All Publications

  • Fragility of Life: Recurrent Intestinal Perforation Due to Vascular Ehlers-Danlos Syndrome DIGESTIVE DISEASES AND SCIENCES Sceats, L. A., Sukerkar, P. A., Raghavan, S. S., Shandiz, A., Shelton, A., Kin, C. 2019; 64 (8): 2120–23
  • A Patient with Sjogren's Syndrome and Subsequent Diagnosis of Inclusion Body Myositis and Light-Chain Amyloidosis JOURNAL OF GENERAL INTERNAL MEDICINE Hom, J., Marwaha, S., Postolova, A., Kittle, J., Vasquez, R., Davidson, J., Kohler, J., Dries, A., Fernandez-Betancourt, L., Majcherska, M., Dearlove, J., Raghavan, S., Vogel, H., Bernstein, J. A., Fisher, P., Ashley, E., Sampson, J., Wheeler, M., Undiagnosed Dis Network 2019; 34 (6): 1058–62
  • Immediate intraoperative sentinel lymph node analysis by frozen section is predictive of lymph node metastasis in endometrial cancer. Journal of robotic surgery Renz, M., Marjon, N., Devereaux, K., Raghavan, S., Folkins, A. K., Karam, A. 2019


    Sentinel lymph nodes sampling (SLN) in endometrial cancer is being evaluated as a means to gather prognostic information about lymphatic metastasis while avoiding the morbidity associated with complete lymphadenectomy. SLN ultrastaging has been advocated to identify low-volume metastases, but its value remains uncertain. This study aims to evaluate a pathological protocol for the immediate intraoperative SLN work-up using H&E staining alone. In this retrospective single-center study, patients received standardized cervical injection of indocyanine green, SLN mapping followed by pelvic lymphadenectomy with or without para-aortic lymphadenectomy. SLNs were entirely frozen, multiple H&E stained sections prepared and evaluated intraoperatively. No immunohistochemistry was performed. SLN results were compared with the complete lymphadenectomy specimen. Over 3.5 years, 90 patients were identified who underwent SLN mapping and subsequent complete pelvic lymphadenectomy. At least one SLN was detected in 79 (88%) patients. The median number of SLNs removed was 2.0. Para-aortic SLNs were detected in 7%. Final pathology showed 67% Type I tumors, 76% locally confined. The mean number of lymph nodes removed during complete lymphadenectomy was 21. In this series, only 6 patients had lymph node metastases. 5/6 were identified by the described SLN approach resulting in 83.3% sensitivity and a negative predictive value of 98.7%. Our approach permits immediate intraoperative results and helps guide the primary surgery. The immediate SLN work-up using frozen sections showed both high accuracy and negative predictive value. The comparably lower sensitivity may be related to the low number of patients with positive lymph nodes (7.6%).

    View details for PubMedID 30687881

  • OLIG2 is a marker of the fusion protein-driven neurodevelopmental transcriptional signature in alveolar rhabdomyosarcoma. Human pathology Raghavan, S. S., Mooney, K. L., Folpe, A. L., Charville, G. W. 2019


    Alveolar rhabdomyosarcoma (RMS) is associated with an underlying pathogenic translocation involving either PAX3 or PAX7 and FOXO1. The presence or absence of this fusion defines the biology and clinical behavior of this subtype of RMS and its identification in tumors is relevant to prognostication and treatment planning. To further explore the unique characteristics of fusion-driven RMS, we leveraged a published gene expression data set to perform an unbiased comparison of 33 fusion-positive and 25 fusion-negative RMS cases. Our analyses revealed 1790 expressed loci with more than two-fold differential expression at a threshold of P<.05. Genes with increased expression in fusion-positive relative to fusion-negative RMS were significantly enriched for those involved in "nervous system development," "neuron differentiation," and "neurogenesis," highlighting a neurodevelopmental gene expression signature driven by the alveolar RMS-associated fusion protein. We show that neurodevelopmental genes are enriched near PAX3-FOXO1 fusion protein binding sites, suggesting a genome-wide fusion protein-mediated activation of cis regulatory elements. Among the genes with differential expression in fusion-positive versus fusion-negative RMS, we identified expression of the transcriptional regulator of motor neuron and oligodendrocyte development, OLIG2, as a marker of the fusion protein-dependent neurodevelopmental signature. Immunohistochemical analysis of a cohort of 73 RMS specimens revealed OLIG2 expression in 96.4% of fusion-positive RMS (N=27/28), but only in 6.7% of fusion-negative RMS (N=3/45; P<.001). The proportion of OLIG2-expressing cells in fusion-negative cases did not exceed 5%, while 92.9% of fusion-positive cases showed expression in at least 5% of cells. Our findings identify OLIG2 expression as a unique manifestation of a neurodevelopmental gene expression signature driven by the oncogenic fusion protein characteristic of alveolar RMS, which may aid in the diagnostic and prognostic distinction of fusion-positive cases.

    View details for DOI 10.1016/j.humpath.2019.07.003

    View details for PubMedID 31299267

  • Fragility of Life: Recurrent Intestinal Perforation Due to Vascular Ehlers-Danlos Syndrome. Digestive diseases and sciences Sceats, L. A., Sukerkar, P. A., Raghavan, S. S., Esmaeili Shandiz, A., Shelton, A., Kin, C. 2019

    View details for PubMedID 30656563

  • A Patient with Sjogren's Syndrome and Subsequent Diagnosis of Inclusion Body Myositis and Light-Chain Amyloidosis. Journal of general internal medicine Hom, J., Marwaha, S., Postolova, A., Kittle, J., Vasquez, R., Davidson, J., Kohler, J., Dries, A., Fernandez-Betancourt, L., Majcherska, M., Dearlove, J., Raghavan, S., Vogel, H., Bernstein, J. A., Fisher, P., Ashley, E., Sampson, J., Wheeler, M. 2019


    We discuss a challenging case of a 58-year-old Vietnamese-American woman who presented to her new primary care provider with an 8-year history of slowly progressive dysphagia, hoarseness, muscle weakness with associated frequent falls, and weight loss. She eventually reported dry eyes and dry mouth, and she was diagnosed with Sjogren's syndrome. Subsequently, she was additionally diagnosed with inclusion body myositis and gastric light-chain (AL) amyloidosis. Although inclusion body myositis has been previously associated with Sjogren's syndrome, inclusion body myositis is rare in non-Caucasians, and the trio of Sjogren's syndrome, inclusion body myositis, and AL amyloidosis has not been previously reported. Sjogren's syndrome is a systemic autoimmune condition characterized by ocular and oral dryness. It is one of the most common rheumatologic disorders in the USA and worldwide. Early diagnosis of Sjogren's is particularly important given the frequency and variety of associated autoimmune diseases and extraglandular manifestations. Furthermore, although inclusion body myositis has a low prevalence, it is the most common inflammatory myopathy in older adults and is unfortunately associated with long delays in diagnosis, so knowledge of this disorder is also crucial for practicing internists.

    View details for PubMedID 30887439

  • Utility of CD30, Ki-67, and p53 in assisting with the diagnosis of mycosis fungoides with large cell transformation JOURNAL OF CUTANEOUS PATHOLOGY Raghavan, S. S., Hong, E. K., Kim, Y. H., Kim, J. 2019; 46 (1): 33–43

    View details for DOI 10.1111/cup.13375

    View details for Web of Science ID 000453901400005

  • Utility of CD30, Ki-67, and p53 in assisting with the diagnosis of mycosis fungoides with large cell transformation. Journal of cutaneous pathology Raghavan, S. S., Hong, E. K., Kim, Y. H., Kim, J. 2018


    INTRODUCTION: Mycosis fungoides (MF) with large cell transformation (LCT) is an advanced stage of cutaneous lymphoma with a poor prognosis. Identification of LCT is critical and especially challenging when the number of large abnormal lymphocytes is near but below 25%. We propose that Ki-67 and p53 may be useful in making this diagnosis.METHODS: We identified 17 patients with advanced stage (T3 or T4) MF without LCT and 38 patients with a biopsy-confirmed new diagnosis of MF with LCT treated at our institution's cutaneous lymphoma clinic from 2012 to 2016. Seventeen patients underwent 22 biopsies with advanced stage MF (control), and 38 patients with 46 biopsies of MF with LCT were included in this study.RESULTS: The MF cohort had an average CD30 expression of 4%, while the MF-LCT cohort had an average CD30 expression of 22% (P<0.05). The MF cohort had an average Ki-67 staining of 13%, while the MF-LCT group had an average Ki-67 staining of 57% (P<0.05). Forty-seven percent of the MF-LCT group was positive for p53; on the other hand, none of the MF control group showed increased p53 expression (P<0.05).DISCUSSION: While CD30 shows some value in delineating large cell transformation, Ki-67 and p53 appear to be useful immunohistochemical markers in the diagnosis of LCT.

    View details for PubMedID 30328119

  • Histopathologic approach to epidermotropic lymphocytic infiltrates SEMINARS IN CUTANEOUS MEDICINE AND SURGERY Raghavan, S. S., Kim, J. 2018; 37 (1): 56–60


    Mycosis fungoides is the most common and therefore quintessential cutaneous lymphoma and is typically characterized by an epidermotropic infiltrate of atypical monoclonal CD4+ lymphocytes. Classical histopathologic findings include epidermotropism, lymphocytes with convoluted nuclear contours and surrounding perinuclear "halos," and papillary dermal fibrosis. Atypical lymphocytes may occasionally form Pautrier's microabscesses with tagging of lymphocytes along the basal keratinocytes. Unfortunately, a variety of benign inflammatory infiltrates, as well as other cutaneous lymphomas, may demonstrate some similar histopathologic findings. Herein, we review the wide array of epidermotropic T-cell lymphomas and discuss distinguishing features between these entities. We also offer an algorithmic approach utilizing histopathologic, immunophenotypic, and molecular techniques that can be used for analyzing an epidermotropic T-cell infiltrate in order to render a specific diagnosis.

    View details for PubMedID 29719021

  • Flexor Tendon Sheath Engineering Using Decellularized Porcine Pericardium. Plastic and reconstructive surgery Megerle, K., Woon, C., Kraus, A., Raghavan, S., Pham, H., Chang, J. 2016; 138 (4): 630e-41e


    The flexor tendon sheath is an ideal target for tissue engineering because it is difficult to reconstruct by conventional surgical methods. The authors hypothesized that decellularized porcine pericardium can be used as a scaffold for engineering a biologically active tendon sheath.The authors' protocol removed cellular material from the pericardium and preserved the structural architecture in addition to the collagen and glycosaminoglycan content. The scaffold was successfully reseeded with human sheath synoviocytes and human adipose-derived stem cells. Cells were evaluated for 8 weeks after reseeding.The reseeded construct demonstrated continuous production of hyaluronic acid, the main component of synovial fluid. After being seeded on the membrane, adipose-derived stem cells demonstrated down-regulation of collagen I and III and up-regulation of hyaluronan synthase 2.The results indicate that decellularized porcine pericardium may be a potential scaffold for engineering a biologically active human tendon sheath.

    View details for DOI 10.1097/PRS.0000000000002459

    View details for PubMedID 27673534

  • Co-Culture of Human Adipose-Derived Stem Cells with Tenocytes Increases Proliferation and Induces Differentiation into a Tenogenic Lineage PLASTIC AND RECONSTRUCTIVE SURGERY Kraus, A., Woon, C., Raghavan, S., Megerle, K., Hung Pham, H., Chang, J. 2013; 132 (5): 754E-766E


    Seeding acellularized tendons with cells is an approach for creating tissue-engineered tendon grafts with favorable biomechanical properties. It was the authors' aim to evaluate whether human adipose-derived stem cells could replace tenocytes for scaffold seeding.Adipose-derived stem cells and tenocytes were co-cultured in different ratios (3:1, 1:1, and 1:3) and with three different methods: (1) direct co-culture, (2) tenocyte-conditioned media on adipose-derived stem cells, and (3) an insert system to keep both cell types in the same media without contact. Proliferation, collagen production, and tenogenic marker expression were measured by hematocytometry, immunocytochemistry, enzyme-linked immunosorbent assay, and real-time polymerase chain reaction.Proliferation and collagen production were similar for tenocytes and adipose-derived stem cells alone. Phenotype difference between adipose-derived stem cells and tenocytes was indicated by higher tenascin C and scleraxis expression in tenocytes. Proliferation was increased in direct co-cultures, especially at an adipose-derived stem cells-to-tenocyte ratio of 3:1, and for tenocytes in adipose-derived stem cell-conditioned media. Direct co-culture caused significant up-regulation in tenascin C expression in adipose-derived stem cells (4.0-fold; p<005). In tenocyte-conditioned media, tenascin C expression was up-regulated 2.5-fold (p<0.05). In the insert system, tenascin C expression was up-regulated 2.3-fold (p<0.05).Adipose-derived stem cells are good candidates for tendon tissue engineering because they are similar to tenocytes in proliferation and collagen production. With an optimal ratio of 3:1, they increase proliferation in co-culture and change their phenotype toward a tenogenic direction.

    View details for DOI 10.1097/PRS.0b013e3182a48b46

    View details for PubMedID 24165627

  • Human Flexor Tendon Tissue Engineering: Decellularization of Human Flexor Tendons Reduces Immunogenicity In Vivo TISSUE ENGINEERING PART A Raghavan, S. S., Woon, C. Y., Kraus, A., Megerle, K., Choi, M. S., Pridgen, B. C., Pham, H., Chang, J. 2012; 18 (7-8): 796-805


    In mutilating hand injuries, tissue engineered tendon grafts may provide a reconstructive solution. We have previously described a method to decellularize cadaveric human flexor tendons while preserving mechanical properties and biocompatibility. The purpose of this study is to evaluate the immunogenicity and strength of these grafts when implanted into an immunocompetent rat model.Cadaveric human flexor tendons were divided into two groups. Group 1 was untreated, and Group 2 was decellularized by treatment with sodium dodecyl sulfate (SDS), ethylenediaminetetraacetic acid (EDTA), and peracetic acid (PAA). Both groups were then analyzed for the presence of major histocompatibility complexes by immunohistochemistry (IHC). Pair-matched tendons from each group were then placed into the dorsal subcutaneous tissue and anchored to the spinal ligaments of Wistar rats for 2 or 4 weeks, and harvested. The infiltration of B-cells and macrophages was determined using IHC. The explants where then subjected to mechanical testing to determine the ultimate tensile stress (UTS) and elastic modulus (EM). Statistical analysis was performed using a paired Student's t-test.The decellularization protocol successfully removed cells and MHC-1 complexes. At 2 weeks after implantation, there was increased infiltration of B-cells in Group 1 (untreated) compared with Group 2 (acellular), both in the capsule and tendon substance. There was improved ultimate tensile stress (UTS, 42.7 ± 8.3 vs. 22.8 ± 7.8 MPa, p<0.05) and EM (830.2 ± 206.7 vs. 421.2 ± 171.3 MPa, p<0.05) in tendons that were decellularized. At 4 weeks, there was continued B-cell infiltration in Group 1 (untreated) compared with Group 2 (acellular). There was no appreciable difference in macrophage infiltration at both time points. At 4 weeks Group 2 (acellular) demonstrated persistently greater UTS (40.5 ± 9.1 vs. 14.6 ± 4.2 MPa, p<0.05) and EM (454.05 ± 101.5 vs. 204.6 ± 91.3 MPa, p<0.05) compared with Group 1 (untreated).Human flexor tendons that were decellularized with SDS, EDTA, and PAA resulted in removal of cellular antigens and a decreased immune response when placed into Wistar rats. These grafts showed better mechanical properties at 2 and 4 weeks when compared with control tendons. Decellularization is an important step toward the use of tissue engineered flexor tendons in upper extremity reconstruction.

    View details for DOI 10.1089/ten.tea.2011.0422

    View details for PubMedID 22011137

  • Optimization of Human Tendon Tissue Engineering: Synergistic Effects of Growth Factors for Use in Tendon Scaffold Repopulation PLASTIC AND RECONSTRUCTIVE SURGERY Raghavan, S. S., Woon, C. Y., Kraus, A., Megerle, K., Hung Pham, H., Chang, J. 2012; 129 (2): 479-489


    Tissue-engineered flexor tendon grafts may allow reconstruction of severe tendon losses. One critical factor is the optimization of cell proliferation and reseeding. Use of growth factors--basic fibroblast growth factor (bFGF), insulin-like growth factor (IGF)-1, and platelet-derived growth factor (PDGF)-BB--may improve culture conditions for human fibroblasts, tenocytes, and adipose-derived stem cells and increase repopulation of a tendon scaffold.All cell types were plated at a density of 10,000 cells per well and cultured in F12 media supplemented with varying concentrations of bFGF, IGF-1, and PDGF-BB. After 72 hours, cell proliferation was determined using the CellTiter assay. Human flexor tendon segments were acellularized and reseeded in a cell suspension of 5 × 10(5) cells/ml. After 5 days, tendon repopulation was determined using the MTS assay and histology. Statistical significance was determined with analysis of variance and a t test.For all cell types, there was enhanced proliferation with growth factors. Among single growth factors, PDGF-BB at 50 ng/ml was the most efficient stimulator of proliferation. With multiple growth factors, the optimal concentration was determined to be 5 ng/ml bFGF, 50 ng/ml IGF-1, and 50 ng/ml PDGF-BB (increase when compared with control: fibroblasts, 2.92-fold; tenocytes, 2.3-fold; and adipose-derived stem cells, 2.4-fold; p < 0.05). Tendons reseeded with this optimal combination of growth factors showed improved reseeding compared with the control group (fibroblasts, 2.01-fold; tenocytes, 1.78-fold; and adipose-derived stem cells, 1.76-fold; p < 0.05).bFGF, IGF-1, and PDGF-BB can be used to improve cellular proliferation and repopulation of an acellularized scaffold. The use of growth factors may be an important step in the tissue engineering of human flexor tendons.

    View details for DOI 10.1097/PRS.0b013e31823aeb94

    View details for PubMedID 22286428

  • Three-Dimensional-Construct Bioreactor Conditioning in Human Tendon Tissue Engineering TISSUE ENGINEERING PART A Woon, C. Y., Kraus, A., Raghavan, S. S., Pridgen, B. C., Megerle, K., Pham, H., Chang, J. 2011; 17 (19-20): 2561-2572


    Human tendon tissue engineering attempts to address the shortage of autologous tendon material arising from mutilating injuries and diseases of the hand and forearm. It is important to maximize the tissue-engineered construct's (TEC's) biomechanical properties to ensure that the construct is in its strongest possible state before reimplantation. In this study, we sought to determine the bioreactor treatment parameters that affect these properties. Using small- and large-chamber three-dimensional-construct bioreactors (SCB and LCB, respectively), we applied cyclic axial load to TECs comprising reseeded human flexor and extensor tendons of the hand. First, small-sample pilot studies using the LCB were performed on matched-paired full-length flexor tendons to establish proof of concept. Next, large-sample studies using the SCB were performed on matched-paired extensor tendon segments to determine how reseeding, load duty cycle, load magnitude, conditioning duration, and testing delay affected ultimate tensile stress (UTS) and elastic modulus (EM). We found that compared with reseeded matched-paired controls under dynamic-loading at 1.25 N per TEC for 5 days, (1) acellular TECs had lower UTS (p=0.04) and EM (p<0.01), (2) unloaded TECs had lower UTS (p=0.01) and EM (p=0.02), (3) static-loaded TECs had lower UTS (p=0.01) and EM (p<0.01), (4) TECs conditioned for 3 days had lower UTS (p=0.03) and EM (p=0.04), and (5) TECs conditioned for 8 days had higher UTS (p=0.04) and EM (p=0.01). However, TECs conditioned at higher loads (2.5 N per TEC) and lower loads (0.625 N per TEC) possessed similar UTS (p=0.83 and p=0.89, respectively) and EM (p=0.48 and p=0.89, respectively) as controls stimulated with 1.25 N per TEC. After cycle completion, there is attrition of UTS (p=0.03) and EM (p=0.04) over a 2-day period. Our study showed that the material properties of human allograft TECs can be enhanced by reseeding and dynamic-conditioning. While conditioning duration has a significant effect on material properties, the load magnitude does not. The issue of attrition in biomechanical properties with time following cycle completion must be addressed before bioreactor preconditioning can be successfully introduced as a step in the processing of these constructs for clinical application.

    View details for DOI 10.1089/ten.tea.2010.0701

    View details for PubMedID 21612572

  • The utility of endovascular simulation to improve technical performance and stimulate continued interest of preclinical medical students in vascular surgery. Journal of surgical education Lee, J. T., Qiu, M., Teshome, M., Raghavan, S. S., Tedesco, M. M., Dalman, R. L. 2009; 66 (6): 367-373


    New training paradigms in vascular surgery allow for early specialization out of medical school. Surgical simulation has emerged as an educational tool for trainees to practice procedures in a controlled environment allowing interested medical students to perform procedures without compromising patient safety. The purpose of this study is to assess the ability of a simulation-based curriculum to improve the technical performance and interest level of medical students in vascular surgery.Prospective observational cohort study of medical student performance.Academic medical center.Forty-one medical students (23 first year, 15 second year, 3 other) enrolled in a vascular surgery elective course. Students completed a survey of their interests and performed a renal stent procedure on an endovascular simulator (pretest). The curriculum consisted of didactic teaching and weekly mentored simulator sessions and concluded with a final renal stent procedure on the simulator (posttest). Objective procedural measures were determined during the pre- and posttest by the simulator, and subjective performance was graded by expert observers utilizing a structured global assessment scale. After the course, the students were surveyed as to their opinions about vascular surgery as a career option. Finally, 1 year after the course, all students were again surveyed to determine continued interest in vascular surgery.The objective and subjective criteria measured on the simulator and structured global assessment scale significantly improved from pre- to posttest in terms of performer technical skill, patient safety measures, and structured global assessments. Before beginning the course, 8.5% of the students expressed high interest in vascular surgery, and after completing the course 70% were seriously considering vascular surgery as a career option (p = 0.0001). More than 95% of the students responded that endovascular simulation increased their knowledge and interest in vascular surgery. In the 1-year follow-up survey (n = 23 medical students), 35% had already entered their clinical years. Seventy percent of the students were still considering vascular surgery, while several other career options were still popular including the surgical subspecialties (70%), interventional cardiology (57%), and interventional radiology (48%). Most respondents indicated the major reasons for continued interest in vascular surgery were the ability to practice endovascular procedures on the simulator (100%) and mentorship from vascular surgery faculty (78%).The use of high fidelity endovascular simulation within an introductory vascular surgery course improves medical student performance with respect to technical skill, patient safety parameters, and global performance assessment. Mentored exposure to endovascular procedures on the simulator positively impacts long term medical student attitudes towards vascular surgery. Simulator-based courses may have the potential to be an important component in the assessment and recruitment of medical students for future surgical training programs.

    View details for DOI 10.1016/j.jsurg.2009.06.002

    View details for PubMedID 20142137

  • Major Blood Vessel Reconstruction During Sarcoma Surgery ARCHIVES OF SURGERY Song, T. K., Harris, E. J., Raghavan, S., Norton, J. A. 2009; 144 (9): 817-822


    To evaluate the outcomes of major vessel reconstruction as part of surgery to remove sarcomas.Retrospective review.Tertiary academic medical center.Fourteen patients (10 female) with retroperitoneal or extremity sarcomas and major blood vessel involvement who underwent surgery to remove the tumor and had blood vessel reconstruction between 2003 and 2008. Each patient underwent computed tomography angiography.Early (<30 days) and late (>30 days) operative morbidity and mortality, freedom from disease, and graft patency.Seven patients had retroperitoneal sarcomas and 7, extremity sarcomas. Thirteen tumors were malignant (7 high grade and 6 low grade) and 1, benign (leiomyoma). Seven patients had replacement of artery and vein; 5, artery only; and 2, vein only. In all, 16 arteries were reconstructed (2 common femoral; 5 iliac; 2 superficial femoral; 1 brachial; 1 popliteal; and 2 aorta, one with implantation of both iliac arteries and the other with implantation of the left renal, superior mesenteric, and hepatic arteries). Eight patients (57%) had 9 veins reconstructed (3 external iliac, 3 superficial femoral, 2 vena cava, and 1 popliteal). Primary arterial patency was 58% and primary-assisted patency was 83%. Venous patency was 78%. Local recurrence occurred in 3 patients (21%). Five-year disease-free and overall survival were 52% and 68%, respectively. Limb salvage was achieved in 93%.Involvement of vascular structures is not a contraindication for resection of sarcomas, but appropriate planning is necessary to optimize outcome.

    View details for PubMedID 19797105

  • Relationship Between Hypotension and Distribution of Microemboli on DW-MRI Following Carotid Angioplasty and Stenting 81st Annual Scientific Session of the American-Heart-Association Lee, J. T., Kleinman, J. T., Teshome, M., Raghavan, S., Tedesco, M. M., Lane, B., Zhou, W., Dalman, R. L. LIPPINCOTT WILLIAMS & WILKINS. 2008: S1077–S1077