Retroperitoneal Fasciitis: Spectrum of CT Findings in the Abdomen and Pelvis.

Retroperitoneal fasciitis is a rare but potentially lethal complication of infection. Early diagnosis is crucial and is usually made when there is a high degree of clinical suspicion combined with characteristic imaging findings leading to early surgical intervention. Computed tomography (CT) can play a central role in demonstrating early findings, assessing the extent of disease to help determine the best surgical approach, identifying the primary source of infection, and evaluating the treatment response. The possible presence of retroperitoneal fasciitis should be considered in patients presenting with symptoms of sepsis, including pain that is disproportionate with the clinical abnormality. When retroperitoneal fasciitis is suspected, emergency CT can facilitate early diagnosis and evaluation of the extent of disease. Common findings at CT include fascial thickening and enhancement, muscular edema, fat stranding, fluid collections, and abscess formation. Gas tracking along fascial planes in the retroperitoneum is the hallmark of retroperitoneal fasciitis but is not seen in all cases. Another important clue to the diagnosis is asymmetric involvement of the retroperitoneal fascial planes and deep tissues. Fasciitis in the retroperitoneum may originate from infected retroperitoneal organs or from infection that spreads along indirect and/or direct pathways from a primary source elsewhere in the body. Findings of indirect tracking and transgression of fascial planes may indicate more severe infection associated with the necrotizing form of retroperitoneal fasciitis. Despite aggressive antibiotic treatment, early and repeated surgical débridement may be required to remove nonviable tissue in patients with the necrotizing form of retroperitoneal fasciitis. Awareness of the anatomy of the retroperitoneum, potential routes of spread of infection, and the spectrum of CT findings in retroperitoneal fasciitis is needed to achieve prompt diagnosis and guide treatment.

Survey of radiologist attitudes and perceptions regarding the incorporation of a departmental peer review system.

PURPOSE: The aim of this study was to investigate the attitudes and perceptions of staff radiologists regarding the incorporation of a nonanonymous peer review system at an academic hospital. METHODS: A questionnaire gauging knowledge of, attitudes toward, and perceptions regarding peer review was distributed to all staff radiologists at a large academic hospital. The survey was distributed before the implementation of a nonanonymous peer review system. Data were analyzed using descriptive statistics. Responses were cross-tabulated according to subspecialty and number of years in practice. RESULTS: The majority of respondents agreed that peer review is important for improving patient care (31 of 36 [86%]) and professional development (29 of 36 [81%]), but the vast majority (33 of 36 [92%]) believed that peer review should be anonymous. Twenty-six of 36 respondents (72%) believed that peer review will not be safe from malpractice issues, 24 of 36 (67%) agreed that it has the potential to damage interpersonal relationships within the department, and 15 of 36 (42%) believed that it may influence their job security or rankings within the department. Significant differences were identified between radiologists with more and fewer years of practice experience. CONCLUSIONS: The incorporation of a nonanonymous peer review system generates anxiety and uncertainty within a radiology department. The investigation of physicians' attitudes toward and perceptions about peer review is important for understanding the potential impact not only on patient care but also on radiologists' relationships and psychology in the workplace.

Treatment of hypertriglyceridemia with fibric acid derivatives: impact on lipid subfractions and translation into a reduction in cardiovascular events.

This review investigates how the treatment of hypertriglyceridemia with fibric acid derivatives impacts lipid concentrations, lipid particle size, and the rate of cardiovascular events: expressly, to decide whether the use of fibric acid derivatives is an effective treatment option in the reduction of cardiovascular endpoints for patients with specific lipid parameters at baseline. Fibric acid derivatives reduce fasting triglyceride (TG) values by 15% to 50% (depending on baseline level) and low-density lipoprotein cholesterol (LDL-C) by 8%, and raise high-density lipoprotein cholesterol (HDL-C) by 9%. In conjunction with a statin, the amount of TG lowering is approximately doubled with the addition of the fibrate. When measured, fibrates decrease the TG concentration of very low-density lipoprotein cholesterol particles while increasing the TG content of LDL particles. The mean size of LDL particles increases and there is a substantial reduction in the number and proportion of small, dense LDL. In randomized trials in primary and secondary prevention populations, fibrates were associated with a significant reduction in nonfatal myocardial infarction in most studies. In the subgroup with elevated TG and/or depressed HDL-C at baseline, all trials have found statistically significant relative risk reductions of 27% to 65% in the primary cardiovascular endpoint of myocardial infarction and cardiovascular death.

Brief report: retrospective review of efficacy of erlotinib or gefitinib compared to docetaxel as subsequent line therapy in advanced non-small cell lung cancer (NSCLC) following failure of platinum-based chemotherapy.

BACKGROUND: Randomized trials of advanced non-small cell lung cancer (NSCLC) have demonstrated the activity of docetaxel in second-line and erlotinib in the third-line setting after failure of platinum-based chemotherapy. The role of epidermal growth factor receptor tyrosine kinase inhibitors (EGFRTKI) as second-line treatment prior to docetaxel is currently the subject of ongoing trials. Here we explore the outcomes of these agents' uses in clinical practice. METHOD: A retrospective review of the NSCLC database at Princess Margaret Hospital in Toronto, Canada was undertaken. Patients who have previously received docetaxel after failure of platinum-based chemotherapy were identified and a chart review was undertaken to further identify those who also received an EGFRTKI to assess their clinical benefits. Primary outcome assessed was response rate and secondary outcomes were time to progression (TTP) and overall survival (OS). RESULTS: Seventy-four patients received docetaxel for advanced NSCLC from 2001 to 2006, 52 (70%) as second line and 22 (30%) as third line. Twenty-two and 31 of these patients received second- and third-line EGFRTKI, respectively. In the second-line setting, the overall response rate was 10% in the EGFRTKI group and 9% in the docetaxel-treated patients. In the third-line setting, this was 20% and 5%, respectively (p-value 0.29). In both the second- and third-line setting, TTP and OS were not significantly different between the two groups. CONCLUSION: For patients with advanced NSCLC who progressed following first-line platinum-based chemotherapy, the use of an EGFRTKI in second line appears to be equivalent to docetaxel chemotherapy, and docetaxel has activity third line, post EGFRTKI therapy.

The Src-like adaptor protein 2 regulates colony-stimulating factor-1 receptor signaling and down-regulation.

Src-like adaptor protein 2 (SLAP-2) is a hematopoietic adaptor protein previously implicated as a negative regulator of T-cell antigen receptor (TCR)-mediated signaling. SLAP-2 contains an SH3 and an SH2 domain, followed by a unique carboxyl-terminal tail, which is important for c-Cbl binding. Here we describe a novel role for SLAP-2 in regulation of the colony-stimulating factor 1 receptor (CSF-1R), a receptor tyrosine kinase important for growth and differentiation of myeloid cells. SLAP-2 co-immunoprecipitates with c-Cbl and CSF-1R in primary bone marrow-derived macrophages. Using murine myeloid cells expressing CSF-1R (FD-Fms cells), we show that SLAP-2 is tyrosine-phosphorylated upon stimulation with CSF-1 and associates constitutively with both c-Cbl and CSF-1R. In addition, we show that expression of a dominant negative form of SLAP-2 impairs c-Cbl association with the CSF-1R and receptor ubiquitination. Impaired c-Cbl recruitment also correlated with changes in the kinetics of CSF-1R down-regulation and trafficking. CSF-1-mediated differentiation of FD-Fms cells and activation of downstream signaling events was also enhanced in cells stably expressing dominant negative SLAP-2. Together, these results demonstrate that SLAP-2 plays a role in c-Cbl-dependent down-regulation of CSF-1R signaling.

Identification of differentially expressed and developmentally regulated genes in medulloblastoma using suppression subtraction hybridization.

To increase our understanding of the molecular pathogenesis of medulloblastoma (MB), we utilized the technique of suppression subtractive hybridization (SSH) to identify genes that are dysregulated in MB when compared to cerebellum. SSH-enriched cDNA libraries from both human and Ptch+/- heterozygous murine MBs were generated by subtracting common cDNAs from corresponding non-neoplastic cerebellum. For the human classic MB library, total human cerebellar RNA was used as control tissue; for the Ptch+/- heterozygous MB, non-neoplastic cerebellum from an unaffected Ptch+/- littermate was used as the control. Through differential screening of these libraries, over 100 upregulated tumor cDNA fragments were isolated, sequenced and identified with the NCBI BLAST program. From these, we selected genes involved in cellular proliferation, antiapoptosis, and cerebellar differentiation for further analysis. Upregulated genes identified in the human MB library included Unc33-like protein (ULIP), SOX4, Neuronatin (NNAT), the mammalian homologue of Drosophila BarH-like 1(BARHL1), the nuclear matix protein NRP/B (ENC1), and the homeobox OTX2 gene. Genes found to be upregulated in the murine MB library included cyclin D2 (Ccnd2), thymopoietin (Tmpo), Musashi-1 (Msh1), protein phosphatase 2A inhibitor-2 (I-2pp2a), and Unc5h4(D). Using semiquantitative reverse transcription-polymerase chain reaction (RT-PCR), the mRNA expression levels for these genes were markedly higher in human MBs than in cerebellum. Western blot analysis was used to further confirm the overexpression of a subset of these genes at the protein level. Notch pathway overactivity was demonstrated in the TE671 MB cell line expressing high levels of MSH1 through HES1-Luciferase transfections. This study has revealed a panel of developmentally regulated genes that may be involved in the pathogenesis of MB.

Cloning and characterization of human Src-like adaptor protein 2 and a novel splice isoform, SLAP-2-v.

Src-like adaptor protein 2 (SLAP-2) is a recently characterized adaptor protein bearing sequence and structural similarity to the Src-like adaptor protein (SLAP). SLAP-2 expression is hematopoietic-specific, and it has been demonstrated to function as a negative regulator of T-cell antigen receptor (TCR)-mediated signalling by virtue of its interaction with c-Cbl. Here we report the cloning of a cDNA encoding the human homologue of SLAP-2, as well as the genomic structure of the human SLAP-2 gene. Similar to its murine counterpart, two human SLAP-2 protein isoforms exist because of alternative translation initiation, and SLAP-2 protein expression is observed in a variety of hematopoietic cell lines of both lymphoid and myeloid lineages. The human SLAP-2 gene is located on chromosome 20q, and the SLAP-2 coding region consists of seven exons. Concurrent with the cloning of the full-length SLAP-2 cDNA, a unique cDNA encoding an alternatively spliced SLAP-2 isoform has been identified, and designated as SLAP-2-v. The SLAP-2-v transcript encodes a putative protein of 210 amino acids that lacks the c-Cbl interaction region, and consequently is impaired in its ability to both bind to c-Cbl, and inhibit TCR signalling relative to SLAP-2.

Functional cooperation between c-Cbl and Src-like adaptor protein 2 in the negative regulation of T-cell receptor signaling.

Adaptor proteins assemble multiprotein signaling complexes, enabling the transduction of intracellular signals. While many adaptor proteins positively regulate signaling in this manner, a subgroup of adaptors function as negative regulators. Here we report the identification of a hematopoiesis-specific adaptor protein that we have designated Src-like adaptor protein 2 (SLAP-2). SLAP-2 is most closely related to SLAP and contains a Src homology 3 (SH3) domain and an SH2 domain, as well as an amino-terminal myristoylation site that mediates SLAP-2 association with membranes. Following stimulation of primary thymocytes with anti-CD3 and anti-CD28, SLAP-2 coimmunoprecipitates with tyrosine-phosphorylated c-Cbl and an unidentified protein of approximately 72 kDa. In activated Jurkat T cells, SLAP-2 also binds an additional 70-kDa phosphoprotein, identified as ZAP-70. Binding of SLAP-2 to both p72 and ZAP-70 is dependent on its SH2 domain, while c-Cbl interacts with the carboxy-terminal region. Overexpression of wild-type SLAP-2 alone or in combination with c-Cbl in Jurkat T cells leads to inhibition of T-cell antigen receptor-induced activation of nuclear factor of activated T cells. The inhibitory effect of SLAP-2 requires the carboxy-terminal c-Cbl binding region. Expression of SLAP-2 with SYK or ZAP-70 in COS cells or Jurkat T cells causes the degradation of these kinases, and SLAP-2 overexpression in Jurkat T cells reduces the surface expression of CD3. These results suggest that the mechanism of action of SLAP-2 and the related protein SLAP is to promote c-Cbl-dependent degradation of the tyrosine kinases SYK and ZAP-70 and down-regulation of CD3 at the cell surface.