Systematic review.
To review the published literature on the use of pedicle screws in pediatric spinal deformity to quantify the risks and complications associated with pedicle screw instrumentation, ...particularly in the thoracic spine.
The use of pedicle screws in adolescent scoliosis surgery is common. Although many reports have been published regarding the use of pedicle screws in pediatric patients, there has been no systematic review on the risks of complications.
PubMed, Ovid Medline, and Cochrane databases were searched for studies reporting the use of thoracic pedicle screws in pediatric deformity. We excluded articles dealing with neuromuscular scoliosis or bone dysplasia to focus mostly on adolescent thoracic idiopathic scoliosis and the likes. We then searched for cases reports dealing with thoracic pedicle screws complications.
This systematic review retrieved 21 studies with a total of 4570 pedicle screws in 1666 patients. The mean age of the patients was 17.6 years; 812 patients were women and 252 were men, and 5 studies did not identify sex. Overall, 518 (4.2%) screws were reported as malpositioned. However, in studies in which postoperative computed tomography scans were done systematically, the rate of screw malpositioning was as high as 15.7%. The reported percentage of patients with screw malpositioned is around 11%. Eleven patients underwent revision surgery for instrumentation malposition. Other complications reported include loss of curve correction, intraoperative pedicle fracture or loosening, dural laceration, deep infection, pseudarthrosis, and transient neurologic injury. There were no major vascular complications reported in these 21 studies. We could identify 9 case report articles dealing with complications of pedicle screws. Such complications were mostly either vascular (10 cases) or neurologic (4 cases), without any irreversible complications.
Malposition is the most commonly reported complication of thoracic pedicle screw placement, at a rate of 15.7% per screw inserted with postoperative computed tomography scans. The use of pedicle screws in the thoracic spine for the treatment of pediatric deformity has been reported to be safe despite the high rate of patients with malpositioned screws (11%). Major complications, such as neurologic or vascular injury, were almost never reported in this literature review of case series. Cases reports on the other hand have started to identify such complications.
Engineered T cells are effective therapies against a range of malignancies, but current approaches rely on autologous T cells, which are difficult and expensive to manufacture. Efforts to develop ...potent allogeneic T cells that are not rejected by the recipient's immune system require abrogating both T- and natural killer (NK)-cell responses, which eliminate foreign cells through various mechanisms. In the present study, we engineered a receptor that mediates deletion of activated host T and NK cells, preventing rejection of allogeneic T cells. Our alloimmune defense receptor (ADR) selectively recognizes 4-1BB, a cell surface receptor temporarily upregulated by activated lymphocytes. ADR-expressing T cells resist cellular rejection by targeting alloreactive lymphocytes in vitro and in vivo, while sparing resting lymphocytes. Cells co-expressing chimeric antigen receptors and ADRs persisted in mice and produced sustained tumor eradication in two mouse models of allogeneic T-cell therapy of hematopoietic and solid cancers. This approach enables generation of rejection-resistant, 'off-the-shelf', allogeneic T-cell products to produce long-term therapeutic benefit in immunocompetent recipients.
The X-linked BCL-6 co-repressor (BCOR) gene encodes a key constituent of a variant polycomb repressive complex (PRC) that is mutated or translocated in human cancers. Here we report on the ...identification of somatic internal tandem duplications (ITDs) clustering in the C terminus of BCOR in 23 of 27 (85%) pediatric clear cell sarcomas of the kidney (CCSK) from two independent cohorts. We profile CCSK tumours using a combination of whole-exome, transcriptome and targeted sequencing. Identical ITD mutations are found in primary and relapsed tumour pairs but not in adjacent normal kidney or blood. Mutant BCOR transcripts and proteins are markedly upregulated in ITD-positive tumours. Transcriptome analysis of ITD-positive CCSKs reveals enrichment for PRC2-regulated genes and similarity to undifferentiated sarcomas harbouring BCOR-CCNB3 fusions. The discovery of recurrent BCOR ITDs defines a major oncogenic event in this childhood sarcoma with significant implications for diagnostic and therapeutic approaches to this tumour.
Capital and Growth was published in 1965, and rapidly established itself as a landmark in economic theory. In this volume, Sir John takes his earlier work and examines it critically for its ...present-day value. The result is a substantially reworked book based on the first and best part of his 1965 publication. The theme, now more clearly identified, is a comparative study of the economics of change, and brings in many of Hicks's subsequent developments and refinements - in particular a 'neo-Austrian' theory of capital which he developed in Capital and Time(1973). A new chapter on Keynes's methods has been added. The sum is a more complete classification of the family of models appropriate for analysing dynamic economics. Available in OSO: http://www.oxfordscholarship.com/oso/public/content/economicsfinance/0198772874/toc.html
Langerhans cell histiocytosis (LCH) is a clonal disorder with elusive etiology, characterized by the accumulation of CD207(+) dendritic cells (DCs) in inflammatory lesions. Recurrent BRAF-V600E ...mutations have been reported in LCH. In this study, lesions from 100 patients were genotyped, and 64% carried the BRAF-V600E mutation within infiltrating CD207(+) DCs. BRAF-V600E expression in tissue DCs did not define specific clinical risk groups but was associated with increased risk of recurrence. Strikingly, we found that patients with active, high-risk LCH also carried BRAF-V600E in circulating CD11c(+) and CD14(+) fractions and in bone marrow (BM) CD34(+) hematopoietic cell progenitors, whereas the mutation was restricted to lesional CD207(+) DC in low-risk LCH patients. Importantly, BRAF-V600E expression in DCs was sufficient to drive LCH-like disease in mice. Consistent with our findings in humans, expression of BRAF-V600E in BM DC progenitors recapitulated many features of the human high-risk LCH, whereas BRAF-V600E expression in differentiated DCs more closely resembled low-risk LCH. We therefore propose classification of LCH as a myeloid neoplasia and hypothesize that high-risk LCH arises from somatic mutation of a hematopoietic progenitor, whereas low-risk disease arises from somatic mutation of tissue-restricted precursor DCs.
Langerhans cell histiocytosis (LCH) is a myeloproliferative disorder characterized by lesions composed of pathological CD207+ dendritic cells with an inflammatory infiltrate. BRAFV600E remains the ...only recurrent mutation reported in LCH. In order to evaluate the spectrum of somatic mutations in LCH, whole exome sequencing was performed on matched LCH and normal tissue samples obtained from 41 patients. Lesions from other histiocytic disorders, juvenile xanthogranuloma, Erdheim-Chester disease, and Rosai-Dorfman disease were also evaluated. All of the lesions from histiocytic disorders were characterized by an extremely low overall rate of somatic mutations. Notably, 33% (7/21) of LCH cases with wild-type BRAF and none (0/20) with BRAFV600E harbored somatic mutations in MAP2K1 (6 in-frame deletions and 1 missense mutation) that induced extracellular signal-regulated kinase (ERK) phosphorylation in vitro. Single cases of somatic mutations of the mitogen-activated protein kinase (MAPK) pathway genes ARAF and ERBB3 were also detected. The ability of MAPK pathway inhibitors to suppress MAPK kinase and ERK phosphorylation in cell culture and primary tumor models was dependent on the specific LCH mutation. The findings of this study support a model in which ERK activation is a universal end point in LCH arising from pathological activation of upstream signaling proteins.
•Recurrent somatic mutations in MAP2K1 were identified in 33% of LCH lesions with wild-type BRAF. The mutant MAPK kinase 1 proteins activate ERK.•The ability of MAPK pathway inhibitors to suppress MAPK kinase and ERK phosphorylation in vitro was dependent on the specific LCH mutation.
During development of the spontaneously hypertensive rat (SHR), several distinct but closely related lines were generated. Most lines are resistant to hypertensive renal disease. However, the SHR-A3 ...line (stroke-prone SHR) experiences end-organ injury (EOI) and provides a model of injury susceptibility that can be used to uncover genetic causation. In the present study, we generated a congenic line in which three distinct disease loci in SHR-A3 are concurrently replaced with homologous loci from an injury-resistant SHR line (SHR-B2). Verification that all three loci were homozygously replaced in this triple congenic line SHR-A3(Trip B2) while the genetic background of SHR-A3 was fully retained was obtained by whole genome sequencing. Congenic genome substitution was without effect on systolic blood pressure 198.9 ± 3.34 mmHg, mean ± SE, SHR-A3(Trip B2) = 194.7 ± 2.55 mmHg. Measures of renal injury (albuminuria, histological injury scores, and urinary biomarker levels) were reduced in SHR-A3(Trip B2) animals, even though only 4.5 Mbases of the 2.8 Gbases of the SHR-B2 genome (0.16% of the genome) was transferred into the congenic line. The gene content of the three congenic loci and the functional effects of gene polymorphism within suggest a role of immunoglobulin in EOI pathogenesis. To prove the role of antibodies in EOI in SHR-A3, we generated an SHR-A3 line in which expression from the immunoglobulin heavy chain gene was knocked out (SHR-A3-IGHKO). Animals in the SHR-A3-IGHKO line lack B cells and immunoglobulin, but the hypertensive phenotype is not affected. Renal injury, however, was reduced in this line, confirming a pathogenic role for immunoglobulin in hypertensive EOI in this model of heritable risk.
Here, we used a polygenic animal model of hypertensive renal disease to show that genetic variation affecting antibody formation underlies hypertensive renal disease. We proved the genetic thesis by generating an immunoglobulin knockout in the susceptible animal model.
This article discusses the experiences from the development and deployment of two image-based environmental monitoring sensor applications using an embedded wireless sensor network. Our system uses ...low-power image sensors and the Tenet general purpose sensing system for tiered embedded wireless sensor networks. It leverages Tenet's built-in support for reliable delivery of high rate sensing data, scalability and its flexible scripting language, which enables mote-side image compression and the ease of deployment. Our first deployment of a pitfall trap monitoring application at the James San Cannot Mountain Reserve provided us with insights and lessons learned into the deployment of and compression schemes for these embedded wireless imaging systems. Our three month-long deployment of a bird nest monitoring application resulted in over 100,000 images collected from a 19-camera node network deployed over an area of 0.05 square miles, despite highly variable environmental conditions. Our biologists found the on-line, near-real-time access to images to be useful for obtaining data on answering their biological questions.
Vα24-invariant natural killer T cells (NKT) are attractive carriers for chimeric antigen receptors (CAR) due to their inherent antitumor properties and preferential localization to tumor sites. ...However, limited persistence of CAR-NKTs in tumor-bearing mice is associated with tumor recurrence. Here, we evaluated whether coexpression of the NKT homeostatic cytokine IL15 with a CAR enhances the
persistence and therapeutic efficacy of CAR-NKTs.
Human primary NKTs were
expanded and transduced with CAR constructs containing an optimized GD2-specific single-chain variable fragment and either the CD28 or 4-1BB costimulatory endodomain, each with or without IL15 (GD2.CAR or GD2.CAR.15). Constructs that mediated robust CAR-NKT cell expansion were selected for further functional evaluation
and in xenogeneic mouse models of neuroblastoma.
Coexpression of IL15 with either costimulatory domain increased CAR-NKT absolute numbers. However, constructs containing 4-1BB induced excessive activation-induced cell death and reduced numeric expansion of NKTs compared with respective CD28-based constructs. Further evaluation of CD28-based GD2.CAR and GD2.CAR.15 showed that coexpression of IL15 led to reduced expression levels of exhaustion markers in NKTs and increased multiround
tumor cell killing. Following transfer into mice bearing neuroblastoma xenografts, GD2.CAR.15 NKTs demonstrated enhanced
persistence, increased localization to tumor sites, and improved tumor control compared with GD2.CAR NKTs. Importantly, GD2.CAR.15 NKTs did not produce significant toxicity as determined by histopathologic analysis.
Our results informed selection of the CD28-based GD2.CAR.15 construct for clinical testing and led to initiation of a first-in-human CAR-NKT cell clinical trial (NCT03294954).
This collection of essays on money and growth brings together the work of Sir John Hicks. Including two previously unpublished essays, this collection is sure to make readers view Hicks work in a new ...light. Available in OSO: http://www.oxfordscholarship.com/oso/public/content/economicsfinance/0198284071/toc.html
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