bluuebunny/crossref_metadata_2025 huggingface dataset:
Invited review: Mechanisms of endotoxin neutralization by synthetic cationic compounds
Authors: Andrä Jörg , Gutsmann Thomas , Garidel Patrick , Brandenburg Klaus
Published: June 2007

A basic challenge in the treatment of septic patients in critical care units is the release of bacterial pathogenicity factors such as lipopolysaccharide (LPS, endotoxin) from the cell envelope of Gram-negative bacteria due to killing by antibiotics. LPS aggregates may interact with serum and membrane proteins such as LBP (lipopolysaccharide-binding protein) and CD14 leading to the observed strong reaction of the immune system. Thus, an effective treatment of patients infected by Gram-negative bacteria must comprise beside bacterial killing the neutralization of endotoxins. Here, data are summarized for synthetic compounds indicating the stepwise development to very effective LPS-neutralizing agents. These data include synthetic peptides, based on the endotoxin-binding domains of natural binding proteins such as lactoferrin, Limulus anti-LPS factor, NK-lysin, and cathelicidins or based on LPS sequestering polyamines. Many of these compounds could be shown to act not only in vitro, but also in vivo (e.g . in animal models of sepsis), and might be useful in future clinical trials and in sepsis therapy.
Transcriptional regulation of lipopolysaccharide (LPS)-induced Toll-like receptor (TLR) expression in murine macrophages: role of interferon regulatory factors 1 (IRF-1) and 2 (IRF-2)
Authors: Nhu Quan M. , Cuesta Natalia , Vogel Stefanie N.
Published: June 2007

Activation of TLRs is most closely associated with induction of pro-inflammatory gene expression; however, expression of many other genes, including the TLR genes themselves, has also been shown to be modulated following TLR engagement. A large family of nuclear transcription factors, the interferon regulatory factors (IRFs), have been implicated in TLR signaling leading to pro-inflammatory gene expression. Given that IRF-1 and IRF-2 counter-regulate the transcriptional activity of many genes, we hypothesized that IRF-1 and IRF-2 might also regulate TLR gene expression following LPS stimulation of murine macrophages. mRNA derived from medium- or LPS-treated primary peritoneal macrophages was analyzed for TLR gene expression using quantitative real-time PCR. In wild-type macrophages, LPS up-regulated expression of TLRs 1—3 and 6—9 steady-state mRNA, while TLR4 mRNA was modestly downregulated. IRF-2—/ — macrophages responded to LPS with dysregulated expression of TLR3, TLR4, and TLR5 mRNA, whereas IRF-1 deficiency dampened LPS-induced mRNA expression for TLR3, TLR6, and TLR9. Functional studies revealed aberrant TLR3 signaling in IRF-2—/ — macrophages. Collectively, these findings reveal an additional level of complexity associated with TLR transcriptional regulation and suggest that the trans-acting factors, IRF-1 and IRF-2, contribute to the innate immune response to infections by regulating TLR gene expression.
Review: Pathogen-associated molecular pattern contamination as putative endogenous ligands of Toll-like receptors
Authors: Tsan Min-Fu , Baochong Gao
Published: June 2007

Extensive work in recent years has suggested that a number of endogenous molecules, their derivatives or degradation products may be potent activators of the innate immune system capable of inducing pro-inflammatory cytokine production by the monocyte—macrophage system and the activation and maturation of dendritic cells. The cytokine-like effects of these endogenous molecules are mediated via Toll-like receptor (TLR) signal transduction pathways in a manner similar to pathogen-associated molecular patterns (PAMPs). However, recent evidence suggests that the reported cytokine effects of some of these putative endogenous ligands are in fact due to contaminating PAMPs. The reasons for the failure to recognize PAMP contaminants being responsible for the putative TLR ligands of these endogenous molecules include: (i) failure to use highly purified preparations free of PAMP contamination; (ii) failure to recognize the heat sensitivity of lipopolysaccharide (LPS); and (iii) failure to consider contaminant(s) other than LPS. Strategies are proposed to avoid future designation of PAMP contamination as putative endogenous ligands of TLRs.
Hematological indices, inflammatory markers and neutrophil CD64 expression: comparative trends during experimental human endotoxemia
Authors: van der Meer Wim , Pickkers Peter , Scott Colin S. , van der Hoeven Johannes G. , Gunnewiek Jacqueline Klein
Published: June 2007

CD64 is a high-affinity FcγRI receptor expressed by activated neutrophils that has been recently evaluated as a potential sepsis parameter. In the present study, the kinetics of neutrophil membrane CD64 expression were examined during a standardized inflammatory response, using a human endotoxemia model, and compared with hematological indices, CRP, cytokines and interleukins. Ten healthy subjects received 2 ng/kg intravenous Escherichia coli lipopolysaccharide (LPS). After administration of LPS, neutrophil CD64 showed a biphasic response, characterized by a first increase from 108.5 ± 7.5 to 133 ± 6 AFU after 1 h ( P = 0.047) and a second increase that started at 6 h and reached its maximum of 167 ± 13 AFU at 22 h ( P < 0.0001). CRP concentrations increased to 40 ± 5 mg/dl 22 h after the administration of LPS. The cytokines and interleukins reached their maximum response within 1—2 h. The maximum values of pro-inflammatory cytokines (TNF-α, IFN-γ and IL-6) correlated with the CD64 expression at 22 h after LPS administration ( r2 = 0.76, r2 = 0.78, r2 = 0.81, respectively, all P < 0.05), whereas this correlation was not found for the anti-inflammatory IL-10 ( r2 = 0.058, P = 0.54), suggesting that neutrophil CD64 expression might be a quantitative marker for innate immunity that could easily be used in the clinical setting.
Investigation on the agonistic and antagonistic biological activities of synthetic Chlamydia lipid A and its use in in vitro enzymatic assays
Authors: Heine Holger , Gronow Sabine , Zamyatina Alla , Kosma Paul , Brade Helmut
Published: June 2007

The synthetic 1,4′-bisphosphorylated penta-acyl and tetra-acyl lipid A structures representing the major molecular species of natural chlamydial lipid A were tested for their endotoxic activities as measured by interleukin-8 release from human embryonic kidney (HEK) 293 cells expressing Toll-like receptor (TLR) 2 or TLR4. Both compounds were unable to activate HEK293 cells transiently transfected with TLR2. The penta-acyl lipid A was a weak activator of HEK293 cells expressing TLR4/MD-2/CD14 whereas tetra-acyl lipid A was inactive even at high concentrations. The weak activity of the penta-acyl lipid A could be antagonized by the tetra-acyl derivative of Escherichia coli lipid A (compound 406) or the anti-CD14 monoclonal antibody MEM-18. Both, tetra- and pentaacyl lipid A were unable to antagonize the activity of synthetic E. coli-type lipid A (compound 506) or smooth lipopolysaccharide of Salmonella enterica serovar Friedenau. Tetra- and penta-acyl lipid A served as acceptors for Kdo transferases from E. coli, Chlamydia trachomatis and Chlamydophila psittaci as shown by in vitro assays and detection of the products by thin layer chromatography and immune staining with monoclonal antibody.
Induction of hypersensitivity to endotoxin lethality in mice by treatment with trehalose 6,6′-dimycolate but not with 2,3,6,6′-tetraacyl trehalose 2′-sulfate
Authors: Watanabe Kenji , Hasunuma Ryoichi , Horikoshi Tomoko , Yamana Hironobu , Maruyama Hiroko , Fujiwara Nagatoshi , Kumazawa Yoshio , Yano Ikuya
Published: June 2007

The mechanism by which priming with trehalose 6,6′-dimycolate (TDM, cord factor) induced hypersensitivity to endotoxin lethality was investigated. C57BL/6 and BALB/c mice primed with TDM succumbed to endotoxin shock, but BALB/c IFN-γ knock-out (IFN-γ —/—) mice showed resistance to LPS lethality. The levels of serum IFN-γ peaked on day 4 after priming with TDM and kept significant levels, indicating that IFN-γ plays a critical role for inducing hypersensitivity to LPS lethality. After challenge with LPS, TDM-primed mice produced higher amounts of serum TNFα and soluble CD14. A sulfolipid (SL, 2,3,6,6′-tetraacyl trehalose 2′-sulfate) did not induce the hypersensitivity and, conversely, suppressed the activity of TDM when administered together. Administration of TDM induced infiltration of mononuclear cells in liver, and apoptosis of cells present in the liver sinus was observed after LPS challenge. These results suggest that the hypersensitivity to LPS lethality is due to overproduction of cytokines and other molecules.
Endotoxin effects on hypothalamic gene expression in swine following sequencing of porcine c-fos mRNA
Authors: Vellucci S.V. , Parrott R.F. , Mimmack M.L. , Coadwell W.J.
Published: June 2007

Intravenous (i.v.) endotoxin causes fever and induces cortisol and vasopressin release in prepubertal pigs. In order to investigate CNS events associated with these responses, the sequence of the porcine c-fos gene was determined. An oligonucleotide probe complementary to part of the c-fos mRNA sequence was then designed and used to examine the effect of i.v. lipopolysaccharide (LPS: 0.7 µg/kg) on gene expression in the hypothalamus. An increase in c-fos mRNA was detected in the paraventricular and supraoptic nuclei; expression was greater ( P < 0.05) than in normal animals at 30 min, but not at 120, min after LPS injection. These results are consistent with an activational effect of LPS on neuroendocrine pathways involved in the release of anterior and posterior pituitary hormones.
Assembly of the R1-type core oligosaccharide of Escherichia coli lipopolysaccharide
Authors: Whitfield Chris , Heinrichs David E. , Yethon Jeremy A. , Amor Karen L. , Monteiro Mario A. , Perry Malcolm B.
Published: June 2007

There are 5 known core oligosaccharide (core OS) structures in the lipopolysaccharides of Escherichia coli. The different structures reflect diversity in the chromosomal waa locus, primarily in the central waaQ operon encoding enzymes involved in the assembly of the core OS. The R1 core type is most prevalent among clinical isolates and provides our prototype for functional studies of core OS assembly. To establish the core OS assembly pathway, non-polar insertions were used to mutate each of 9 genes in the major operon of the R1 waa locus. Core OS structures were then determined for each mutant to assign functions to the relevant gene products. From currently available sequence data, five genes (designated waaA, waaC, waaQ, waaP, and waaY) are highly conserved in all of the core types; their products are responsible for assembly and phosphorylation of the inner-core region. Also conserved is waaG, whose product is an α-glucosyltransferase that adds the first residue (HexI) of the outer core. A family of related HexII and HexIII αglycosyltransferases extend the outer core OS backbones in all of the core OS types. The waaO and waaT gene products fulfil these roles in the R1 core OS type. A related glycosyltransferase (WaaW) adds the α-galactosyl substituent on HexIII. The last step in assembly of the core OS carbohydrate backbone involves substitution of HexII by a β-linked glucosyl residue. This residue distinguishes the R1 core OS and it provides the attachment site for ligation of O antigen.
Distinctive structural features are shared by human, lapine, and murine acyloxyacyl hydrolases
Authors: Staab Janet F. , Fosmire Susan , Mei Zhang  , Varley Alan W. , Munford Robert S.
Published: June 2007

Human acyloxyacyl hydrolase is an unusual lipase, found in phagocytic cells, that removes acyl chains from bacterial lipopolysaccharides (LPS) and glycerolipids. It is a heterodimer in which two glycosylated peptides are linked by disulfide bonding. The large subunit contains the active site serine, while the smaller subunit has striking sequence similarity to the saposins, peptide cofactors for several sphingolipid hydrolases. Since rabbits and mice are widely used for studies of LPS—animal interactions, we asked if murine and lapine AOAHs resemble the human enzyme. We report here that murine and lapine AOAHs share the distinctive features of the human AOAH primary sequence and have similar affinity for LPS. The structure of this unusual lipase appears to have been highly conserved.
Stress signaling of apoptosis via ceramide and c-jun kinase
Authors: Rosie Xing  , Kolesnick Richard
Published: June 2007

Mammalian systems respond to environmental stress by either adapting for survival or undergoing programmed cell death (apoptosis). While it is generally believed that the caspase family of proteases are essential effectors of the apoptotic response, much less is clear about the signaling machinery required to activate the caspase system in response to stress stimuli. In the past few years, increasing evidence has linked the sphingomyelin and c-jun kinase (JNK) pathways to the death response in various cellular systems. Both signaling pathways are evolutionarily conserved through yeast. Since yeast does not undergo apoptosis, these pathways appear evolutionarily older than the caspase-mediated death programs. This paper reviews the role of sphingomyelin/ceramide and the JNK pathways in co-ordinating the signaling events leading to apoptosis.
Involvement of CD14 in LPS-induced liver injury in Propionibacterium acnes-primed mice
Authors: Matsuura Keiko , Kataoka Masashi , Higuchi Yasunori , Tamura Yoichi , Akizuki Shin'ichiro , Yamamoto Shunsuke
Published: June 2007

The size of granulomas induced by an intraperitoneal administration of Propionibacterium acnes in M14M mice 7 days after priming was smaller than that in non-transgenic mice. The number of CD14-positive cells in granulomas was fewer in M14M mice than in non-transgenic mice. An LPS challenge induced apoptotic and necrotic changes in hepatocytes in non-transgenic mice but not in M14M mice. TNFα expression was found in monocytic cells in granulomas and Kupffer cells in non-transgenic mice 7 days after priming and was significantly upregulated after LPS injection, whereas the expression was very low in these cells in M14M mice. The expression of IFN-γ, IL-12 and iNOS mRNAs produced by LPS challenge in M14M mice were low compared with those in non-transgenic mice. IL-18 mRNA expression was upregulated in P. acnes-primed nontransgenic mice but not in M14M mice. The production of sCD14 was increased by both P. acnes priming and LPS challenge. The high sCD14 concentration may account for lethality without liver damage in M14M mice. The levels of ELAM-1 mRNA expression in several organs in M14M mice 1—3 h after LPS challenge were, however, lower than those in non-transgenic mice.
Potential role of bacterial lipopolysaccharides in the development of autoimmune gastritis induced by neonatal thymectomy
Authors: Kodaira Hisamasa , Mizoroki Tatsuya , Shimada Hideyo , Ishii Kunio , Hosono Masamichi , Kumazawa Yoshio
Published: June 2007

The role of LPS in the development of autoimmune gastritis (AIG) in BALB/c mice thymectomized on day 3 after birth (d3-Tx) was investigated in LPS-non-responder BALB/lps d mice. The symptoms were classified into three types: (i) hypertrophic stomach (HS) and lymphocyte infiltration (LI)-double negative; (ii) HS-negative and LI-positive; and (iii) HS- and LI-double positive. The double positive type-3 was termed AIG. Following d3-Tx, LPS-responder BALB/c ( Lps n) mice showed the following incidence: type-1 (14%), type-2 (14%) and type-3 (72%). In contrast, the incidence in BALB/lpsd mice was 67%, 22% and 11%, respectively. Thus the frequency of AIG development in BALB/lpsd mice was much lower than in BALB/c mice. A single administration of LPS on day 2 post-d3-Tx induced severe AIG incidence in all d3-Tx BALB/c mice but not in d3-Tx BALB/lpsd mice, suggesting that LPS influences the progression of AIG development. Formation of auto-antibodies against the proton pump (H+/K+-ATPase) seemed to be related to AIG incidence in d3-Tx BALB/c mice. In d3-Tx BALB/lpsd mice, however, higher levels of auto-antibodies were detected in the type-2 mice, whereas AIG incidence was much lower than that in d3-Tx BALB/c mice. Thus, formation of auto-antibodies against the proton pump in d3-Tx BALB/lps d mice does not appear to correlate with AIG pathogenesis.
High context illness and dying in a low context medical world
Authors: Hallenbeck James
Published: June 2007

This article provides an introduction to thefield of intercultural communication. Miscommunication among patients, families, and clinicians often results when participants are contextually ”out-of-synch.“ High context communication embeds more information in the contexts within which people communicate and is less dependent on language. Very sick and dying patients often use high context communication strategies. Low context communication stresses explicit verbal communication and is commonly used by clinicians. When clinicians use low context forms of communication with patients using high context styles, misunderstandings frequently arise. Suggestions are given for avoiding miscommunication and enhancing mutual understanding.
Introducing hospice into allied health curricula: A challenge for educators
Authors: Paradis Lenora Finn
Published: June 2007

Including hospice, as a concept of care, into existing allied health curricula is very important. Hospiceshould be integrated into the curricula of allied healthp rograms. In addition tooffering courses on hospice care, there are many novel ideasfor exposing students to aspects ofhospice care including grand rounds, self-instruction packets, journal clubs, honors program presentations, monthly forums, and clerkships. Federalfunding is importanttosupportand develop hospice trainingaswellasotherresources.
An educational model for explaining hospice services
Authors: Welk Thomas A.
Published: June 2007

Explaining the concept and philosophy of hospice can be difficult. There is a reluctance in our society to openly address dyingldeath issues; there is a reluctance on the part of many healthcare professionals to look beyond physical issues.

The following model has been used successfully to explain hospice to both the generalpublic and health care professionals. It is not intended to introduce hospice to a patientlfamily during the initial referrallassessment visit.
Haven Hugs & Bugs
Authors: Bimbaum Aiton
Published: June 2007

This article describes the development and implementation of a unique, two-day therapeutic program for bereaved families. Issues relevant to program design are presented along with evaluation results. The family focus, the therapeutic value of nature, and the relationship of this program to Multiple Family Therapy, time-limited psychotherapy, and wilderness, camping, or recreation therapy approaches are discussed. Questions and suggestionsforfuture evaluation research are noted. The high potential therapeutic and cost-effectiveness of such innovative approaches to bereavement counseling should motivatefurtherprogram development and outcome research. Information on other weekend bereavement programs is appended.
Management of intestinal obstruction in hospice care
Authors: Baumrucker Steven J.
Published: June 2007

Bowel obstruction in the terminally ill is a relatively common complication. The classic therapy of IV hydration with nasogastric suction is contraindicated due to inefficacy and patient discomfort. Modern therapy consists of state-of-the-art pharmacologic treatments, as well as the judicious use of surgical interventions in selected cases. Many patients can be relatively symptom-free and can eat and drink as tolerated.
Writing to Learn by Learning to Write in the Disciplines
Authors: Carter Michael , Ferzli Miriam , Wiebe Eric N.
Published: June 2007

The traditional distinction between writing across the curriculum and writing in the disciplines (WID) as writing to learn versus learning to write understates WID's focus on learning in the disciplines. Advocates of WID have described learning as socialization, but little research addresses how writing disciplinary discourses in disciplinary settings encourages socialization into the disciplines. Data from interviews with students who wrote lab reports in a biology lab suggest five ways in which writing promotes learning in scientific disciplines. Drawing on theories of situated learning, the authors argue that apprenticeship genres can encourage socialization into disciplinary communities.
In Praise of Carbon, In Praise of Science
Authors: Casper Christian F.
Published: June 2007

This article explores the nature of epideictic rhetoric in science through a close textual analysis of three Nobel lectures. It examines the effects of the genre shift from original research reports to ceremonial speeches, revealing significant differences from Fahnestock's analysis of the genre shift from forensic research reports to epideictic articles in the popular press, especially a move toward greater candidness about the research process. Epideictic scientific rhetoric, therefore, can be said to celebrate the scientific method in general as much as it does the particular line of research at hand.
The Psychology of Ownership and Worker-Owner Productivity
Authors: Pierce Jon L. , Rodgers Loren
Published: June 2007

The theoretical and empirical linkages between employee ownership and performance are reviewed. In response to the inconsistent and inconclusive findings of a simple ownership-performance relationship, the authors revisit the conceptualization of ownership and ask how does ownership produce its performance effects. The study offers a “psychology of ownership” perspective on employee ownership, suggesting that ownership be thought of as a dual creation—part an objective and part a psychological state. In response to the question “how” does ownership produce its performance effects, a detailed model is presented that depicts a within-individual, self-esteem-based motivational effect explanation for the ownership-performance relationship.
Marital Cohesion, Flexibility, and Communication in the Marriages of Nontraditional and Traditional Women
Authors: Rhoden J. Lyn
Published: June 2007

The purpose of this study was to compare reported levels of marital quality, marital stability, and the marital processes of cohesion, flexibility, and communication in the marriages of nontraditional and traditional women. Selected data from the Marital Instability Over the Life Course Data Set were used. A subsample of 74 married women who were defined as nontraditional and a comparison group of 274 traditional women were selected according to their occupational status and gender role orientation. Nontraditional women included those reporting a nontraditional gender role orientation and employment in a professional or managerial position. Traditional women included those who reported a traditional gender role orientation and employment in a clerical, sales, service, or private household worker occupation. Results of repeated measures multivariate analysis of covariance indicated many similarities between the two groups; however, nontraditional women reported greater flexibility in their marriages. Implications of the findings for practice in clinical work with couples are addressed.
Differential Expression of Myoepithelial Markers in Salivary, Sweat and Mammary Glands
Authors: Foschini Maria P. , Scarpellini Francesca , Gown Allen M. , Eusebi Vincenzo
Published: June 2007

Myoepithelial cells (MECs) are contractile elements showing a combined epithelial and smooth muscle phenotype. Among the numerous immunohistochemical markers employed to detect MECs, smooth muscle actin (SMA) is the most widely used. Recently, other markers of smooth muscle differentiation have been demonstrated in MECs, such as calponin, heavy caldesmon (h-caldesmon), and smooth muscle myosin heavy chain (SMM-HC). In the present study normal salivary, mammary, and sweat glands have been studied with four markers of smooth muscle differentiation (SMA, calponin, h-caldesmon, and SMM-HC). The four markers were differentially expressed in the various types of glands. In parotid glands MECs mainly expressed calponin and caldesmon; in submandibular and in cutaneous apocrine and eccrine glands, MECs strongly expressed SMA, calponin, and caldesmon; in minor salivary glands all four markers were equally strongly expressed; and in mammary glands SMA, calponin, and SMM-HC were present both in periductal and periacinar MECs while caldesmon was present in periductal MECs only. In addition to MECs, SMA stained stromal myofibroblasts, sometimes hampering the identification of MECs. Among the other markers, calponin stained only rare stromal myofibroblasts, while caldesmon and SMM-HC were confined to MECs. In conclusion, these latter markers are very useful for identifying MECs. It is suggested that the differential expression of smooth muscle contractile proteins might reflect different functions of MECs in the various sites.
Epithelial Phenotype in Ewing's Sarcoma/Primitive Neuroectodermal Tumor
Authors: Vakar-Lopez Funda , Ayala Alberto G. , Raymond A. Kevin , Czerniak Bogdan
Published: June 2007

Neural differentiation is an integral component of Ewing's sarcoma/primitive neuroectodermal tumor (PNET), which exhibits a continuous spectrum from minimal to prominent neural phenotype. Differentiation of Ewing's sarcomas/PNETs along other lineages or the expression of an epithelial phenotype is less common and-if present-may cause diagnostic difficulties. In this study we evaluated the frequency of epithelial differentiation in formalin-fixed and paraffin-embedded tissues of 33 (22 primary and 11 metastatic) Ewing's sarcomas/PNETs by using an immunohistochemical assay with several antikeratin antibodies. Focal positivity for lowor highmolecular-weight keratins was documented in 18% of the cases, and diffuse coexpression of lowand high-molecular-weight keratins was observed in two cases. Expression of the MIC-2 gene product was documented in 94% of the tumors. The primitive neural phenotype as revealed by expression of either neuron-specific enolase or synaptophysin was observed in 30% of the cases, but coexpression of both neural markers was present in only 15% of the tumors. This study documents that, in addition to primitive neural differentiation, Ewing's sarcomas/PNETs frequently exhibit focal positivity for keratins, with rare strong diffuse coexpression of both lowand high-molecular-weight keratins. The findings indicate that the expression of an epithelial phenotype, at least in a focal fashion, is a relatively frequent finding in otherwise typical Ewing's sarcomas/PNETs.
Pleomorphic Angiomyolipoma of Digestive Tract: A Heretofore Unrecognized Entity
Authors: Prasad Manju L. , Keating John P. , Teoh H. Heng , McCarthy S. W. , Battifora Hector , Wasef Eva , Rosai Juan
Published: June 2007

Two cases of pleomorphic angiomyolipoma (AML) composed of bizarre epithelioid smooth muscle cells located in the gastrointestinal tract are reported. One involved the appendix of a 6-year-old girl, and the second the cecum of a 22-year-old woman. In both instances the tumor cells were immunoreactive for HMB-45 and A103. To the best of our knowledge, this peculiar variant of an AML has not previously been recognized in this location.
Predicting Metastatic Risk of Gastrointestinal Stromal Tumors: Role of Cell Proliferation and Cell Cycle Regulatory Proteins
Authors: Panizo-Santos Angel , Sola Iosu , Vega Francisco , De Alava Enrique , Lozano María Dolores , Idoate Miguel Angel , Pardo-Mindín Javier
Published: June 2007

Gastrointestinal stromal tumors (GIST) are a heterogeneous group of neoplasms whose biologic behavior is difficult to predict. The aim of this study is to evaluate the prognostic value in GIST of some oncoproteins involved in regulation of cell proliferation. Tumor size, mitosis, necrosis, and p53, c-myc, and bcl-2 protein expression of 32 GIST were studied. Proliferative index was assessed with Ki67. The 32 cases were grouped into the following clinical categories: (1) clinically benign (BN) were defined as disease-free survival greater than 3 years (n=10); (2) clinically malignant (MN) in which local recurrence or metastasis occurred regardless of the follow-up time (n=1 5); and (3) clinically indeterminate (ID) owing to follow-up <3 years without metastasis or local recurrence (n=seven). Discriminant analysis was used to allocate any tumor to one of the two prognostic groups (BN or MN). In univariate analysis all six factors studied above proved to be of significant prognostic value. Using a multivariate stepwise discriminant analysis to take into account the interrelationship between factors, we found that c-myc expression was the most important prognostic factor, followed, in order of statistical weight, by size and Ki67. These were combined to define a discriminant score ([10.75 x c-myc]+[0.39 x size]+[0.078 x Ki67]-15.54=score), which was capable of correctly identifying tumors in our series whose known clinical behavior was BN or MN in 92% of the cases. The classification score was applied subsequently to the seven clinically ID cases: Three (42.9%) were predicted as BN, and four (57.1%) were predicted as MN. Both expression of oncoprotein c-myc and the proliferative index provide prognostic information in GIST, in addition to morphologically established prognostic factors such as size. These factors in a discriminant analysis proved to be useful for the clinical classification of GIST into BN or MN and to predict the clinical outcome of clinically ID tumors.
The Perivascular Cuff of Large Lymphoid Cells: A Clue to Diagnosis of Anaplastic Large Cell Lymphoma
Authors: Chan John K. C.
Published: June 2007

The small cell and lymphohistiocytic variants of anaplastic large cell lymphoma are commonly misdiagnosed as reactive lymphadenopathies. A helpful histologic clue is the presence of perivascular cuffs of large lymphoid cells, and the diagnosis can be readily confirmed by immunostaining for CD30 and ALK.
Mesenchymal Chondrosarcoma: A Small Cell Neoplasm with Polyphenotypic Differentiation
Authors: Hoang Mai P. , Suarez Patricia A. , Donner Ludvik R. , Ro Jae Y , Ordñez Nelson G. , Ayala Alberto G. , Czerniak Bogdan
Published: June 2007

We analyzed the clinicoradiographic, microscopic, and immunophenotypic features of 21 tumors from 13 patients with mesenchymal chondrosarcoma (1 primary and 10 metastatic) and addressed the issue of their potential polyphenotypic differentiation. The immunophenotypic profile of the tumors was analyzed by studying the expressions of the MIC2 gene protein (p30/32MIC2), S-100 protein, desmin, myoDI, myogenin, myoglobin, smooth-muscle actin, cytokeratin, neuron-specific enolase, and HMB-45. The expression of p30/32MIC2 was typically restricted to the small cell component of the mesenchymal chondrosarcoma and could be documented in 17 tumors. The cartilaginous areas were positive for S-100 protein in 20 tumors. Scattered positivity of small cells for desmin was seen in 8 cases. In 2 primary tumors from different patients (1 intraosseous and 1 extraskeletal) a diffuse expression of desmin with focal coexpression of myoD 1 was present within the small cell component of the tumor. The positivity for smooth-muscle actin was documented in 2 cases. Either the small cell or cartilaginous components were at least focally positive for neuron-specific enolase in 11 tumors. All tumors were negative for myogenin, myoglobin, cytokeratins (AE1/AE3, CAM5.2) and HMB-45. This study showed that, in addition to cartilaginous differentiation, mesenchymal chondrosarcomas may exhibit focal expression of desmin. In rare cases more diffuse rhabdomyoblastic differentiation can be seen within the small cell component of the tumor. Thus, mesenchymal chondrosarcoma is another primitive neoplasm with polyphenotypic differentiation and features that overlap those of other small cell malignances of bone and soft tissue.
34βE 12 Cytokeratin Immunodetection in the Differential Diagnosis of Small Cell Tumors of Lung
Authors: Viberti Laura , Bongiovanni Massimo , Croce Sabrina , Bussolati Gianni
Published: June 2007

The group of small cell tumors of the lung includes the following: (1) small cell carcinoma (SCC) of neuroendocrine (NE) origin, (2) poorly differentiated squamous carcinoma, (3) the rare basaloid (basal cell) carcinomas, and (4) malignant lymphomas, primitive neuroectodermal tumors (PNETs), and rhabdomyosarcomas. The differential diagnosis among these entities carries a heavy therapeutic impact but may be difficult in small biopsy specimens or in cytologic material, especially if necrosis or artifactual alterations are present. The use of additional techniques such as immunostaining for NE markers is not always helpful, since immunoreactive chromogranin A is detectable in only a small percentage of small cell carcinomas. It has recently been reported that in the aerodigestive tract 34βE12 cytokeratin (CK) immunostaining selectively labels non-NE carcinomas, including squamous cell carcinoma, adenocarcinoma, and the rare basaloid carcinoma. We evaluated the role of such CK immunodetection in the differential diagnosis of small cell lung tumors in cytologic and biopsy specimens. Eighty-one lung tumors diagnosed by means of endoscopic bronchial biopsy, fine needle aspirate, or bronchial washing were collected. They included 43 small cell NE carcinomas and 38 cases used as controls (comprehensive of 2 large cell neuroendocrine carcinomas, 4 carcinoid tumors, 30 cases of non-NE lung carcinomas, 2 cases of bronchial infiltration by non-Hodgkin lymphomas). 34βE12 CK immunoreactivity was found in 29/30 cases of non-NE carcinomas, but in only 3/43 SCCs. The latter showed positivity in only a few scattered cells. The 2 cases of bronchial infiltration by malignant lymphoma as well as the 4 cases of carcinoid tumors and the 2 cases of large cell neuroendocrine carcinomas were negative. These findings were confirmed in the surgical specimens of operatedon cases. We conclude that, in lung carcinoma biopsies showing a small cell pattern, presence of 34βE12 CK immunoreactivity favors a non-NE carcinoma, whereas its absence supports the diagnosis of SCC.
Hyalinized Uterine Mesenchymal Neoplasms with HMB-45-Positive Epithelioid Cells: Epithelioid Leiomyomas or Angiomyolipomas? Report of Four Cases
Authors: Michal Michal , Zamecnikt Michal
Published: June 2007

We present 4 cases of uterine mesenchymal tumors that were located mostly in the myometrium in middle-aged women. Grossly the tumors vaguely resembled conventional leiomyomas. All tumors were extremely hyalinized. The tumor cells were remarkable because of their large size and epithelioid shape. They occurred singly or more often in variously sized clusters with pericellular clear spaces looking like a halo. The extracellular matrix often formed lacunae around the neoplastic cells. The lacunar type of growth was somewhat reminiscent of immature cartilage. In some places the cells lined up in vague cord-like structures. The epithelioid cells often grew within vessel walls and subendothelially, simulating angioinvasion. In 2 cases there were periodic acid-Schiff (PAS)-positive, needle-shaped crystalloids in the cytoplasm of the tumor cells. No atypias and no mitoses were found in any of the 4 tumors. Mucicarmine stain was negative in all cases. Immunohistochemically the tumor cells were negative for cytokeratins, synaptophysin, chromogranin, epithelial membrane antigen (EMA), S-I 00 protein, and inhibin. They were instead strongly positive for smooth muscle actin, desmin and HMB-45. All patients are disease free after a 1-4-year follow-up.
Massive Exfoliation of Markedly Atypical Cells in Urine Resulting from Polyoma Virus Interstitial Nephritis
Authors: Papadimitriou John C. , Drachenberg Cinthia B. , Bourquin Patricia M.
Published: June 2007

Polyoma virus nephritis is increasingly being recognized as a cause of allograft dysfunction in renal transplant patients. We describe and illustrate the findings in a renal biopsy and a concurrent urine sample from a patient with polyoma virus nephritis. The urine cytology findings were highly suggestive of a tumor due to the presence of large number of atypical cells with marked hyperchromasia, high nuclear/cytoplasmic ratio in a necrotic background. Scattered cells with viral cytopathic changes were also identified, therefore indicating an infectious process with associated reactive cellular changes rather than a tumor. The cytological findings could thus be explained by the viral cytopathic and cytolytic changes, as well as marked reactive and degenerative changes in tubular epithelial cells.
Histologic Recurrence-Free Outcome After Orthotopic Liver Transplantation For Chronic Hepatitis B
Authors: Tabatabai Z. Laura , Lewis W. David , Gordon Fredric D. , Jenkins Roger L. , Khettry Urmila
Published: June 2007

Recurrent hepatitis B (HB) following orthotopic liver transplantation (OLT) for chronic disease is common. However, an unpredictable minority of patients follow a recurrence-free course. Clinical, virologic, and pathologic data from patients surviving longer than 60 days (n=24) with pathologically confirmed nonrecurrence of HB following OLT for chronic HB were reviewed to identify factors associated with non-recurrence of HB. Nine of 24 patients had no histologic and immunohistologic evidence of recurrent HB. In addition to pre-OLT hepatitis B e antigen (HBeAg) negativity, coexisting delta and anti-HB therapy/prophylaxis, other acquired viral infections and their therapy, and severe acute rejection due to noncompliance were considered the possible protective factors against HB recurrence in these 9 patients. Histologic and, particularly immunopathologic, evaluation of liver biopsies must be utilized in definitively diagnosing recurrence of HB.
Papillary Thyroid Carcinoma of the Thyroglossal Duct Cyst
Authors: Falconieri Giovanni , Libera Duilio Della , Zanella Micaela
Published: June 2007

We report a cytohistologic and immunohistochemical study of 2 cases of papillary thyroid carcinoma occurring in a thyroglossal duct cyst. The patients were a 21-yearold woman and a 48-year-old man. Needle aspiration cytology smears were consistent with papillary thyroid carcinoma. The Sistrunk procedure was done. Papillary carcinoma was found within a thyroglossal duct cyst. In 1 case, the tumor spread outside the cyst. Follow-up was uneventful in both patients (2 and 9 years, respectively). Our results would indicate that papillary carcinoma of thyroglossal duct cyst, though indistinguishable from its thyroid homologue, has a more indolent course and could therefore be singled out as a clinicopathologic entity. Needle aspiration cytology reliably assists in planning patient management.
Atypical Cystic Lobules in Patients with Lobular Neoplasia
Authors: Brogi Edi , Oyama Tetsunari , Koerner Frederick C.
Published: June 2007

We analyzed the frequency and anatomic distribution of atypical cystic lobules (ACLs) in patients whose index biopsy specimen contained lobular neoplasia (LN). Thirty of 54 patients (56%) had ACLs in their index biopsy specimen. Five of the patients whose index biopsy lacked ACLs underwent an additional biopsy, and 4 of these patients had ACLs in an additional specimen, bringing the total number of patients having both ACLs and LN to 34 of 54 (62.9%). ACLs involved both breasts with equal frequency and neither the extent of the involvement nor the anatomic location of the LN paralleled the distribution of the ACLs. The presence of ACLs in patients with LN might explain its increased risk for the development of ductal carcinomas and their bilateral distribution.
Metastatic Metanephric Adenoma with Foci of Papillary Carcinoma in a Child
Authors: Drut Ricardo , Drut R. Mónica , Ortolani Cristina
Published: June 2007

We report an example of metastatic metanephric adenoma containing foci of papillary carcinoma in the primitive tumor arising in the left kidney of an 11 -year-old girl. Histology revealed a monomorphous population of small cells with bland cytology arranged in pseudoglandular, tubular, papillary, and glomeruloid structures with frequent Samoa bodies. Intermixed there were foci of and small cavities lined by larger cells with eosinophilic cytoplasm and larger nuclei with small nucleoli. A regional lymph node contained metastatic deposits with the former histologic pattern. By immunohistochemistry the small cells were negative for carcinoembryonic antigen (CEA) and keratin 7 while these antibodies reacted positively in the larger cells. A fluorescent in-situ hybridization (FISH) study for chromosome 17 in imprints from the primitive tumor revealed 3 signals in about 10% of the nuclei while the rest was disomic. Disaggregated cells from the metastatic lymph node consistently revealed 2 signals for chromosomes 7, 16, and 17. Histology of the primitive tumor resembled the epithelial component of the so-called metanephric adenofibroma while the metastatic lymph node exhibited histologic and FISH genomic features of metamorphic adenoma.
The Histopathology of Pediatric Celiac Disease: Order Must Prevail Out of Chaos
Authors: Drut Ricardo , Ruia Eduardo Cueto
Published: June 2007

The role of histopathology for diagnosing celiac disease (CD) has been recently challenged. However, based in our experience with roughly 4,600 distal duodenal and jejunal biopsies in children it is apparent that appropriate biopsy site, handling, processing, and microscopic evaluation result in a consistent pattern of microscopic changes which allows strong clinical-pathologic correlation. A simple way for establishing the villous/crypt (V/C) ratio is proposed. Normal mucosa displays a V/C ratio of 2.5 or more. Villous atrophy is then graded according to the V/C ratio as follows: Grade 1: 2.5-2; Grade 2: 1-2; Grade 3: 1-0.5, and Grade 4: less than 0.5. The grading should be done in areas of the biopsy where at least 2 to 3 crypts are present in almost its full length. CD disease was consistently associated with villous atrophy grades 3 and 4, which fully recovered or maintained Grade 1 after gluten-free diet. Grade 2 biopsies were rare and related to incomplete gluten-free diet. Patchy lesions were never seen as were patients with normal biopsies later developing mucosal atrophy. Histopathologic evaluation of mucosal biopsies to rule out CD requires adequate biopsy site (distal duodenum or proximal jejunum), and proper handling (oriented material), processing (cutting on edge) and interpretation. The proposed villous atrophy grading may help to adequately compare experiences from different centers as well as to reconcile apparent different findings in separate biopsies. In children histopathology keeps on having a central role for CD diagnosis.
Diagnosis of Gastrointestinal Stromal Tumors:A Consensus Approach
Authors: Fletcher Christopher D. M. , Berman Jules J. , Corless Christopher , Gorstein Fred , Lasota Jerzy , Longley B. Jack , Miettinen Markku , O'Leary Timothy J. , Remotti Helen , Rubin Brian P. , Shmookler Barry , Sobin Leslie H. , Weiss Sharon W.
Published: June 2007

As a result of major recent advances in understanding the biology of gastrointestinal stromal tumors (GIST), specifically recognition of the central role of activating KIT mutations and associated KIT protein expression in these lesions, and thedevelop-ment of novel and effective therapy for GISTs using thereceptor tyrosine kinase in hibitor STI-571, these tumors have become the focus of considerable attention among pathologists, clinicians, and patients. Stromal/mesenchymal tumors of the gastrointestinal tract have long been a sourceof confusion and controversy with regard to classification, line(s) of differentiation, and prognostication. Characterization of the KIT pathway and its phenotypic implications has helped to resolve some but not all of these issues. Given the now critical role of accurate and reproducible pathologic diagnosis in ensuring appropriate treatment for patients with GIST, the National Institutes of Health (NIH) convened a GIST workshop in April 2001 with the goal of developing a consensus approach to diagnosis and morphologic prognostication. Key elements of the consensus, as described herein, are the defining role of KIT immunopositivity indiagnosis and a proposed scheme for estimating metastatic riskin these lesions, based on tumor size and mitotic count, recognizing that it is probably unwise to use the definitive term benign for any GIST, at least at the present time.
Liver Transplantation for Alcoholic Liver Disease with or Without Hepatitis C
Authors: Goldar-Najafi Atoussa , Gordon Fredric D. , Lewis W. David , Pomfret Elizabeth , Pomposelli James J. , Jenkins Roger L. , Khettry Urmila
Published: June 2007

Alcoholic cirrhosis with or without hepatitis C is a common indication for liver transplantation (LT). Comparative post-LT data for the 2 groups are not available. Our aim is to compare the clinicopathologic features of patients with alcoholic liver disease (ETOH) and ETOH/HCV at the time of and after LT and to determine the impact of concomitant hepatitis C virus (HCV) on ETOH patients undergoing LT. A comparative clinical and pathologic analysis at LT and after LT was performed for 56 patients with ETOH and 32 patients with ETOH/HCV. All 88 had cirrhosis at LT. Other native liver features for ETOH and ETOH/HCV, respectively, were: >2+ inflammation 50/56 and 26/32, Mallory's hyalin 12/56 and 6/32, steatosis 9/56 and7/32, large cell dysplasia 12/56 and 6/32, hepatoma 4/56 and 4/32, iron deposition 24/56 and 12/32; none was statistically significant. The post-LT findings for ETOH and ETOH/HCV were as follows: 1-year survival 93% and 97%; alive 36/56 (419-4,348 days) and 27/32 (488-5,516 days); deaths 20/56 and 5/32; ETOH recurrence 5/56 (all alive) and 3/32 (1 dead); post-LT HCV 4/56 (acquired) and 22/32 (recurrent). Native liver histology in ETOH and ETOH/HCV patients was similar. Post-LT HCV recurrence was common (69%) O in ETOH/HCV patients but resulted in death inonly 6%. Post-LT ETOH recurrence was uncommon (9%) and progression to liver failure was rare (1.1%). Post-LT outcome for ETOH was excellent, and concomitant HCV did not affect survival.
Poorly Differentiated Carcinomas of the Thyroid Gland
Authors: Sobrinho-Simoes Manuel , Sambade Clara , Fonseca Elsa , Soares Paula
Published: June 2007

We evaluated the clinicopathologic, immunohistochemical, lectin histochemical, ultrastructural and morphometric characteristics of a series of 28 poorly differentiated carcinomas of the thyroid (PDCT). The 28 tumors were classified according to their predominant growth pattern as insular (n=12), trabecular (n=10) and solid subtypes (n=6). The overall mortality rate was 46%. No significant differences were found among the 3 subtypes. Data obtained by lectin histochemistry, electron microscopy, and morphometry point to a closer relationship of PDCT to follicular than to papillary carcinoma. Our results do not support the subdivision of PDCT into subtypes.
Lymph Node Infarction Associated with Infectious Mononucleosis
Authors: Kojima Masaru , Nakamura Shigeo , Sugihara Shiro , Sakata Noriyuki , Masawa Nobuhide
Published: June 2007

A completely infarcted lymph node should alert the pathologist to the high possibility of malignant lymphoma. The lymph node lesion of infectious mononucleosis (IM) shows marked histologic diversity and occasionally may be confused with malignant lymphoma. We report a rare case of IM showing extensive lymph node infarction whose lymph node lesion was similar to lymph node infarction associated with maligant lymphoma. This case describes a 32-year-old Japanese man who had signs and symptoms consistent with IM, which he was later proven serologically to have, but whose cervical lymph node showed extensive lymph node infarction with a thin area of granulation tissue beneath the capsule. The infarcted tissue contained numerous eosinophilic ghosts of large lymphoid cells. The thin granulation tissue was composed of numerous small lymphocytes, plasma cells, and histiocytes, in addition to large lymhoid cells including immunoblasts and granulocytes. CD20, CD3, and CD45RO imunostains revealed the mixed Bnd T-cell nature of the ghosts of large lymphoid cells in the infarcted tissue as well as viable large cells in the granulation tissue. The patient was free from disease after 50 months' follow-up.