Hibernoma-like brown fat in the bone marrow: report of a unique case.

We report on a bone-marrow biopsy of a 61-year-old female patient that was performed because of the clinical suspicion of a myeloproliferative disease. The trephine biopsy showed morphological features that were consistent with an essential thrombocythaemia (ET). The diagnosis of a myeloproliferative disease could be corroborated by demonstration of the V617F mutation of JAK2. Besides the histological features of ET, the marrow showed a peculiar infiltrate that consisted of multivacuolated cells that were immunohistochemically identified as brown adipose tissue with a hibernoma-like picture. To the best of our knowledge, this is the first report on brown adipose tissue in the bone marrow.

Granulocyte colony-stimulating factor does not affect contusion size, brain edema or cerebrospinal fluid glutamate concentrations in rats following controlled cortical impact.

INTRODUCTION: Granulocyte colony-stimulating factor (G-CSF) is an established treatment in the neutropenic host. Usage in head-injured patients at risk for infection may aggravate brain damage. In contrast, evidence of G-CSF neuroprotective effects has been reported in rodent models of focal cerebral ischemia. We investigated effects of G-CSF in acute focal traumatic brain injury (TBI) in rats. METHODS: Thirty-six male Sprague-Dawley rats were anesthetized with 1.2%) to 2.0% isoflurane and subjected to controlled cortical impact injury (CCII). Thirty minutes following CCII, either vehicle or G-CSF was administered intravenously. Animals were sacrificed 24 hours following CCII. Glutamate concentrations were determined in cisternal cerebrospinal fluid (CSF). Brain edema was assessed gravimetrically. Contusion size was estimated by 2,3,5-triphenyltetrazolium chloride staining and volumetric analysis. RESULTS: Dose-dependent leukocytosis was induced by infusion of G-CSF. Physiological variables were unaffected. Water content of the traumatized hemisphere and CSF glutamate concentrations were unchanged by treatment. Contusion volume was similar in all groups. CONCLUSIONS: A single injection of G-CSF did not influence cortical contusion volume, brain edema, or glutamate concentrations in CSF determined 24 hours following CCII in rats. G-CSF, administered 30 minutes following experimental TBI, failed to exert neuroprotective effects.

Bulk glasses and ultrahard nanoceramics based on alumina and rare-earth oxides.

Although often regarded as a network-former in conventional silicate glasses, Al(2)O(3) alone cannot be obtained as a bulk glass. Until now, glasses comprising continuously linked [AlO(x)] polyhedra have been prepared in only a few systems under very fast cooling conditions, which limits their dimensions to a few millimetres. Yet it is desirable to prepare bulk, or monolithic, alumina-rich glasses, with the prospect of superior mechanical, chemical and optical properties. Here we report a novel process for preparing very-high-alumina glasses and nanoscale glass-ceramics. Fully dense bulk articles in net shape are obtained through viscous sintering of glass microbeads. Additional heat treatment of the consolidated glasses leads to fully crystallized transparent glass-converted nanoceramics with a hardness similar to that of alumina. This method avoids the impracticably high applied pressures (more than 1 GPa) that have been required in most cases to prepare nanocrystalline ceramics by sintering, owing to the concurrent nature of densification and grain growth under pressureless conditions. The reported techniques can be extended to form glasses and nanoceramics in other oxide systems that do not include a conventional glass-forming component.

Resident utilization of information technology.

OBJECTIVE: To determine if a simple educational intervention can increase resident physician literature search activity. DESIGN: Randomized controlled trial. SETTING: University hospital-based internal medicine training program. PATIENTS/PARTICIPANTS: Forty-eight medical residents rotating on the general internal medicine service. INTERVENTIONS: One-hour didactic session, the use of well-built clinical question cards, and practical sessions in clinical question building. MEASUREMENTS AND MAIN RESULTS: Objective data from the library information system that included the number of log-ons to medline, searching volume, abstracts viewed, full-text articles viewed, and time spent searching. Median search activity as measured per person per week (control vs intervention): number of log-ons to medline (2.1 vs 4.4, P <.001); total number of search sets (24.0 vs 74.2, P <.001); abstracts viewed (5.8 vs 17.7, P=.001); articles viewed (1.0 vs 2.6, P=.005); and hours spent searching (0.8 vs 2.4, P <.001). CONCLUSIONS: A simple educational intervention can markedly increase resident searching activity.

Web-based distance continuing education: a new way of thinking for students and instructors.

As people have more difficulty taking time away from work to attend conferences and workshops, the idea of offering courses via the Web has become more desirable. Addressing a need voiced by Medical Library Association membership, the authors developed a Web-based continuing-education course on the subject of the librarian's role in evidence-based medicine. The aim of the course was to provide medical librarians with a well-constructed, content-rich learning experience available to them at their convenience via the Web. This paper includes a discussion of the considerations that need to be taken into account when developing Web-based courses, the issues that arise when the information delivery changes from face-to-face to online, the changing role of the instructor, and the pros and cons of offering Web-based versus traditional courses. The results of the beta test and future plans for the course are also discussed.

Analysis of growth factor-dependent signalling in human epithelioid sarcoma cell lines. clues To the role of autocrine, juxtacrine and paracrine interactions in epithelioid sarcoma.

Human epithelioid sarcoma (ES) is an extremely aggressive soft tissue tumour of unknown histogenesis. Although growth factor-dependent signalling cascades significantly affect the biological behaviour of malignant tumours, little is known so far about their role in human ES. The present investigation, therefore, analyses the coexpression and function of different growth factors and their receptors in the human ES cell line GRU-1 and its clonal subpopulations (GRU-1A, GRU-1B and GRU-1C). As shown by Northern blot, flow cytometry, immunocytochemistry and MTT assay, all ES cell lines expressed transforming growth factor (TGF)-alpha and the epidermal growth factor receptor (EGF-R). Although no response to exogenous TGF-alpha was observed, antagonistic anti-EGF-R antibodies (at 20 microg/ml) induced significant (P<0.05) growth inhibition in all cell lines. All cell lines showed coexpression of platelet-derived growth factor (PDGF)-A and the corresponding receptors. Neutralisation of ES-derived PDGF by anti-hPDGF antibodies resulted in significant (P<0.05) growth inhibition of all clonal subpopulations. Although all cell lines expressed TGF-beta(1) as well as TGF-beta type I and type II receptors (TGF-BI-R and TGF-BII-R), growth inhibition (P<0.05) by exogenous TGF-beta(1) was achieved in the clonal subpopulations only and not in the parental cell line. No ES cell line expressed acidic fibroblast growth factor (FGF) but stimulation of FGF type 3 and type 4 receptors (FGF-3R and FGF-4R) by exogenous acidic FGF (aFGF) resulted in a marked (P<0.05) acceleration of proliferation in all cell lines. In conclusion, our investigation suggests an intricate network of autocrine, juxtacrine and paracrine signalling between ES tumour cells and adjacent non-neoplastic stromal cells.

A novel human malignant fibrous histiocytoma cell line of the heart (MFH-H) with secretion of hematopoietic growth factors.

Primary malignant fibrous histiocytoma (MFH) exhibits an extremely adverse prognosis. Investigations into the principles determining the biological aggressiveness of this cardiac tumor would be facilitated by an appropriate in vitro model. Therefore, we report on the first permanent cell line (MFH-H), derived from a human cardiac MFH. The original tumor had shown coexpression of cytoskeletal filaments typical of mesenchymal (vimentin), epithelial (cytokeratins) and neurogenic (neurofilaments) differentiation. This potential for multidirectional differentiation was observed in the MFH-H cell line as well and indicated marked plasticity of gene activation acquired during the process of neoplastic transformation. Pronounced genetic alterations also became evident from cytogenetic analysis, which revealed a highly variant karyotype with multiple numeric and structural chromosomal aberrations. Secretion of G-CSF, GM-CSF and M-CSF was shown to be another feature of deregulated gene expression in MFH-H cells. Direct autocrine effects of their hematopoietic growth factors, however, were precluded by the lack of the corresponding receptors. In conclusion, the cell line MFH-H will provide an appropriate in vitro model to analyze the biological properties of this cardiac malignancy in more detail, especially with regard to a possible immunomodulating capacity of MFH-derived hematopoietic growth factors.

Going beyond information management: using the Comprehensive Accreditation Manual for Hospitals to promote knowledge-based information services.

In 1987, the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) initiated the Agenda for Change, a major revision in the evaluation process for hospitals. An essential component of that change was to shift the emphasis away from standards for individual departments to standards for hospital-wide functions. In recent years, hospital librarians have focused their energy and attention on complying with the standards for the "Management of Information" chapter, specifically the IM.9 section on knowledge-based information. However, the JCAHO has listed the health sciences librarian and library services as having responsibilities in six other chapters within the Comprehensive Accreditation Manual for Hospitals. These chapters can have a major impact on the services of the hospital library for two reasons: (1) they are being read by hospital leaders and other professionals in the organization, and (2) they articulate specific ways to apply knowledge-based information services to the major functions within the hospital. These chapters are "Education"; "Improving Organizational Performance"; "Leadership"; "Management of Human Resources"; "Management of the Environment of Care"; and "Surveillance, Prevention, and Control of Infection." The standards that these chapters promote present specific opportunities for hospital librarians to apply knowledge-based information resources and service to hospital-wide functions. This article reviews these chapters and discusses the standards that relate to knowledge-based information.

Functional intactness of stimulatory and inhibitory autocrine loops in human renal carcinoma cell lines of the clear cell type.

PURPOSE: The aim of the present study was to analyze the contribution of different stimulatory and inhibitory growth factors to the deregulated proliferation of human RCCs. MATERIALS AND METHODS: The expression of different growth factors and their corresponding receptors were analyzed by Northern blot, FACS, ELISA and immunocytochemistry in 13 permanent human RCC cell lines of the clear cell type. Moreover, the functional intactness of growth factor-related signal transduction pathways was investigated. RESULTS: All RCC cell lines expressed EGF-receptor mRNA and protein and 10 cell lines secreted TGF-alpha. Exogeneously added TGF-alpha resulted in a significant (p < 0.05) stimulation of growth in 6 RCC cell lines and a significant (p < 0.05) inhibition of proliferation in 3 cell lines. PDGF B and the corresponding type beta receptor were expressed in a single cell line. mRNA expression of PDGF A and PDGF-alpha-receptor as well as IGF-1 and its receptor could not be detected in any cell line. Eleven RCC cell lines expressed TGF-beta 1 mRNA and in all cell lines TGF-beta 1 secretion into the supernatant could be demonstrated. Whereas all cell lines exhibited TGF-beta type II-receptor mRNA, type I-receptor mRNA could be detected only in 3 cell lines. TGF-beta type III-receptor was observed in 1 cell line. Exogeneously added TGF-beta1 resulted in a significant (p < 0.05) inhibition of proliferation in 7 RCC cell lines. CONCLUSION: Clear cell RCCs exhibit a complex and heterogeneous expression pattern for various growth factors and their receptors. Growth factor secretion and intact signal transduction pathways in most clear cell RCCs facilitate an intricate modulation of RCC growth by autocrine and paracrine interactions between tumor cells and host tissue.

Soluble intercellular adhesion molecule-1 in patients with lung cancer and benign lung diseases.

Intercellular adhesion molecule-1 (ICAM-1) expression correlates with tumour progression in patients with malignant melanoma or renal cell carcinoma. To assess the value of soluble ICAM-1 (sICAM-1) for lung cancer patients, sICAM-1 was determined by means of an enzyme-linked immunosorbent assay. Sera from 147 patients with lung cancer, from 75 patients with benign lung diseases and from 108 healthy adults were investigated for sICAM-1 expression. Significant differences in sICAM-1 levels were detected in lung cancer patients (387 +/- 176 ng/ml) and patients with benign lung diseases (365 +/- 110 ng/ml) compared to the group of healthy adults (310 +/- 90 ng/ml). There was no difference in sICAM-1 level among the subtypes of lung cancer. Advanced tumour stages and patients with progressive disease tended to be associated with higher sICAM-1 levels, the site of metastasis being relevant for the level attained. Patients with liver metastasis had the highest sICAM-1 levels (547 +/- 295 ng/ml) compared to patients with cerebral metastasis (317.8 +/- 92.2 ng/ml). An increase of sICAM-1 expression during the progression of the disease coincided with a poorer survival prognosis for the patients compared to patients with stable or falling sICAM-1 levels.

In patients with BCR-ABL-positive ALL in CR peripheral blood contains less residual disease than bone marrow: implications for autologous BMT.

Residual leukemic cells are detectable at frequencies as low as 1 in 10(6) normal cells in patients with Philadelphia chromosome/BCR-ABL-positive leukemias in complete remission (CR) using reverse-transcriptase polymerase chain reaction (RT-PCR) with specific nested primers. The level of minimal residual disease (MRD) in the bone marrow (BM) and the peripheral blood (PB) may favor one of the two as the source for an autologous graft. In order to quantify MRD with RT-PCR we analyzed patients ficolled cells after limiting logarithmic dilutions in normal ficolled buffy-coat cells. In six patients with BCR-ABL-pos ALL who were in CR by conventional criteria (5 in CR1 and 1 in CR2), we studied a total of nine paired BM and PB samples prior to scheduled ABMT. A positive RT-PCR signals was detectable in all samples up to dilutions ranging from 1:10(1) to 1:10(3) in PB, and at higher titers ranging from 1:10(3) to 1:10(5) in the BM. The BM titers exceeded the corresponding PB titers in all nine sample pairs by at least 1 log. The mean difference was 1.55 log (geometric mean, n = 9) and is statistically significant (p < 0.03). We conclude that residual leukemia in BCR-ABL-positive ALL preferentially locates in the BM compartment, and we assume that PB may yield autologous grafts with significantly less leukemic contamination.

Differential expression of the intercellular adhesion molecule-1 (ICAM-1) in lung cancer cell lines of various histological types.

Ten small cell lung carcinoma and 12 non-small cell lung carcinoma cell lines of various histological types were studied for constitutive expression of the intercellular adhesion molecule-1 (ICAM-1). ICAM-1 was present in all squamous and large cell carcinoma cell lines whereas two out of five adenocarcinoma and all small cell lung cancer (SCLC) cell lines showed no basal ICAM-1 expression. ICAM-1 expression was upregulated by tumour necrosis factor-alpha (TNF-alpha) in a time- and dose-dependent manner in cell lines with basal ICAM-1 expression. Western blot analysis revealed a molecular size of 85 kDa for ICAM-1 in all but one cell line. The TNF-alpha-induced upregulation of ICAM-1 occurs on the transcriptional level. Adhesion of peripheral blood mononuclear cells to lung tumour cell lines could be inhibited by monoclonal antibodies (MAb) (CD11a;CD18) against the receptor of ICAM-1, the leukocyte function-associated antigen-1 (LFA-1), but not by a MAb (CD54) against ICAM-1 itself.

Expression of insulin-like growth factor receptors I and II in normal human lung and in lung cancer.

Insulin-like growth factors are potent mitogenic factors in human lung cancer in vitro, acting via specific receptors. Using monoclonal antibodies we demonstrate the expression of insulin-like growth factor receptor I in bronchial epithelial cells of normal lung and in primary lung cancer (22/24 cases), being most prominent in squamous cell carcinoma. Electron microscopy on lung cancer cell lines reveals a distinct reaction pattern on the plasma membrane. Immunoreaction with a specific antibody directed against the insulin-like growth factor receptor II suggests a weak expression in primary lung cancer. Our findings underline the significance of the autocrine pathway of insulin-like growth factors in lung cancer.

Characterization of insulin-like growth factor II receptors in human small cell lung cancer cell lines.

Small cell lung cancer (SCLC) cell lines were investigated for the expression of insulin-like growth factor (IGF) II receptor by means of radioreceptor assays, cross-linking techniques, and Northern blot analysis. 125I-IGF II binds to both the IGF I and the IGF II receptor on intact SCLC cells. Detailed receptor assays performed on microsomal and plasma membranes gave evidence that 125I-IGF II binds with high affinity (70-80 pM) to the IGF I receptor and with low affinity (2-4 nM) to the IGF II receptor, and not conversely. The presence of mannose-6-phosphate enhanced the binding of 125I-IGF II to the IGF II receptor of SCLC. Mannose-6-phosphate also increased the efficiency of N-hydroxysuccinimide ester in cross-linking 125I-IGF II to the IGF II receptor and facilitated the cross-linking of 125I-IGF II to a second protein of 240-250 kDa. Soluble IGF II receptor was also detected in conditioned media of SCLC cell lines.

Acute lymphoblastic leukemia with the (4;11) translocation: combined cytogenetic, immunological and molecular genetic analyses.

Five cases of acute leukemia (AL) with the t(4;11) translocation were investigated for the immunoglobulin heavy chain, kappa, lambda, TCR beta and TCR gamma gene rearrangements. All patients presented with high-risk features and had survival times of less than two years. Two cases were classified by immunological phenotyping as acute null-AL(L), one case as pre B-cell ALL (CD10+) and two cases expressed both immature B-cell markers CD19 and CD24 and myelomonocytic markers CD15 and CD14, suggesting mixed lineage leukemia. In two cases more than two rearranged fragments for the immunoglobulin heavy chain gene could be detected by Southern blot analysis. In the other cases at least one allele of the immunoglobulin heavy chain gene was rearranged. Germline configuration of the T-cell receptor genes and lack of light chain gene rearrangement suggest that an early B-precursor cell is involved in the transformational events in these cases of ALL. Our own and published data indicate that acute leukemia with t(4;11) translocation might be more frequently associated with more than two rearranged fragments for the immunoglobulin heavy chain genes and run a very aggressive course.

Presence of more than two rearranged immunoglobulin heavy-chain genes in adult precursor B-cell acute lymphoblastic leukemia.

We examined the configuration of the immunoglobulin genes in the leukemic blast cell DNA of 20 adults with precursor B-cell acute lymphoblastic leukemia (ALL), treated according to the BMFT protocol. Sixteen of 20 (80%) patients expressed HLA-DR antigens and lacked detectable T-cell antigens. Eleven of the 20 patients (55%) were positive for the CD10 antigen and therefore classified as common ALL. Six patients were classified by immunological phenotyping as null-ALL (30%). Three patients (15%) expressed both immature B-cell markers CD19, CD22, or CD24 and myelomonocytic markers CDw65 or CD15, suggesting precursor B-ALL with cross-lineage expression of myeloid markers. In 18 of the 20 patients (90%), rearrangements and/or deletions of the immunoglobulin heavy-chain (IgH) gene locus were found. In none of the patients was a light-chain gene rearrangement observed. Two patients (10%) had a rearrangement of one allele for the J beta 1 gene region of the TCR-beta gene. In four patients (20%) more than two hybridizing bands for the IgH genes were detected. Two of these four patients with multiple hybridizing bands for the IgH genes had a t (4;11) translocation. Two of five patients with the t (4;11) translocation co-expressed both B-cell antigens and the myeloid antigens CD15 or CDw65. No correlation was found between the immunophenotype of the ALL and the arrangement pattern of their IgH genes. Kaplan-Meier plot analysis revealed no significant difference between adult precursor B-ALL patients with monoclonal or oligoclonal IgH gene rearrangements and their disease-free survival rates.