bluuebunny/crossref_metadata_2025 huggingface dataset:
The humoral pattern recognition receptor PTX3 is stored in neutrophil granules and localizes in extracellular traps
Authors: Jaillon Sébastien , Peri Giuseppe , Delneste Yves , Frémaux Isabelle , Doni Andrea , Moalli Federica , Garlanda Cecilia , Romani Luigina , Gascan Hugues , Bellocchio Silvia , Bozza Silvia , Cassatella Marco A. , Jeannin Pascale , Mantovani Alberto
Published: March 2007

The long pentraxin (PTX) 3 is produced by macrophages and myeloid dendritic cells in response to Toll-like receptor agonists and represents a nonredundant component of humoral innate immunity against selected pathogens. We report that, unexpectedly, PTX3 is stored in specific granules and undergoes release in response to microbial recognition and inflammatory signals. Released PTX3 can partially localize in neutrophil extracellular traps formed by extruded DNA. Eosinophils and basophils do not contain preformed PTX3. PTX3-deficient neutrophils have defective microbial recognition and phagocytosis, and PTX3 is nonredundant for neutrophil-mediated resistance against Aspergillus fumigatus. Thus, neutrophils serve as a reservoir, ready for rapid release, of the long PTX3, a key component of humoral innate immunity with opsonic activity.
The Niemann-Pick type C2 protein loads isoglobotrihexosylceramide onto CD1d molecules and contributes to the thymic selection of NKT cells
Authors: Schrantz Nicolas , Sagiv Yuval , Liu Yang , Savage Paul B. , Bendelac Albert , Teyton Luc
Published: March 2007

The Niemann-Pick type C2 (NPC2) protein is a small, soluble, lysosomal protein important for cholesterol and sphingolipid transport in the lysosome. The immunological phenotype of NPC2-deficient mice was limited to an impaired thymic selection of Vα14 natural killer T cells (NKT cells) and a subsequent reduction of NKT cells in the periphery. The remaining NKT cells failed to produce measurable quantities of interferon-γ in vivo and in vitro after activation with α-galactosylceramide. In addition, thymocytes and splenocytes from NPC2-deficient mice were poor presenters of endogenous and exogenous lipids to CD1d-restricted Vα14 hybridoma cells.

Importantly, we determined that similar to saposins, recombinant NPC2 was able to unload lipids from and load lipids into CD1d. This transfer activity was associated with a dimeric form of NPC2, suggesting a unique mechanism of glycosphingolipid transfer by NPC2. Similar to saposin B, NPC2 dimers were able to load isoglobotrihexosylceramide (iGb3), the natural selecting ligand of NKT cells in the thymus, into CD1d. These observations strongly suggested that the phenotype observed in NPC2-deficient animals was directly linked to the efficiency of the loading of iGb3 into CD1d molecules expressed by thymocytes. This conclusion was supported by the rescue of endogenous and exogenous iGb3 presentation by recombinant NPC2. Thus, the loading of endogenous and exogenous lipids and glycolipids onto CD1d is dependent on various small, soluble lipid transfer proteins present in the lysosome.
Intrarectal transmission, systemic infection, and CD4+ T cell depletion in humanized mice infected with HIV-1
Authors: Sun Zhifeng , Denton Paul W. , Estes Jacob D. , Othieno Florence A. , Wei Bangdong L. , Wege Anja K. , Melkus Michael W. , Padgett-Thomas Angela , Zupancic Mary , Haase Ashley T. , Garcia J. Victor
Published: March 2007

Intrarectal infection between men who have sex with men represents a predominant form of human immunodeficiency virus (HIV) transmission in developed countries. Currently there are no adequate small animal models that recapitulate intrarectal HIV transmission. Here we demonstrate that human lymphocytes generated in situ from hematopoietic stem cells reconstitute the gastrointestinal tract of humanized mice with human CD4+ T cells rendering them susceptible to intrarectal HIV transmission. HIV infection after a single intrarectal inoculation results in systemic infection with depletion of CD4+ T cells in gut-associated lymphoid tissue and other pathologic sequela that closely mimics those observed in HIV infected humans. This novel model provides the basis for the development and evaluation of novel approaches aimed at immune reconstitution of human gut-associated lymphoid tissue and for the development, testing, and implementation of microbicides to prevent intrarectal HIV-1 transmission.
CENP-C Is Involved in Chromosome Segregation, Mitotic Checkpoint Function, and Kinetochore Assembly
Authors: Kwon Mi-Sun , Hori Tetsuya , Okada Masahiro , Fukagawa Tatsuo
Published: March 2007

CENP-C is a conserved inner kinetochore component. To understand the precise roles of CENP-C in the kinetochore, we created a cell line with a conditional knockout of CENP-C with the tetracycline-inducible system in which the target protein is inactivated at the level of transcription. We found that CENP-C inactivation causes mitotic delay. However, observations of living cells showed that CENP-C-knockout cells progressed to the next cell cycle without normal cell division after mitotic delay. Interphase cells with two nuclei before subsequent cell death were sometimes observed. We also found that ∼60% of CENP-C–deficient cells had no Mad2 signals even after treatment with nocodazole, suggesting that lack of CENP-C impairs the Mad2 spindle checkpoint pathway. We also observed significant reductions in the signal intensities of Mis12 complex proteins at centromeres in CENP-C–deficient cells. CENP-C signals were also weak in interphase nuclei but not in mitotic chromosomes of cells with a knockout of CENP-K, a member of CENP-H complex proteins. These results suggest that centromere localization of CENP-C in interphase nuclei occurs upstream of localization of the Mis12 complex and downstream of localization of the CENP-H complex.
The Medicinal Mushroom Agaricus blazei Murrill: Review of Literature and Pharmaco‐Toxicological Problems
Authors: Firenzuoli F. , Gori L. , Lombardo G.
Published: March 2007

Agaricus blazei Murrill (ABM) popularly known as ‘Cogumelo do Sol’ in Brazil, or ‘Himematsutake’ in Japan, is a mushroom native to Brazil, and widely cultivated in Japan for its medicinal uses, so it is now considered as one of the most important edible and culinary‐medicinal biotechnological species. It was traditionally used to treat many common diseases like atherosclerosis, hepatitis, hyperlipidemia, diabetes, dermatitis and cancer. In vitro and in vivo ABM has shown immunomodulatory and antimutagenic properties, although the biological pathways and chemical substances involved in its pharmacological activities are still not clear. The polysaccharides phytocomplex is thought to be responsible for its immunostimulant and antitumor properties, probably through an opsonizing biochemical pathway. Clinical studies are positive confirmations, but we are still at the beginning, and there are perplexing concerns especially relative to the content of agaritine. Argantine is a well‐known carcinogenic and toxic substance in animals, that must be completely and fully evaluated.
Approximate disease dynamics in household-structured populations
Authors: Dodd P.J , Ferguson N.M
Published: March 2007

We argue that the large-dimensional dynamical systems which frequently occur in biological models can sometimes be effectively reduced to much smaller ones. We illustrate this by applying projection operator techniques to a mean-field model of an infectious disease spreading through a population of households. In this way, we are able to accurately approximate the dynamics of the system in terms of a few key quantities greatly reducing the number of equations required. We investigate linear stability in this framework and find a new way of calculating the familiar threshold criterion for household systems.
A system with adjustable positive or negative thermal expansion
Authors: Grima Joseph N , Farrugia Pierre S , Gatt Ruben , Zammit Victor
Published: March 2007

We analyse the anisotropic thermal expansion properties of a two-dimensional structurally rigid construct made from rods of different materials connected together through hinges to form triangular units. In particular, we show that this system may be made to exhibit negative thermal expansion coefficients along certain directions or thermal expansion coefficients that are even more positive than any of the component materials. The end product is a multifunctional system with tunable thermal properties that can be tailor-made for particular practical applications.
Phylogeny of the sea spiders (Arthropoda, Pycnogonida) based on direct optimization of six loci and morphology
Authors: Arango Claudia P. , Wheeler Ward C.
Published: March 2007

Higher‐level phylogenetics of Pycnogonida has been discussed for many decades but scarcely studied from a cladistic perspective. Traditional taxonomic classifications are yet to be tested and affinities among families and genera are not well understood. Pycnogonida includes more than 1300 species described, but no systematic revisions at any level are available. Previous attempts to propose a phylogeny of the sea spiders were limited in characters and taxon sampling, therefore not allowing a robust test of relationships among lineages. Herein, we present the first comprehensive phylogenetic analysis of the Pycnogonida based on a total evidence approach and Direct Optimization. Sixty‐three pycnogonid species representing all families including fossil taxa were included. For most of the extant taxa more than 6 kb of nuclear and mitochondrial DNA and 78 morphological characters were scored. The most parsimonious hypotheses obtained in equally weighted total evidence analyses show the two most diverse families Ammotheidae and Callipallenidae to be non‐monophyletic. Austrodecidae + Colossendeidae + Pycnogonidae are in the basal most clade, these are morphologically diverse groups of species mostly found in cold waters. The raising of the family Pallenopsidae is supported, while Eurycyde and Ascorhynchus are definitely separated from Ammotheidae. The four fossil taxa are grouped within living Pycnogonida, instead of being an early derived clade. This phylogeny represents a solid framework to work towards the understanding of pycnogonid systematics, providing a data set and a testable hypothesis that indicate those clades that need severe testing, especially some of the deep nodes of the pycnogonid tree and the relationships of ammotheid and callipallenid forms. The inclusion of more rare taxa and additional sources of evidence are necessary for a phylogenetic classification of the Pycnogonida.

© The Willi Hennig Society 2006.
Protein expression associated with early intrahepatic recurrence of hepatocellular carcinoma after curative surgery
Authors: Yokoo Hideki , Kondo Tadashi , Okano Tetsuya , Nakanishi Kazuaki , Sakamoto Michiie , Kosuge Tomoo , Todo Satoru , Hirohashi Setsuo
Published: March 2007

The poor prognosis of patients with hepatocellular carcinoma (HCC) is attributed to intrahepatic recurrence. To understand the molecular background of early intrahepatic recurrence, we conducted a global protein expression study. We compared the protein expression profiles of the primary HCC tissues of 12 patients who showed intrahepatic recurrence within 6 months post surgery with those of 15 patients who had no recurrence 2 years post surgery. Two‐dimensional difference gel electrophoresis identified 23 protein spots, the intensity of which was highly associated with early intrahepatic recurrence. To validate the prediction performance of the identified proteins, we examined additional HCC tissues from 13 HCC patients; six with early intrahepatic recurrence and seven without recurrence. We found that all but one of the 13 patients were grouped according to their recurrence status based on the intensity of the 23 protein spots. Mass spectrometry identified 23 proteins corresponding to the spots. Although 13 of 23 have been previously reported to be correlated with HCC, their association with early intrahepatic recurrence had not been established. The identified proteins are involved in signal transduction pathways, glucose metabolism, cytoskeletal structure, cell adhesion, or function as antioxidants and chaperones. The identified proteins may be candidates for prognostic markers and contribute to the improvement of existing therapeutic strategies. (Cancer Sci 2007; 98: 665–673)
Loss of smooth muscle calponin results in impaired blood vessel maturation in the tumor–host microenvironment
Authors: Yamamura Hisako , Hirano Noriko , Koyama Hidenori , Nishizawa Yoshiki , Takahashi Katsuhito
Published: March 2007

The interactions between malignant cells and the microenvironment of the local host tissue play a critical role in tumor growth, metastasis and their response to treatment modalities. We investigated the roles of smooth muscle calponin (Cnn1, also called calponin h1 or basic calponin) in the development of tumor vascul ature in vivo by analyzing mutant mice lacking the Cnn1 gene. Here we show that loss of Cnn1 in host mural cells prevents maturation of tumor vasculature. In vitro studies showed that platelet‐derived growth factor B‐induced vascular smooth muscle migration was downregulated by the Cnn1‐deficiency, and forced expression of Cnn1 restored migration. Moreover, destruction of established tumor mass by treatment with an antivascular endothelial growth factor antibody was markedly enhanced in Cnn1‐deficient mice. These data, coupled with the knowledge that structural fragility of normal blood vessels is caused by loss of the Cnn1 gene, suggest that Cnn1 plays an important role in the maturation of blood vessels, and may have implications for therapeutic strategies targeting tumor vasculature for treatment of human cancers. (Cancer Sci 2007; 98: 757–763)
Identification of a predictive gene expression signature of cervical lymph node metastasis in oral squamous cell carcinoma
Authors: Nguyen Su Tien , Hasegawa Shogo , Tsuda Hitoshi , Tomioka Hirofumi , Ushijima Masaru , Noda Masaki , Omura Ken , Miki Yoshio
Published: March 2007

An accurate assessment of the cervical lymph node metastasis status in oral cavity cancer not only helps predict the prognosis of patients, but also helps surgeons to perform the appropriate treatment. We investigated the utilization of microarray technology focusing on the differences in gene expression profiles between primary tumors of oral squamous cell carcinoma that had metastasized to cervical lymph nodes and those that had not metastasized in the hope of finding new biomarkers to serve for diagnosis and treatment of oral cavity cancer. To design this experiment, we prepared two groups: the learning case group with 30 patients and the test case group with 13 patients. All tissue samples were performed using laser captured microdissection to yield cancer cells, and RNA was isolated from purified cancer cells. To identify a predictive gene expression signature, the different gene expressions between the two groups with and without metastasis in the learning case (n = 30) were analyzed, and the 85 genes expressed differentially were selected. Subsequently, to construct a more accurate prediction model, we further selected the genes with a high power for prediction from the 85 genes using the AdaBoost algorithm. The eight candidate genes, DCTD, IL‐15, THBD, GSDML, SH3GL3, PTHLH, RP5‐1022P6 and C9orf46, were selected to achieve the minimum error rate. Quantitative reverse transcription–polymerase chain reaction was carried out to validate the selected genes. From these statistical methods, the prediction model was constructed including the eight genes and this model was evaluated by using the test case group. The results in 12 of 13 cases (∼92.3%) were predicted correctly. (Cancer Sci 2007; 98: 740–746)
Influence of the CYP3A5 and MDR1 genetic polymorphisms on the pharmacokinetics of tacrolimus in healthy Korean subjects
Authors: Choi Ji H. , Lee Yoon J. , Jang Seong B. , Lee Jong‐Eun , Kim Kyung H. , Park Kyungsoo
Published: March 2007

What is already known about this subject

• It was found that the genetic polymorphisms of CYP3A5, CYP3A4 and MDR1 could affect the pharmacokinetics of tacrolimus.

• This study was conducted to find such a possibility in the Korean population.

What this study adds

• CYP3A5 polymorphisms are likely to be associated with altered pharmacokinetics of tacrolimus in Koreans.

• MDR1 polymorphisms have no important role in the pharmacokinetics of tacrolimus.

Aims

To determine the frequencies of the genotypes of CYP3A5 and MDR1 and to examine the influence of the polymorphisms of these genes on tacrolimus pharmacokinetics in the Korean population.

Methods

Twenty‐nine healthy Koreans who participated in the previous tacrolimus pharmacokinetic study were genotyped for CYP3A4*1B, CYP3A5*3, MDR1 c.1236C→T, MDR1 c.2677G→A/T and MDR1 c.3435C→T. The relationship between the genotypes so obtained and tacrolimus pharmacokinetics observed in the previous study was examined.

Results

No subject in this study had the CYP3A4*1B variant. The observed frequencies of CYP3A5*1/*1, *1/*3, and *3/*3 were 0.069 [confidence interval (CI) −0.023, 0.161], 0.483 (CI 0.301, 0.665) and 0.448 (CI 0.267, 0.629), respectively. AUC0–∞ for the CYP3A5*1/*1 or *1/*3 genotype was 131.5 ± 44.8 ng h ml−1 (CI 109.6, 153.5), which was much lower compared with the CYP3A5*3/*3 genotype of 323.8 ± 129.3 ng h ml−1 (CI 253.5, 394.1) (P = 2.063E−07). Similarly, Cmax for the CYP3A5*1/*1 or *1/*3 genotype was 11.8 ± 3.4 ng ml−1 (CI 10.1, 13.5), which was also much lower compared with the CYP3A5*3/*3 genotype of 24.4 ± 12.3 ng ml−1 (CI 17.8, 31.1) (P = 0.0001). However, there was no significant difference in tacrolimus pharmacokinetics among the MDR1 diplotypes of CGC‐CGC, CGC‐TTT, CGC‐TGC, TTT‐TGC or TTT‐TTT (P = 0.2486).

Conclusions

This study shows that the CYP3A5*3 genetic polymorphisms may be associated with the individual difference in tacrolimus pharmacokinetics. An individualized dosage regimen design incorporating such genetic information would help increase clinical efficacy of the drug while reducing adverse drug reactions.
Population pharmacokinetics and bioavailability of tacrolimus in kidney transplant patients
Authors: Antignac Marie , Barrou Benoit , Farinotti Robert , Lechat Philippe , Urien Saïk
Published: March 2007

What is already known about this subject

•  In spite of its success in ensuring graft survival, therapeutic use of tacrolimus is complicated by its narrow therapeutic index and wide intra‐ and interpatient variability.

•  Some studies of population pharmacokinetics have already been conducted in liver transplant recipients and in paediatric patients.

What this study adds

•  Our work determined population pharmacokinetic parameters, in particular bioavailability, in kidney transplant recipients and the relative importance of factors influencing the disposition of tacrolimus.

•  Clearance was modelled and days postoperation and corticosteroids dose were significant covariates.

Aims The use of tacrolimus is complicated by its narrow therapeutic index and wide intra‐ and interpatient variability. Tacrolimus population pharmacokinetics, including bioavailability, were investigated in an adult kidney transplant cohort to identify patient characteristics that influence pharmacokinetics.

Methods The database (drug monitoring data) included 83 adult kidney transplant recipients and analysis was performed by a population approach with NONMEM. Data were collected during the first months after transplantation. Patients were administered oral or intravenous tacrolimus as part of a triple immunosuppressive regimen that also included mycophenolate mofetil and corticosteroids. Subsequent doses were adjusted on the basis of clinical evidence of efficacy and toxicity as in routine therapeutic drug monitoring.

Results A one compartment open model with linear absorption and elimination adequately described the data. The typical value of minimal clearance was 1.8 ± 0.2 l h−1. Clearance increased with time post transplantation to reach 50% of maximal value after 3.8 ± 0.5 days, with a maximal value of 5.6 l h−1. Moreover clearance increased by approximately 1.6 fold (range 0.5–1.6) if the dose of prednisone was >25 mg. The typical value for volume of distribution, V, (98 ± 13 l kg−1) was similar to reported values in kidney transplant patients. The oral bioavailability of tacrolimus was poor and ranged from 11.2 to 19.1%. No covariates significantly influenced V or F.

Conclusions The number of days postoperation and corticosteroid dose were significant covariates influencing tacrolimus clearance.
Detection of urinary bladder cancer with flow cytometry and hexaminolevulinate in urine samples
Authors: Čunderlíková B. , Wahlqvist R. , Berner A. , Vasovič V. , Warloe T. , Nesland J. M. , Peng Q.
Published: March 2007

Objectives:  Urinary bladder urothelial carcinoma is diagnosed by a combination of cystoscopy and biopsy, with cytology as a valuable additional technique. The accuracy of cytological diagnosis depends on the experience of the cytologist and can inevitably vary from one cytologist to another. There is a need for an easy, reliable and objective diagnostic method. In the present study a new method was designed for the detection of bladder cancer cells in urine.

Methods:  Flow cytometry was utilized to detect protoporphyrin IX in an artificial model consisting of normal urinary bladder transitional epithelial cells (NBECs) from healthy volunteers’ urine and an established human urinary bladder carcinoma cell line, TCCSUP, after incubation with hexaminolevulinate (HAL). In addition, urine samples from 19 patients with histopathologically confirmed superficial bladder cancer were examined.

Results:  Incubation of NBECs or TCCSUP cells with HAL for 1 hour resulted in production of protoporphyrin IX only in the TCCSUP cells. Incubation of a mixture of NBECs and TCCSUP cells with HAL gave rise to a separated subpopulation of cells with protoporphyrin IX fluorescence. After cell sorting by flow cytometry the protoporphyrin IX‐containing subpopulation of cells was confirmed as TCCSUP cells on cytological examination. It was possible to detect 5% TCCSUP cells in the mixture of NBECs/TCCSUP cells. To test the feasibility of the method in clinica diagnosis, urine samples from patients with bladder cancer were also measured with comparable, although preliminary and limited, results to those of cytological examination.

Conclusions:  The preliminary results show that the technique may be feasible for the detection of bladder cancer cells in urine with possible advantages of simplicity, reliability and objectivity.
European guidelines for quality assurance in cervical cancer screening: recommendations for cytology laboratories*
Authors: Wiener H. G. , Klinkhamer P. , Schenck U. , Arbyn M. , Bulten J. , Bergeron C. , Herbert A.
Published: March 2007

The quality of a cervical cytology laboratory depends on adequate handling and staining of the samples, screening and interpretation of the slides and reporting of the results. These guidelines give an overview of procedures recommended in Europe to manage the balance between best patient care possible, laboratory quality assurance and cost effectiveness and will be published as a chapter 4 in the European Guidelines for Quality Assurance in Cervical Cancer Screening. The laboratory guidelines include protocols for personnel and organisation, material requirements, handling and analysing cervical samples, recording of results, quality management and communication. The section on quality management is comprehensive and includes protocols for all aspects of internal and external quality assurance. The guidelines are extensively referenced and as far as possible the recommendations are evidence‐based.
F8 gene mutation profile and ITT response in a cohort of Italian haemophilia A patients with inhibitors
Authors: SALVIATO R. , BELVINI D. , RADOSSI P. , SARTORI R. , PIEROBON F. , ZANOTTO D. , ZANON E. , CASTAMAN G. , GANDINI G. , TAGARIELLO G.
Published: March 2007

Summary.  Anti factor VIII (FVIII) antibodies represent the main complication of replacement therapy in severe cases of haemophilia and most patients with inhibitor have gross gene rearrangements or point mutations that hamper the production of normal circulating FVIII. In this study we have investigated 82 haemophilia A patients with inhibitors. Seventy six were severe, three were moderate and three were mild. We screened the patients for the causative mutations using long range PCR for the recurrent intron 22 inversion (invint22), multiplex PCR for intron 1 inversion (invint1) and conformation sensitive gel electrophoresis followed by DNA sequencing for all other mutation types in the F8 gene. Diverse genetic defects were detected in the severe cases (with a predominance of severe molecular defects): F8 gene inversions, large deletions and non‐sense mutations account for 71% of the mutations. Only missense and splicing mutations were identified in the non‐severe patients and we confirmed that the presence of inhibitors correlates well with the presence of severe mutations, but a proportion of severe patients develops inhibitors despite the presence of diverse less severe mutations. When we have analysed the subgroup of patients who underwent immunetolerance, we have found that F8 gene large deletions are likely to be a high risk factor also for immunetolerance therapy unresponsiveness, while no clear evidence has been demonstrated for other mutation types.
The endocrine component of prostatic carcinomas, mixed adenocarcinoma‐carcinoid tumours and non‐tumour prostate. Histochemical and ultrastructural identification of the endocrine cells
Authors: CAPELLA C. , USELLINI L. , BUFFA R. , FRIGERIO B. , SOLCIA E.
Published: April 2007

Two types of endocrine‐paracrine (EP) cells have been detected histochemically and ultrastructurally in normal and hyperplastic prostates; i.e. type 1 cells resembling intestinal EC (enterochromaffin) cells and type 2 cells similar to urethral EP cells previously reported by Casanova et al. (1974). About one‐third of the 40 prostatic carcinomas studied contained EP cells. Four tumours showed a very large number of EP cells: two of these were composite tumours exhibiting both adenocarcinomatous and carcinoid patterns. These four tumours have also been studied histochemically and ultrastructurally. ACTH and β‐endorphin immuno‐reactive cells, ultrastructurally resembling pituitary corticotrophic cells, have been identified in three tumours. Cells identical with type 1 and type 2 cells of the normal prostate were detected in two cases and in a further case, respectively.
Breast reductions: What to do with all the tissue specimens?
Authors: BONDESON L. , LINELL F. , RINGBERG ANITA
Published: April 2007

In order to find some guidelines for adequate examination of the often very large amount of tissue removed at reduction mammaplasties, a thorough macro‐ and microscopic study of a total of 400 specimens from 200 consecutive cases of bilateral breast reductions was done. The majority of patients were younger than 30 years of age. In these cases no abnormalities were found and a thorough macroscopic examination performed by an experienced pathologist is believed to be sufficient in this age group. In older women we encountered diverse findings, the most noteworthy being lobular carcinoma in situ in 8% of patients in this series who were over 40 years of age. This indicates the need for generous histological sampling in this age group. The potential value of roentgenological examination is also discussed.
Enteroendocrine cell hyperplasia, carcinoid tumours and adenocarcinoma in long‐standing ulcerative colitis
Authors: GLEDHILL ANN , HALL P.A. , CRUSE J.P. , POLLOCK D.J.
Published: April 2007

Chronic ulcerative colitis may be accompanied by a variety of epithelial changes, including loss of goblet cells, Paneth cell metaplasia, villous metaplasia, and dysplasia. Total colitis is also accompanied by an increased incidence of adenocarcinoma. All these changes are assumed to be secondary to repeated mucosal damage, but how they develop is unknown. Little attention has been paid to the enteroendocrine cell population, despite the postulated role of these cells as producers of trophic hormones. We describe two patients with long‐standing ulcerative colitis who developed both adenocarcinoma and carcinoid tumours. In both, there were increased numbers of enteroendocrine cells in the uninvolved colonic mucosa. We suggest that an increased enteroendocrine cell mass may be part of a non‐specific reaction to chronic mucosal injury, and by producing an elevated level of trophic hormones may act as a promoter in the development of neoplasia.
Sclerosing mucoepidermoid tumour of the parotid gland: report of a case
Authors: CHAN J.K.C. , SAW D.
Published: April 2007

A case of a low‐grade mucoepidermoid tumour showing an unusual pattern of extensive central keloid‐like sclerosis is reported. The sparsity of tumour islands renders recognition of its neoplastic nature difficult. It is postulated that the sclerosis results from exaggerated post‐inflammatory scarring due to extravasation of mucin from the tumour into the stroma.
Ultrastructural changes in scleral proteoglycans precede destruction of the collagen fibril matrix in necrotizing scleritis
Authors: YOUNG R.D. , POWELL J. , WATSON P.G.
Published: April 2007

Proteoglycans were localized using cuprolinic blue and visualized by electron microscopy in sclera from the eye of a 58‐year‐old woman with necrotizing scleritis. Samples of sclera taken from clinically normal anterior and posterior sclera and from sites involved in anterior necrotizing scleritis with ulceration and posterior scleritis showed markedly different patterns of proteoglycan distribution. Proteoglycans appeared as stain‐positive filaments associated regularly with the ‘d/e’ bands of the collagen fibrils in normal anterior sclera, but were absent from intact collagen fibrils in the zone of anterior ulcerative scleritis. In posterior sclera including a site of posterior scleritis, proteoglycans were reduced in number with more heterogeneous associations with collagen fibrils. Depletion of scleral proteoglycans therefore precedes the degradation of scleral collagen in necrotizing scleritis, which may also involve the synthesis of atypical proteoglycan types in pathological sclera.
Pathology of the testis in acquired immunodeficiency syndrome
Authors: ROGERS C. , KLATT E. C.
Published: April 2007

The acquired immunodeficiency syndrome (AIDS) is most often a sexually transmitted disease acquired via male genital tract secretions. We performed a retrospective controlled study of testicular tissue taken from 100 AIDS patients at autopsy to determine the nature and spectrum of macroscopic and microscopic changes associated with AIDS in the testis. The AIDS patients showed a highly significant constellation of findings that included lymphocytic infiltration, perivasculitis, germ‐cell loss, interstitial fibrosis, decreased mean tubular diameter and increased mean tubular wall thickness. Only four cases showed evidence of testicular involvement with opportunistic infectious agents. In 48 cases gross pathological findings were present. Only four cases had histologically normal testes. We conclude that AIDS should be part of the differential diagnosis of testicular atrophy.
Monoclonality and polyclonality of plasma cells in Castleman's disease of the plasma cell variant
Authors: RADASZKIEWICZ T. , HANSMANN M.‐L. , LENNERT K.
Published: April 2007

Castleman's disease of the plasma cell variant observed in 21 patients was investigated morphologically and by immunohistochemistry. The male to female ratio was 2.5:1. The age ranged from 18 to 71 years (mean age 47.6 years). Histologically, the lesions were characterized by numerous, evenly distributed germinal centres ranging from large hyperplastic to small hyaline‐vascular types with moderate to extensive sheets of plasma cells in between. In all cases with generalized lymph node enlargement dilated sinuses could be found. Immunohistochemical studies demonstrated a polyclonal plasma cell population in 11 of 18 lesions. Seven lesions contained a monoclonal plasma cell population, five with IgG/lambda and two with IgA/lambda; clinically, two of these patients had generalized lymphadenopathy; in none could manifestation of a plasmacytoma be found outside the lymph node lesion: only two of the seven patients exhibited a paraproteinaemia (IgG/lambda and IgA/lambda, respectively) corresponding to the Ig type of the proliferated plasma cells. Six patients with polyclonal lesions had constitutional symptoms such as fever, anaemia, polyclonal hypergamma‐globulinaemia; one of these six patients manifested symptoms consistent with a diagnosis of Takatsuki syndrome. The monoclonal plasma cell type of Castleman's disease did not progress to a generalized disease. This monoclonal variant may be a lymph node‐based type of benign monoclonal gammopathy.
Sclerosing lymphocytic lobulitis of the breast–evidence for an autoimmune pathogenesis
Authors: LAMMIE G.A. , BOBROW L.G. , STAUNTON M.D.M. , LEVISON D.A. , PAGE G. , MILLIS R.R.
Published: April 2007

We describe 13 cases of inflammatory lesion of breast lobules in young and middle‐aged women, presenting as breast lumps, with, in five cases, associated breast pain. The patient with the most florid bilateral disease subsequently developed Hashimoto's thyroiditis. This prompted us to consider an autoimmune pathogenesis for all the breast lesions. We confirm a previously documented association of such breast lesions with diabetes mellitus and review the evidence for a possible HLA association. Increased HLA‐DR expression by breast epithelial cells was observed in cases available for study. Of the seven patients screened for circulating autoantibodies, three had none, one had smooth muscle antibodies, one parietal cell, one parietal cell and thyroid microsomal, and the seventh had the thyroid autoantibodies expected in Hashimoto's disease. Five of seven patients whose HLA‐status was determined were HLA‐DR or 5 positive, either singly or in combination. Immunophenotypic analysis of the mammary lymphoid infiltrate showed that the majority of infiltrating lymphocytes were B‐cells.
Immunohistochemical comparison of chromogranins A and B and secretogranin II with calcitonin and calcitonin gene‐related peptide expression in normal, hyperplastic and neoplastic C‐cells of the human thyroid
Authors: SCHMID K.W. , KIRCHMAIR R. , LADURNER D. , FISCHER‐COLBRIE R. , BÖCKER W.
Published: April 2007

Normal and hyperplastic thyroid C‐cells and 14 cases of medullary thyroid carcinoma were investigated immunohistochemically with antibodies against chromogranins A and B, secretogranin II, calcitonin and calcitonin gene‐related peptide (CGRP). Normal and hyperplastic C‐cells showed strong calcitonin and chromogranin A immunoreactivity whereas CGRP, chromogranin B and secretogranin II expression was less intense. Strong calcitonin and chromogranin A immunoreactivity was also found in the majority of tumour cells in medullary thyroid carcinoma. The CGRP, chromogranin B and secretogranin II staining observed was present in variable patterns. In some cases CGRP, chromogranin B and secretogranin II could only be demonstrated in isolated tumour cells with elongated processes suggestive of neuronal differentiation of these cells. The biological function(s) of the chromogranins/secretogranins remain(s) still unclear. There is evidence that these proteins are pro‐peptides which give rise to functionally active compounds. Studies on normal C‐cells and medullary thyroid carcinoma may elucidate the role of chromogranins/secretogranins in endocrine and neuronal cells.
Familial oesophageal leiomyomatosis and nephropathy
Authors: LONSDALE R.N. , ROBERTS P.F. , VAUGHAN R. , THIRU S.
Published: April 2007

Four female members of the same family suffering from a rare combination of oesophageal leiomyomatosis and an Alport‐like nephropathy are described. The disease is characterized by marked thickening of the oesophageal wall, usually also involving the proximal stomach, with or without discernible leiomyomatous nodule formation. All cases were treated surgically by oesophagectomy with symptomatic relief, and there was no evidence of recurrence on follow‐up (2–37 years). The syndrome appears to be dominantly inherited, affects children and young adults, and may also be associated with leiomyomatosis of other viscera. Previously reported cases and possible aetiologies are reviewed, and evidence that this association represents a new variant of Alport's syndrome is discussed.
Melanoma botryoides: a distinctive myxoid pattern of sino‐nasal malignant melanoma
Authors: CHETTY R. , SLAVIN J.L. , PITSON G.A. , DOWLING J.P.
Published: April 2007

Two primary sino‐nasal melanomas are presented which were characterized by their botryoid growth pattern and myxoid stroma. These polypoid tumours contained small amounts of melanin and only focal areas of epithelioid cells. An in situ component was present in both of the tumours. Malignant melanoma should be considered when confronted by a myxoid tumour (with or without melanin) in the sino‐nasal region. These tumours are widely infiltrative, and there is no evidence to suggest that they will behave any differently from conventional, non‐botryoid, non‐myxoid sino‐nasal melanomas.
The histopathology of human melioidosis
Authors: WONG K.T. , PUTHUCHEARY S.D. , VADIVELU J.
Published: April 2007

We examined human tissues infected by Burkholderia (Pseudomonas) pseudomallei which is endemic in Malaysia to study the types of inflammation invoked, and to look for histopathological clues to its diagnosis. The lesions which varied from acute to chronic granulomatous inflammation were not tissue‐specific. In five autopsy cases, the inflammation was usually a focal or diffuse, acute necrotising inflammation with varying numbers of neutrophils, macrophages, lymphocytes and ‘giant cells’. The ‘giant cells’ probably represent giant macrophages with phagocytosed leukocytes. There were numerous gram‐negative, non‐acid‐fast, intra‐ and extracellular bacilli, occurring either singly or in chains. Intracellular bacteria within macrophages and ‘giant cells’ were so numerous as to resemble globi. This feature has not been previously reported and may be a useful diagnostic clue in melioidosis. In 14 surgical cases biopsies showed acute inflammatory lesions that appeared no different from acute inflammation due to other causes. In many biopsies, however, the inflammation was either an acute‐on‐chronic inflammation with a focal granulomatous component, or was purely granulomatous in character. Bacilli were difficult to demonstrate in surgical biopsies even with the gram strain.
p53 protein expression in putative precursor lesions of epithelial ovarian cancer
Authors: HUTSON R. , RAMSDALE J. , WELLS M.
Published: April 2007

p53 protein expression has been studied in epithelial inclusion cysts adjacent to and contralateral to serous carcinoma of the ovary and compared to epithelial inclusion cysts associated with borderline tumours and in normal ovaries. Atypia was found in epithelial inclusion cysts in eight of the thirteen advanced (stage III) serous ovarian carcinomas. Of these eight with atypical epithelial inclusion cysts, five showed immunoreactivity for p53. In the borderline tumours and normal ovaries no atypia in such cysts was found. p53 expression was also seen more frequently in surface epithelium associated with ovarian serous adenocarcinoma (ten of 13) than in normal ovaries (one of 13). We postulate that focal areas of atypia (ovarian intra‐epithelial neoplasia) in epithelial inclusion cysts are the precursors of ovarian malignancy. In some cases, at least, p53 protein expression may precede overt cytological abnormalities.
Mesothelioma‐binding antibodies: thrombomodulin, OV 632 and HBME‐1 and their use in the diagnosis of malignant mesothelioma
Authors: ATTANOOS R.L. , GODDARD H. , GIBBS A.R.
Published: March 2007

The aim of this study was to examine the expression of three putative mesothelioma‐binding antibodies, thrombomodulin, OV 632 and HBME‐1 in 42 malignant mesotheliomas (27 pleural and 15 peritoneal) and 32 pulmonary adenocarcinomas. Evaluation of their use in differentiating between the mesotheliomas and pulmonary adenocarcinomas was assessed. Thrombomodulin was expressed by 22 of 42 (52%) mesotheliomas but was seen in eight of 12 pure epithelial‐type mesotheliomas of the pleura and in all four papillary epithelial peritoneal mesotheliomas. For pure epithelial mesotheliomas thrombomodulin was 75% sensitive. Only two of 32 pulmonary adenocarcinomas were immunoreactive yielding a 94% specificity for thrombomodulin. In comparison, OV 632 and HBME‐1 showed 67% and 62% antibody sensitivity, respectively, for malignant mesothelioma but this was accompanied by low specificity (OV 632, 37%; HBME‐1, 28%). Both OV 632 and HBME‐1 are considered unsuitable for use in differentiating between mesotheliomas and pulmonary adenocarcinomas. We advocate the use of thrombomodulin as a mesothelioma‐binding antibody in the standard panel of antibodies used in the evaluation of malignant mesothelioma.
Proliferation, ploidy and prognosis in uterine smooth muscle tumours
Authors: JEFFERS M.D. , OAKES S.J. , RICHMOND J.A. , MACAULAY E.M.
Published: March 2007

DNA ploidy, mitotic rate (per 10 high power fields), mitotic index (per 1000 tumour nuclei), Ki‐67 labelling index and S phase fraction were measured in 23 uterine leiomyosarcomas and 10 tumours of uncertain malignant potential. Correlations were calculated by Spearmann rank correlation. Univariate survival analysis was performed by log rank analysis and multivariate analysis performed by the Cox linear regression method. Ki‐67 index and S phase fraction were significantly higher in leiomyosarcomas than in tumours of uncertain malignant potential. There was significant correlation between mitotic rate, mitotic index, Ki‐67 index and S phase fraction in cases of leiomyosarcoma. Fifteen of 22 leiomyosarcomas and one of 10 tumours of uncertain malignant potential were DNA aneuploid. On univariate analysis of all the smooth muscle tumours, DNA ploidy, presence of significant nuclear atypia and presence of coagulative tumour cell necrosis were associated with outcome. Only DNA ploidy was associated with outcome in the group of leiomyosarcomas. On multivariate analysis of all of the smooth muscle tumours. DNA ploidy, age and grade of atypia were independently associated with outcome. No single factor was independently predicitive of outcome in the group of leiomyosarcomas. Alternative indices of cell proliferation correlate with mitotic rate in uterine leiomyosarcoma and do not provide additional useful prognostic information. DNA ploidy, age and grade of atypia are independently associated with outcome in uterine smooth muscle tumours and measurement of DNA ploidy may be useful in identification of cases with an adverse prognosis.
Immunohistochemical differentiation of metastatic breast carcinomas from metastatic adenocarcinomas of other common primary sites
Authors: KAUFMANN O. , DEIDESHEIMER T. , MUEHLENBERG M. , DEICKE P. , DIETEL M.
Published: March 2007

To test the possibility of immunohistochemical differentiation of cytostatically treatable metastatic breast carcinomas from other metastatic adenocarcinomas of unknown primary site, we studied a total of 328 metastatic adenocarcinomas including 35 bronchogenic, 26 pancreatic, 25 colonic, 39 gastric, 45 renal, 29 ovarian and 129 breast carcinomas with a panel of 13 commercially available monoclonal antibodies. The expression of gross cystic disease fluid protein 15 and/or oestrogen or progesterone receptors had a sensitivity of 0.83, a specificity of 0.93 and a predictive accuracy of 0.92 for carcinomas of the breast against all other carcinomas. Excluding ovarian carcinomas, this combination had a sensitivity, specificity and predictive accuracy for mammary carcinomas of 0.83, 0.98 and 0.98, respectively. Carcinoembryonic antigen and/or cytokeratin 20 identified bronchogenic, gastric, pancreatic and colorectal carcinomas versus breast carcinomas lacking gross cystic disease fluid protein 15 and oestrogen or progesterone receptors with a sensitivity, specificity and predictive accuracy of 0.82, 0.99 and 0.95, respectively. Vimentin differentiates renal cell carcinomas from gross cystic disease fluid protein 15 and oestrogen or progesterone receptor negative breast carcinomas with a sensitivity, specificity and predictive accuracy of 0.93, 0.82 and 0.84. Thus, it should be possible to differentiate most metastatic mammary carcinomas from metastatic adenocarcinomas of other common primary sites, even if the former lack expression of gross cystic disease fluid protein 15 and oestrogen or progesterone receptors.
Medullary breast carcinoma vs. poorly differentiated ductal carcinoma: an immunohistochemical study with keratin 19 and oestrogen receptor staining
Authors: JENSEN M.L. , KIÆR H. , MELSEN F.
Published: March 2007

Sixty breast carcinomas previously indexed as medullary carcinomas over a 24‐year‐period were reviewed and reclassified according to definitions suggested by Ridolfi et al. as typical medullary carcinoma, atypical medullary carcinoma, and non‐medullary carcinoma. Paraffin sections of tumour tissue were examined by an avidin‐biotin complex method using two keratin 19‐specific monoclonal antibodies (BA17, DAKO and clone 170–2–14, Boehringer) and a monoclonal oestrogen receptor antibody (DAKO). For comparison 52 ductal carcinomas of grade II and grade III were immunostained as well. The results showed that all 60 tumours with medullary features and all 52 ductal carcinomas reacted moderately to strongly positive with anti‐keratin 19 (Boehringer). The staining was diffuse in all cases, except one case of ductal carcinoma (grade III), which stained focally. Immunostaining with the second keratin 19 antibody (BA17) revealed similar results with positive staining in 59 (95%) cases of carcinomas with medullary features and 51 (98%) cases of ductal carcinomas. Only one case in each group did not express keratin 19 (BA17), one re‐classified case of non‐medullary carcinoma with neuroendocrine features and one case of ductal carcinoma of grade III. None of the 13 cases of typical medullary carcinoma were oestrogen receptor positive and only seven (12%) of the carcinomas with medullary features (2 atypical, 5 non‐medullary) were oestrogen receptor positive with quantitative values from 20 to 100%. The 52 ductal carcinomas of grade II and III were oestrogen receptor positive in 56% and 47% of cases. It is concluded that keratin 19 staining is of no particular value in differentiating medullary from poorly differentiated ductal carcinoma. A carcinoma with positive oestrogen receptor staining is not likely to be a typical medullary carcinoma.
Gynandroblastoma of ovary with juvenile granulosa cell component and heterologous intestinal type glands
Authors: McCLUGGAGE W.G. , SLOAN J.M. , MURNAGHAN M. , WHITE R.
Published: March 2007

An ovarian gynandroblastoma in a 15‐year‐old girl is described. The predominant component was juvenile granulosa cell tumour. Areas of adult granulosa cell tumour and Sertoli cell elements were also present. Stromal theca and luteinised cells were identified. An additional histological finding was the presence of heterologous intestinal type glands. There was positive immunohistochemical staining of juvenile and adult granulosa cell areas with inhibin and MIC2 antibodies. Electronmicroscopy showed a close ultrastructural resemblance between tumour cells in granulosa and Sertoli cell areas, in spite of differences in architectural pattern, suggesting that both morphological components may derive from a single cell of origin. The tumour demonstrates a unique combination of elements which has not previously been described.