bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic Information as Instructional Content*
Authors: Stegmann Ulrich E.
Published: December 2005

The concept of genetic information is controversial because it attributes semantic properties to what seem to be ordinary biochemical entities. I argue that nucleic acids contain information in a semantic sense, but only about a limited range of effects. In contrast to other recent proposals, however, I analyze genetic information not in terms of a naturalized account of biological functions, but instead in terms of the way in which molecules determine their products during processes known as template-directed syntheses. I argue that determining an outcome in a certain way is constitutive for being an instruction. On this account, the content of genetic information is identified with the template's properties, which determine the product in the way constitutive for instructions.
Concepts Are Not a Natural Kind*
Authors: Machery Edouard
Published: December 2005

In cognitive psychology, concepts are those bodies of knowledge that are stored in long-term memory and are used by default in human beings’ higher cognitive processes (categorization, inductive and deductive reasoning, etc.). Most psychologists of concepts assume that these mental representations share many scientifically important properties, and the psychology of concepts is expected to describe those properties. Psychologists assume thereby thatconcepts constitute a natural kind. I call this assumption thenatural kind assumption. This article challenges the natural kind assumption. It is argued that a growing body of evidence suggests that concepts do not constitute a natural kind. Hence, the notion of concept is inappropriate, if one aims at formulating scientifically relevant inductive generalizations about the human mind.
Discussion: The Foundations of Statistical Mechanics—Questions and Answers*
Authors: Hagar Amit
Published: December 2005

Huw Price (1996, 2002, 2003) argues that causal-dynamical theories that aim to explain thermodynamic asymmetry in time are misguided. He points out that in seeking a dynamical factor responsible for the general tendency of entropy to increase, these approaches fail to appreciate the true nature of the problem in the foundations of statistical mechanics (SM). I argue that it is Price who is guilty of misapprehension of the issue at stake. When properly understood, causal-dynamical approaches in the foundations of SM offer a solution for adifferentproblem; a problem that unfortunately receives no attention in Price's celebrated work.
Discussion: What, If Anything, Is “The Strategy of Model Building in Population Biology?” A Comment on Levins (1966) and Odenbaugh (2003)*
Authors: Orzack Steven Hecht
Published: December 2005

In our 1993 paper, “A Critical Look,” Elliott Sober and I concluded that the famous claim about model formulation and constraints made by Richard Levins in his influential 1966 article on model building in population biology is neither true nor normative. Here, I comment upon the claim of Odenbaugh (2003) that the conclusions of “A Critical Look” are incorrect. My conclusions remain that Levins’ claim about the tradeoff between model properties (1) lacks logical coherence, (2) generates an arbitrary model classification, and (3) lacks normative utility. Accordingly, I view his claim as providing no useful insight into the nature of models and model building in population biology.
Accurate prediction of HIV-1 drug response from the reverse transcriptase and protease amino acid sequences using sparse models created by convex optimization
Authors: Rabinowitz Matthew , Myers Lance , Banjevic Milena , Chan Albert , Sweetkind-Singer Joshua , Haberer Jessica , McCann Kelly , Wolkowicz Roland
Published: December 2005

Motivation: Genotype–phenotype modeling problems are often overcomplete, or ill-posed, since the number of potential predictors—genes, proteins, mutations and their interactions—is large relative to the number of measured outcomes. Such datasets can still be used to train sparse parameter models that generalize accurately, by exerting a principle similar to Occam's Razor: When many possible theories can explain the observations, the most simple is most likely to be correct. We apply this philosophy to modeling the drug response of Type-1 Human Immunodeficiency Virus (HIV-1). Owing to the decreasing expense of genetic sequencing relative to in vitro phenotype testing, a statistical model that reliably predicts viral drug response from genetic data is an important tool in the selection of antiretroviral therapy (ART). The optimization techniques described will have application to many genotype–phenotype modeling problems for the purpose of enhancing clinical decisions.

Results: We describe two regression techniques for predicting viral phenotype in response to ART from genetic sequence data. Both techniques employ convex optimization for the continuous subset selection of a sparse set of model parameters. The first technique, the least absolute shrinkage and selection operator, uses the l1 norm loss function to create a sparse linear model; the second, the support vector machine with radial basis kernel functions, uses the ε-insensitive loss function to create a sparse non-linear model. The techniques are applied to predict the response of the HIV-1 virus to 10 reverse transcriptase inhibitor and 7 protease inhibitor drugs. The genetic data are derived from the HIV coding sequences for the reverse transcriptase and protease enzymes. When tested by cross-validation with actual laboratory measurements, these models predict drug response phenotype more accurately than models previously discussed in the literature, and other canonical techniques described here. Key features of the methods that enable this performance are the tendency to generate simple models where many of the parameters are zero, and the convexity of the cost function, which assures that we can find model parameters to globally minimize the cost function for a particular training dataset.

Availability: Results, tables and figures are available at

Contact:  mrabinowitz@genesecurity.net

Supplementary information: An Appendix to accompany this article is available at Bioinformatics online.
Multidimensional local false discovery rate for microarray studies
Authors: Ploner Alexander , Calza Stefano , Gusnanto Arief , Pawitan Yudi
Published: December 2005

Motivation: The false discovery rate (fdr) is a key tool for statistical assessment of differential expression (DE) in microarray studies. Overall control of the fdr alone, however, is not sufficient to address the problem of genes with small variance, which generally suffer from a disproportionally high rate of false positives. It is desirable to have an fdr-controlling procedure that automatically accounts for gene variability.

Methods: We generalize the local fdr as a function of multiple statistics, combining a common test statistic for assessing DE with its standard error information. We use a non-parametric mixture model for DE and non-DE genes to describe the observed multi-dimensional statistics, and estimate the distribution for non-DE genes via the permutation method. We demonstrate this fdr2d approach for simulated and real microarray data.

Results: The fdr2d allows objective assessment of DE as a function of gene variability. We also show that the fdr2d performs better than commonly used modified test statistics.

Availability: An R-package OCplus containing functions for computing fdr2d() and other operating characteristics of microarray data is available at

Contact:  alexander.ploner@meb.ki.se
Local RNA base pairing probabilities in large sequences
Authors: Bernhart Stephan H. , Hofacker Ivo L. , Stadler Peter F.
Published: December 2005

Summary: The genome-wide search for non-coding RNAs requires efficient methods to compute and compare local secondary structures. Since the exact boundaries of such putative transcripts are typically unknown, arbitrary sequence windows have to be used in practice. Here we present a method for robustly computing the probabilities of local base pairs from long RNA sequences independent of the exact positions of the sequence window.

Availability: The program RNAplfold is part of the Vienna RNA Package and can be downloaded from

Contact:  ivo@tbi.univie.ac.at
Perceptions of Health and Well‐Being Among Women in a Work‐Based Welfare Program
Authors: Hildebrandt Eugenie , Kelber Sheryl T.
Published: December 2005

Abstract  Women who are single parents, poor, and employed in low‐paying jobs have little choice about being dependent on public assistance programs to meet basic personal and family needs. Objective: To explore women's perceptions of their health and well‐being while enrolled in a work‐based welfare program. This is the second in a series of articles about Temporary Assistance for Needy Families. Design and Sample: Qualitative interviews and quantitative survey methods were used to explore perceptions of health and well‐being in a purposive sample of mothers (n = 34) enrolled in a work‐based welfare program in a city in the U.S. Midwest. Methods: Instruments used were a semistructured interview guide, a demographic data form, and the General Well‐Being Schedule (i.e., a survey tool developed for the U.S. Health and Nutrition Examination Survey). Data collection was completed in June 2000. The data were triangulated; using both quantitative and qualitative data added to the in‐depth understanding of the subjects. Results: Distress levels reported by participants were significantly higher than in the general U.S. population. Conclusions: Results of this study suggest that current policies do not effectively support health and well‐being of single mothers enrolled in work‐based welfare programs.
Self‐Rated Health and Risk Factors for Metabolic Syndrome Among Middle‐Aged Men
Authors: Näslindh‐Ylispangar Anita , Sihvonen Marja , Vanhanen Hannu , Kekki Pertti
Published: December 2005

Abstract 
Objectives:
To examine lifestyle and clinical risk factors for metabolic syndrome (MBO) and compare their significance between levels of self‐rated health among middle‐aged men. Design: A cross‐sectional baseline study. Sample: 273 men, aged 40, living in Helsinki, Finland. Methods: Postal questionnaires and health examinations by public health nurses were used in data collection. Statistical differences between groups of self‐rated health and risk factors were analyzed by chi‐square tests. Results: Of all the respondents, 55% rated their health as good and 45% as average. Two thirds were overweight or obese, and 35% had waist‐hip ratio more than 100 cm. Approximately 43% had diastolic blood pressure greater than 90 mmHg. Over half of the men smoked daily, and 28% used alcohol excessively. Conclusions: The men in this sample were found to be at high risk of developing MBO. The results underscore the importance of understanding the contradiction that exists between subjective and objective health ratings. Public health nurses are in a key position to educate men on how to use simple measurements to objectively assess their risk factors and, thus, potentially reduce their risk of developing diabetes, heart attack, or stroke.
Feeding Better Food Habits in Mid‐20th‐Century America
Authors: Abrams SaraH. E. , Wells Miriam E.
Published: December 2005

Abstract Public health nursing work has always involved education about nutrition and food habits. Nurses serve as interpreters of scientific and medical knowledge and as agents of behavioral change among the individuals and groups for whom they provide care. For public health nurses in mid‐20th‐century America, this meant direct involvement in many aspects of family life at home. Meal preparation and the eating patterns of family members were two areas into which most public health nurses had access. This brief history provides an introduction to some of the issues confronting American public health nurses at mid‐century. Examining the content of articles related to nutrition in families around mid‐century yields evidence about the role of the nurse, the state of the art in nutritional knowledge, and opinions and prejudices related to eating habits prevalent at the time. These glimpses into concerns expressed in the originalPublic Health Nursingjournal may enhance understanding of the role of public health nurses in preventing diet‐related disorders and form the basis for additional historical research.
Gastric and intestinal phenotypes and histogenesis of advanced glandular stomach cancers in carcinogen‐treated, Helicobacter pylori‐infected Mongolian gerbils
Authors: Mizoshita Tsutomu , Tsukamoto Tetsuya , Takenaka Yoshiharu , Cao Xueyuan , Kato Sosuke , Kaminishi Michio , Tatematsu Masae
Published: December 2005

The Helicobacter pylori‐infected Mongolian gerbil (MG) has been established as an appropriate animal model for studies of stomach cancer development. However, there have hitherto been no data on the phenotypic classification of glandular stomach cancers in H. pylori‐infected and non‐infected MG. We therefore examined the phenotypes of 50 and six advanced glandular stomach cancers in H. pylori‐infected and non‐infected MG, respectively, as well as adjacent non‐neoplastic mucosa, using several gastrointestinal epithelial phenotypic markers. The lesions were divided phenotypically into 21 gastric, 24 gastric‐and‐intestinal mixed, four intestinal and one null types, with 90.0% of the lesions harboring gastric elements and 56.0% demonstrating intestinal phenotypic expression in H. pylori‐infected MG. All six lesions were classified as gastric type in non‐infected MG. There was no clear correlation with the presence of intestinal metaplasia in surrounding mucosa. In conclusion, our data suggest that most advanced adenocarcinomas retain a gastric cellular phenotype in the glandular MG stomach. Thus, it might be proposed that intestinal metaplasia is a paracancerous phenomenon rather than a premalignant condition. H. pylori infection may trigger intestinalization of both stomach cancers and non‐neoplastic mucosa. (Cancer Sci 2006; 97: 38 – 44)
Chemical genomic screening for methylation‐silenced genes in gastric cancer cell lines using 5‐aza‐2′‐deoxycytidine treatment and oligonucleotide microarray
Authors: Yamashita Satoshi , Tsujino Yoshimi , Moriguchi Kazuki , Tatematsu Masae , Ushijima Toshikazu
Published: December 2005

To identify novel methylation‐silenced genes in gastric cancers, we carried out a chemical genomic screening, a genome‐wide search for genes upregulated by treatment with a demethylating agent, 5‐aza‐2′‐deoxycytidine (5‐aza‐dC). After 5‐aza‐dC treatment of a gastric cancer cell line (AGS) 579 genes were upregulated 16‐fold or more, using an oligonucleotide microarray with 39 000 genes. From these genes, we selected 44 known genes on autosomes whose silencing in gastric cancer has not been reported. Thirty‐two of these had CpG islands (CGI) in their putative promoter regions, and all of the CGI were methylated in AGS, giving an estimated number of 421 ± 75 (95% confidence interval) methylation‐silenced genes. Additionally, we analyzed the methylation status of 16 potential tumor‐related genes with promoter CGI that were upregulated four‐fold or more, and 14 of these were methylated in AGS. Methylation status of the 32 randomly selected and 16 potential tumor‐related genes was analyzed in 10 primary gastric cancers, and 42 genes (ABHD9, ADFP, ALDH1A3, ANXA5, AREG, BDNF, BMP7, CAV1, CDH2, CLDN3, CTSL, EEF1A2, F2R, FADS1, FSD1, FST, FYN, GPR54, GREM1, IGFBP3, IGFBP7, IRS2, KISS1, MARK1, MLF1, MSX1, MTSS1, NT5E, PAX6, PLAGL1, PLAU, PPIC, RBP4, RORA, SCRN1, TBX3, TFAP2C, TNFSF9, ULBP2, WIF1, ZNF177 and ZNF559) were methylated in at least one primary gastric cancer. A metastasis suppressor gene, MTSS1, was located in a genomic region with frequent loss of heterozygosity (8q22), and was expressed abundantly in the normal gastric mucosa, suggesting its role in gastric carcinogenesis. (Cancer Sci 2006; 97: 64 –71)
Strong HLA‐DR antigen expression on cancer cells relates to better prognosis of colorectal cancer patients: Possible involvement of c‐myc suppression by interferon‐γin situ
Authors: Matsushita Kazuyuki , Takenouchi Toshinao , Shimada Hideaki , Tomonaga Takeshi , Hayashi Hideki , Shioya Ayumi , Komatsu Aki , Matsubara Hisahiro , Ochiai Takenori
Published: December 2005

Strong HLA‐DR antigen expression on cancer cells relates to better prognosis of colorectal cancer patients, although the precise mechanism is controversial. From an immunological point of view, HLA‐DR antigen, induced by interferon (IFN)‐γ, is required for tumor‐associated antigen recognition by CD4+ T cells. For instance, as reported previously, the expression of HLA‐DR antigen in normal colorectal epithelium immediately adjacent to cancer coincided significantly with the existence of IFN‐γ mRNA in the tissue. From another aspect, IFN‐γ has been revealed to suppress c‐myc expression in vivo through a stat1‐dependent mechanism, which is important for cell growth, cell cycle and chromosome instability. In the present study, strong HLA‐DR‐positive expression on cancer cells was significantly related to better prognosis for colorectal cancer patients. High IFN‐γ mRNA expression in situ indicated significantly less activation of c‐myc mRNA expression. Further, HLA‐DR antigen expression in cancer cells, as well as Dukes stages, was an independent factor for better long‐term survival by multivariate analysis. Taken together, IFN‐γ, which induces HLA‐DR antigens on the cell surface, also suppresses c‐myc expression in situ, and is a possible non‐immunological mechanism involved in the better long‐term survival of colorectal cancer patients. (Cancer Sci 2006; 97: 57– 63)
Treatment of primary central nervous system lymphoma with induction of complement‐dependent cytotoxicity by intraventricular administration of autologous‐serum‐supplemented rituximab
Authors: Takami Akiyoshi , Hayashi Tomoe , Kita Daisuke , Nishimura Ryosei , Asakura Hidesaku , Nakao Shinji
Published: December 2005

We describe an immunocompetent 19‐year‐old man with CD20‐positive primary central nervous system (CNS) lymphoma refractory to chemotherapy and irradiation. After intraventricular administration of rituximab, a chimeric anti‐CD20 monoclonal antibody, supplemented with autologous serum, a remarkable response developed to the CNS parenchymal lymphoma. Cytotoxicity assays showed that untreated patient's serum with rituximab, but not that of heat‐inactivated patient's serum with rituximab or rituximab alone, induced potent rituximab‐mediated cytotoxicity against tumor cells in the patient's cerebrospinal fluid, suggesting induction of complement‐dependent cytotoxicity against CNS lymphoma. (Cancer Sci 2006; 97: 80 –83)
Fluorescence (Förster) resonance energy transfer imaging of oncogene activity in living cells
Authors: Kiyokawa Etsuko , Hara Shigeo , Nakamura Takeshi , Matsuda Michiyuki
Published: December 2005

A hallmark of cancer cells is their uncontrolled activation of growth signal transduction cascades comprised of oncogene products. Overexpression and activating mutations of the growth factor receptors Ras and Raf are frequently observed in human cancer cells. Several research groups, including our own, have been developing probes based on the principle of fluorescence (Förster) resonance energy transfer (FRET) to visualize how signaling molecules, including oncogene products, are regulated in normal and cancerous cells in the living state. In this review, we will briefly introduce the principle of FRET‐based probes, present an overview of the probes reported to date, and discuss the perspectives of these probes and fluorescent imaging systems in cancer biology. (Cancer Sci 2006; 97: 8–15)
Japanese single nucleotide polymorphism database for 267 possible drug‐related genes
Authors: Iida Aritoshi , Saito Susumu , Sekine Akihiro , Takahashi Atsushi , Kamatani Naoyuki , Nakamura Yusuke
Published: December 2005

To establish ‘personalized medicines’ that can provide the right drug at the appropriate dose for each individual patient on the basis of genetic background, we have been building the infrastructure for a Japanese single nucleotide polymorphism (SNP) database of the genes encoding various enzymes, transporters and receptors that are involved in the metabolism, transportation and action of drugs. We have so far screened a genomic region of 4068.3 kb, and identified a total of 7552 genetic variations, including 6733 SNP and 819 genetic variations of other types among 267 genes in Japanese populations. Interestingly, among the 212 non‐synonymous substitutions we found, six would be considered to be nonsense mutations. In this review, we focused on the molecular features of the non‐synonymous substitutions and insertion/deletion polymorphisms within coding regions detected in drug‐related gene loci. The database established in this study makes us confident of achieving one of our goals, which is establishment of personalized medicine. (Cancer Sci 2006; 97: 16–24)
Using the chicken genome sequence in the development and mapping of genetic markers in the turkey (Meleagris gallopavo)
Authors: Chaves L. D. , Knutson T. P. , Krueth S. B. , Reed K. M.
Published: December 2005

The efficacy of employing the chicken genome sequence in developing genetic markers and in mapping the turkey genome was studied. Eighty previously uncharacterized microsatellite markers were identified for the turkey using BLAST alignment to the chicken genome. The chicken sequence was then used to develop primers for polymerase chain reaction where the turkey sequence was either unavailable or insufficient. A total of 78 primer sets were tested for amplification and polymorphism in the turkey, and informative markers were genetically mapped. Sixty‐five (83%) amplified turkey genomic DNA, and 33 (42%) were polymorphic in the University of Minnesota/Nicholas Turkey Breeding Farms mapping families. All but one marker genetically mapped to the position predicted from the chicken genome sequence. These results demonstrate the usefulness of the chicken sequence for the development of genomic resources in other avian species.
Sequence diversity and rates of molecular evolution between sheep and cattle genes
Authors: Kijas J. W. , Menzies M. , Ingham A.
Published: December 2005

Experiments that aim to identify genes of importance in sheep are currently inhibited by a paucity of genomic resources. One approach, therefore, is to exploit the wealth of data and associated capabilities becoming available for the bovine genome. Cross‐species application of microarrays and comparative sequencing to identify single nucleotide polymorphisms are two possibilities; however, both are dependant on the level of nucleotide sequence similarity between the two species. This study used 120 gene orthologues consisting of over 60 kb of aligned sequence to estimate the gene diversity between cattle and sheep. Less than 3% of protein‐coding nucleotide positions were found to be different, indicating that the prospect for successfully using cross‐species strategies is high. Substitution at synonymous sites ranged between 6.9 and 7.7% (± 0.3%), and was higher than at non‐synonymous sites (1.4–1.7 ± 0.1%). The relative rate test was used to determine whether the observed mutation rates were constant between the two lineages. While the rate at synonymous sites appeared constant, the rate at non‐synonymous sites was significantly higher within the caprinae lineage (sheep) when compared with bovinae (cattle; χ2 = 10.03; d.f. = 1, P < 0.01). This is the first demonstration that variable rates of molecular evolution may be present within the family Bovidae.
Genome‐wide identification of quantitative trait loci in a cross between Hampshire and Landrace I: carcass traits
Authors: Karlskov‐Mortensen P. , Bruun C. S. , Braunschweig M. H. , Sawera M. , Markljung E. , Enfält A. C. , Hedebro‐Velander I. , Josell Å. , Lindahl G. , Lundström K. , von Seth G. , Jørgensen C. B. , Andersson L. , Fredholm M.
Published: December 2005

We report the identification of quantitative trait loci (QTL) affecting carcass composition, carcass length, fat deposition and lean meat content using a genome scan across 462 animals from a combined intercross and backcross between Hampshire and Landrace pigs. Data were analysed using multiple linear regression fitting additive and dominance effects. This model was compared with a model including a parent‐of‐origin effect to spot evidence of imprinting. Several precisely defined muscle phenotypes were measured in order to dissect body composition in more detail. Three significant QTL were detected in the study at the 1% genome‐wide level, and twelve significant QTL were detected at the 5% genome‐wide level. These QTL comprise loci affecting fat deposition and lean meat content on SSC1, 4, 9, 10, 13 and 16, a locus on SSC2 affecting the ratio between weight of meat and bone in back and weight of meat and bone in ham and two loci affecting carcass length on SSC12 and 17. The well‐defined phenotypes in this study enabled us to detect QTL for sizes of individual muscles and to obtain information of relevance for the description of the complexity underlying other carcass traits.
Recurrent childhood anaplastic large cell lymphoma: a retrospective analysis of registered cases in Japan
Authors: Mori Tetsuya , Takimoto Tetsuya , Katano Naoyuki , Kikuchi Akira , Tabuchi Ken , Kobayashi Ryoji , Ayukawa Hiroshi , Kumagai Masa‐aki , Horibe Keizo , Tsurusawa Masahito
Published: December 2005

This report presents a retrospective study of 26 Japanese children with recurrent anaplastic large cell lymphoma. The first relapses were documented at a median of 10·5 months after the initial diagnosis. Twenty‐four patients achieved a second remission. After a median follow‐up period of 47 months, 18 patients are still alive: 15 patients are in second complete remission (CR), three patients are in third CR or later. The 5 year overall and relapse‐free survival rates were 61 ± 12% and 51 ± 12% respectively. The patients who received allogeneic haematopoietic stem cell transplantation during second CR showed a superior outcome to other patients.
Cellular folate vitamer distribution during and after correction of vitamin B12 deficiency: a case for the methylfolate trap
Authors: Smulders Y. M. , Smith D. E. C. , Kok R. M. , Teerlink T. , Swinkels D. W. , Stehouwer C. D. A. , Jakobs C.
Published: December 2005

Haematological sequellae of vitamin B12 deficiency are attributed to disturbed DNA synthesis, but vitamin B12 itself plays no role in DNA biosynthesis. A proposed explanation for this is the methylfolate trap hypothesis. This hypothesis states that B12 deficiency impairs overall folate metabolism because 5‐methyltetrahydrofolate (5MTHF) becomes metabolically trapped. This trap results from the fact that 5MTHF can neither be metabolised via the methionine synthase pathway, nor can it be reconverted to its precursor, methylenetetrahydrofolate. Other manifestations of the methylfolate trap include cellular folate loss because of shorter 5MTHF polyglutamate chains and global hypomethylation. The methylfolate trap has never been demonstrated in humans. We describe a patient with B12 deficiency who was homozygous for the common methylenetetrahydrofolate reductase (MTHFR) C677T mutation. We analysed red blood cell (RBC) folate vitamers and global DNA methylation by liquid chromatography (LC) in combination with tandem mass spectrometry, and 5MTHF polyglutamate length by LC‐electrochemical detection. Compared to post‐B12 supplementation values, homocysteine was higher (52·9 μmol/l vs. 16·8 μmol/l), RBC folate was lower (268·92 nmol/l vs. 501·2 nmol/l), the 5MTHF fraction of RBC folate was much higher (94·5% vs. 67·4%), polyglutamate chain length was shorter (more tetra‐ and pentaglutamates), and global DNA methylation was 22% lower. This is the first time that virtually all features of the methylfolate trap hypothesis have been demonstrated in a human with vitamin B12 deficiency.
Myeloid lineage‐selective growth of revertant cells in Fanconi anaemia
Authors: Hamanoue Satoshi , Yagasaki Hiroshi , Tsuruta Toshihisa , Oda Tsukasa , Yabe Hiromasa , Yabe Miharu , Yamashita Takayuki
Published: December 2005

Fanconi anaemia (FA) is a genetically heterogeneous chromosome instability syndrome characterised by bone marrow failure and congenital anomalies. Although an increasing number of reports suggest that reversion mosaicism noted in peripheral blood lymphocytes (PBLs) is associated with mild haematopoietic failure in FA, myeloid cells are rarely directly examined. We here report a patient with prolonged mild pancytopenia in whom proliferation of revertant cells was detected in mature myeloid cells but not in PBLs. While this patient had inherited heterozygous mutations, 2546delC and 3720–3724del, in the major FA gene FANCA, Epstein–Barr virus‐immortalised lymphoblastoid cells from the patient had 2546C > T instead of 2546delC, resulting in expression of a functional missense protein. As the identical reversion was detected in polymorphonuclear granulocytes and mononuclear phagocytes, sustained haematopoiesis in the patient can be attributed to a selective growth advantage of revertant myeloid cells. It is noteworthy that such a myeloid lineage‐selective mosaicism is overlooked in routine examination of PBLs. Recognition of this status will expand the role of reversion mosaicism in the pathophysiology of FA.
Immunogenicity of sequential pneumococcal vaccination in subjects splenectomised for hereditary spherocytosis
Authors: Stoehr Gerhard A. , Rose Markus A. , Eber Stefan W. , Heidemann Katrin , Schubert Ralf , Zielen Stefan
Published: December 2005

Splenectomy predisposes for invasive pneumococcal disease. We investigated the immune response of splenectomised hereditary spherocytosis (HS) patients upon sequential pneumococcal vaccination. Thirty‐nine HS‐patients (2‐ to 18‐year‐old) had undergone near‐total or total splenectomy. All received one dose of 7‐valent pneumococcal conjugate vaccine (PCV‐7) and 23‐valent‐pneumococcal‐polysaccharide vaccine (PPV‐23) 2 months apart. Pneumococcal antibodies against serotypes 5/6B/7/14/18C/19F/23F and immunoglobulin serum concentrations were determined before PCV‐7 and 4 weeks after PPV‐23. Significant rises in antibody geometric mean concentrations were observed after PCV‐7 except for serotypes 5 and 7, which increased after PPV‐23. We found no impact of the mode of splenectomy.
Prothrombin Saint‐Denis: a natural variant with a point mutation resulting in Asp to Glu substitution at position 552 in prothrombin
Authors: Rouy Stanislas , Vidaud Dominique , Alessandri Jean‐Luc , Dautzenberg Marie‐Dominique , Venisse Laurence , Guillin Marie‐Claude , Bezeaud Annie
Published: December 2005

A new prothrombin variant, with a point mutation at nucleotide 20 029 resulting in Asp 552 to Glu substitution (prothrombin numbering), has been identified in a male newborn. Plasma prothrombin level was <3%, 16% and 60% when measured by clotting, chromogenic and immunological assays respectively. The substitution did not affect the rate of prothrombin conversion to thrombin but altered thrombin activity. Amino acid 552 has been reported to be involved in the allosteric transition, which is induced by sodium binding to thrombin. This is the first known amino acid substitution at this site to result in dysprothrombinaemia.
Order of patient entry influences outcome for metastatic renal cell cancer after non‐myeloablative allogeneic stem cell transplantation
Authors: Artz Andrew S. , Kocherginsky Masha , Van Besien Koen
Published: December 2005

Allogeneic transplantation for renal cell carcinoma has shown encouraging preliminary results. We reviewed the published literature to evaluate the impact of patient selection. Most studies did not include information on prognostic factors. We used patient entry rank within individual studies as a novel surrogate for patient selection, motivated by our own experience of an apparent impact of entry rank. One hundred patients were identified from nine studies. Twenty‐six per cent of patients demonstrated either a partial or complete response. Median overall survival was 12·3 months. Grade 2–4 acute graft‐versus‐host disease correlated with an increased likelihood of response (odds ratio: 5·4, 95% confidence interval: 1·6–18·1, P = 0·006) but not survival. Earlier patient entry rank on each trial was associated with a higher probability of response (P = 0·004) and superior survival (P = 0·004). Patient entry rank served as a powerful prognostic factor, suggesting bias in patient selection that evolved over the course of the study. Further studies are warranted to determine the influence of order of patient entry in other early clinical trial settings.
Application of diffuse reflectance FT‐IR spectroscopy and partial least‐squares regression to predict NMR properties of soil organic matter
Authors: Leifeld J.
Published: December 2005

Carbon 13 nuclear magnetic resonance spectroscopy (13C NMR) is a powerful technique for studying the structure and turnover of soil organic matter, but is time consuming and expensive. It is therefore worth seeking swifter and cheaper methods. Diffuse reflectance FT‐IR spectroscopy (DRIFT), along with partial least squares (PLS) algorithms, provides statistical models to quantify soil properties, such as contents of C, N and clay. I have applied DRIFT−PLS to quantify soil organic C species, as measured by solid state 13C NMR spectroscopy, for several bulk soils and physical soil fractions. Calibration and prediction models for organic C and for particular NMR regions, namely alkyl C, O−alkyl C and carboxyl C, attained R2 values of between 0.94 and 0.98 (calibration) and 0.70–0.93 (cross‐validation). The prediction of unknown soil samples, after pre‐selection by statistical indices, confirmed the applicability of DRIFT−PLS. The prediction of aromatic C failed, probably because of superimposition of aromatic bands by signals from minerals. Results from fractions of particulate organic matter suggest that the chemical homogeneity of the material hampers the quantification of its constituting C species by DRIFT−PLS. For alkyl C, prediction of carbon species by DRIFT−PLS was better than direct peak‐area quantification in the IR spectra, but advantageous in parts only compared with a linear model correlating C species with soil C contents. In conclusion, DRIFT−PLS calibrated with NMR data provides quantitative information on the composition of soil organic matter and can therefore complement structural studies by its application to large numbers of samples. However, it cannot replace the information provided by more specific methods. The actual potential of DRIFT−PLS lies in its capacity to predict unknown samples, which is helpful for classification and identification of environmental outliers or benchmarks.
Roots, rhizosphere and soil: the route to a better understanding of soil science?
Authors: Gregory P.J.
Published: December 2005

The centenary of Hiltner's recognition of a rhizosphere effect is a convenient point to assess the impact of such thinking on the direction of soil science. A review of the major soil journals suggests that for much of the last century, Hiltner's insight had little effect on mainstream thinking outside of soil microbiology, but this situation is changing rapidly as the consequences of spatial and temporal heterogeneity on soil functioning assumes greater importance. Studies of root growth, root distributions and of rhizosphere processes over the last 25 years demonstrate both the size and distribution of root systems and the associated inputs from roots to soils. These inputs result in a plethora of dynamic reactions at the root–soil interface whose consequences are felt at a range of temporal and spatial scales. Root growth and respiration, rhizodeposition, and uptake of water and nutrients result in biological, chemical and physical changes in soils over variable distances from the root surface so that the rhizosphere has different dimensions depending on the process considered. At the root length densities common for many crop species, much of the upper 0.1 m of soil might be influenced by root activity for mobile nutrients, water and root‐emitted volatile compounds for a substantial proportion of the growing season. This brief review concludes that roots are an essential component of soil biology and of soil science.
The representation of complex soil variation on wavelet packet bases
Authors: Lark R.M.
Published: December 2005

The discrete wavelet packet transform (DWPT) is an advanced wavelet technique that has distinct advantages over the discrete wavelet transform (DWT) previously used in soil science. Because the DWT divides the spatial frequencies of the data into non‐uniform intervals, it may fail to resolve features of the spatial variation that a simpler spectral analysis might identify under stationary conditions. However, the DWPT allows us to retain the advantages of the DWT (particularly the lack of stationarity assumptions) while achieving much better resolution in the spatial frequency domain. This is at the cost of poorer spatial resolution at the higher frequencies. However, by selecting a best wavelet packet basis from among the many possible, according to some appropriate criterion, we can find a compromise between frequency and spatial resolution that is best suited to the representation of our particular data set. In this paper, I describe a number of analyses based on the DWPT and apply them to two data sets on the soil. The advantages of the DWPT with best basis selection are clearly illustrated. In particular, non‐stationary behaviour of a significant periodic component of variation was identified that could not be effectively resolved by the DWT. Improved resolution in the frequency domain allowed aspects of the non‐stationary variation of soil to be resolved in a multiresolution analysis (MRA) adapted to the variation of the data.
Modelling the effect of particle size, shape and orientation of light transfer through porous media
Authors: Bänninger D. , Lehmann P. , Flühler H.
Published: December 2005

In this study, we present a radiative‐transfer model to simulate reflectance and transmittance of light by soil slabs. The radiative‐transfer model implemented, referred to as the beam‐tracing model, uses cross‐sectional images of scattering media to describe the geometry of the soil, i.e. soil texture and structure. This model traces the optical path of incident beams through such cross‐sectional images. Tracing many light beams simulates the reflected and transmitted light intensities for the media.

The accuracy of the beam‐tracing model was tested by comparing its predictions with those of analytical solutions and with experimentally measured reflectance and transmittance data of soil samples. We implemented this model to explain the systematic deviation between measured data and those calculated with the four‐flux model applied in Bänninger (2004). With the beam‐tracing model, we show that the small systematic inaccuracies of the four‐flux model are caused by the simplified description of the geometry of the scattering medium.

The beam‐tracing model can be used to describe various optical properties of particulate media. As an application, we calculated the decrease of light intensity with depth.
Different T‐bet expression patterns characterize particular reactive lymphoid tissue lesions
Authors: Jöhrens K , Anagnostopoulos I , Dürkop H , Stein H
Published: December 2005

Aims : To investigate T‐bet expression profiles in various lymphoid tissue diseases caused by intracellular pathogens and to compare them in disorders without an infective aetiology. Murine and in vitro experiments have shown that the expression/induction of T‐bet, the master regulator of Th1 differentiation, can be achieved by obligate intracellular pathogens and high interferon (IFN)‐γ levels.

Methods : Lymph node biopsies were analysed immunohistochemically employing single and double labelling for T‐bet and CD20, CD4, CD8 and CD30 detection.

Results : In disorders associated with high IFN‐γ levels and intracellular pathogens (infectious mononucleosis, HIV‐associated lymphadenopathy, cat‐scratch disease, and toxoplasmic lymphadenitis), T‐bet‐expressing CD4 cells were accompanied by significant numbers of T‐bet‐positive CD8 and B cells. A similar profile was also found in histiocytic necrotizing (Kikuchi) lymphadenitis, a disease of unknown cause. In contrast, T‐bet expression in disorders without an infective aetiology was observed in only a small portion of lymphocytes.

Conclusions : Increased T‐bet expression does not only identify intracellular infections in lymphoid tissue associated with high IFN‐γ levels, but also implies that, under these conditions, it becomes induced in B cells, which apparently support the Th1 response. T‐bet expression in Kikuchi lymphadenitis underscores the hypothesis that it is caused by an intracellular microorganism.
Evaluation of neoplastic human mast cells by tryptase‐immunoelectron microscopy
Authors: Samorapoompichit P , Schernthaner G‐H , Worda C , Wimazal F , Krauth M‐T , Sperr W R , Valent P
Published: December 2005

Aims : To analyse and characterize the ultrastructural morphology of normal tissue mast cells (MC) and neoplastic bone marrow MC.

Methods : We have examined the ultrastructure and cytomorphological features of MC derived from cord blood cells, neoplastic bone marrow MC in patients with systemic mastocytosis (SM, n = 4), myelomastocytic leukaemia (MML, n = 2), mast cell leukaemia (MCL, n = 2) and tryptase‐positive acute myeloid leukaemia (AML, n = 4).

Results : Based on their ultrastructure and morphology, four distinct cell types could be delineated: (i) mature well‐granulated tissue MC exhibiting a round central nucleus; (ii) atypical MC type I with oval nuclei, hypogranulated cytoplasm, and prominent surface projections; (iii) immature atypical MC with bi‐ or polylobed nuclei (atypical MC type II = promastocytes); and (iv) metachromatic blasts. Type I atypical MC were detected in a patient with indolent SM, whereas type II MC and metachromatic blasts were primarily found in MML, MCL and tryptase‐positive AML. In all samples examined, the identity of MC could be reconfirmed by immunoelectron microscopy, irrespective of the stage of cell maturation or the disease variant, all types of MC contained tryptase in their cytoplasmic granules.

Conclusion : Immunoelectron microscopy may be a helpful approach in confirming the identity of neoplastic MC in myeloid neoplasms.
Loss of CD19 expression in B‐cell neoplasms
Authors: Masir N , Marafioti T , Jones M , Natkunam Y , Rüdiger T , Hansmann M‐L , Mason D Y
Published: December 2005

Aims : To investigate whether an antibody against an intracellular epitope can detect CD19 in routine biopsy specimens and thus to document in detail its expression in human lymphomas.

Method and results : A polyclonal antibody to the C terminus of CD19 was used to immunostain paraffin‐embedded samples of normal and neoplastic lymphoid tissues. CD19 was widely expressed in normal B cells and in extramedullary plasma cells. It was found in most B‐cell neoplasms, but expression in follicular lymphoma was weak (33/69) or negative (four cases). Similarly, CD19 expression in diffuse large B‐cell lymphomas was weak (28/56) or negative (eight cases). In T‐cell‐rich B‐cell lymphomas, CD19 was also weak (4/10) or negative (three cases). CD19 was often absent in post‐transplant B lymphoproliferative disease, classical Hodgkin's disease and plasma cell neoplasms. An unexpected finding was the frequent absence of CD19 in the neoplastic cells in lymphocyte predominant Hodgkin's disease.

Conclusions : CD19 can now be detected in routine biopsy specimens. In contrast to the classical pan‐B marker CD20, CD19 is not always strongly expressed in B‐cell neoplasms. Furthermore, the lymphocytic and histiocytic (L&H) cells of lymphocyte predominant Hodgkin's disease (which express most B‐cell‐associated markers) commonly lack CD19.
Immunoglobulin and T‐cell receptor gene rearrangement in Castleman's disease: molecular genetic analysis
Authors: Al‐Maghrabi J , Kamel‐Reid S , Bailey D
Published: December 2005

Aims : Castleman's disease (CD) is a rare heterogeneous disorder that is associated with an increased risk of developing lymphoma. Whether CD is primarily hyperplastic or neoplastic in origin is not yet clear. The aim of this study was to investigate CD further by determining the clonality status of its lymphocyte populations.

Methods and results : We reviewed 20 patients with CD, 15 with the hyaline‐vascular type and five with the plasma cell type. Immunoglobulin (JH) and T‐cell receptor (TCR) gene rearrangements were examined using polymerase chain reaction and Southern blotting techniques. B‐lymphocyte clonality was also assessed by flow cytometry (FC) and by immunohistochemistry (IHC). The age range of the patients was 15–66 years: nine female and 11 male. Monoclonal rearrangement of the immunoglobulin (JH) gene was detected in only one case. No cases were positive for monoclonal rearrangement of the TCR gene. All of the cases except one were negative for immunoglobulin light chain restriction by both FC and IHC.

Conclusions : The lymphoid cells in CD are most commonly polyclonal in origin, which supports a non‐neoplastic origin. However, rare cases may show lymphocyte monoclonality, which could represent the development of a neoplastic population. The latter cases should be followed closely.
Comparison of immunohistochemistry by automated cellular imaging system (ACIS) versus fluorescence in‐situ hybridization in the evaluation of HER‐2/neu expression in primary breast carcinoma
Authors: Tawfik O W , Kimler B F , Davis M , Donahue J K , Persons D L , Fan F , Hagemeister S , Thomas P , Connor C , Jewell W , Fabian C J
Published: December 2005

Aims : Immunohistochemistry (IHC) and fluorescence in‐situ hybridization (FISH) are both commonly used assays for evaluation of HER‐2/neu status in breast cancer. However, there is still no consensus on which method is most predictive of patient response to HerceptinTM. Recently, the automated cellular imaging system (ACIS)TM has been shown to improve the accuracy and reproducibility in scoring IHC. Our aim was to compare the results of HER‐2/neu expression and gene amplification in the same patients by IHC using the ACISTM system and by FISH.

Methods and results : Two hundred and forty‐seven breast cancer cases were studied. The concordance rate between IHC‐ACIS (≥ 2.2) and FISH (≥ 2.0) was 94%. Fifteen patients were discordant; three had borderline FISH values and three had borderline IHC values. The other nine discordant cases consisted of five IHC‐ACIS+, FISH– and six IHC‐ACIS–, FISH+. HER‐2/neu overexpression was more common in tumours that were high‐grade, aneuploid, progesterone receptor and bcl‐2 negative, with MIB‐1 > 10%.

Conclusion : HER‐2/neu assessment by the ACIS is reliable, rapid and inexpensive, and correlates highly with results obtained by FISH.