. Experiments and simulations are suggested to verify the acceleration process.
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