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PubMed1983

[Melanotic ectodermal tumor of infancy (melanotic progonoma)--an unusual soft tissue tumor].

In rare cases an utmost uncommonly pigmented lesion is found in young infants which is mostly located in the anterior maxilla. The histogenesis of this unusual soft tissue tumor has provoked a long-lasting debate, which is reflected in many synonyms. There is no anatomical precursor and the possibility of a phylogenetic ancestral form is discussed. Therefore, the term melanotic progonoma was proposed. Because of the derivation from neural crest cells the designation melanotic neuroectodermal tumor of infancy was introduced. This name is now generally accepted. In this study, two typical cases of this rare tumor are described. The tumors are composed of large epithelial-like melanin-producing cells and small nonpigmented cells, so-called lymphocyte- like cells resembling neuroblasts. The diagnostic relevant histological pattern is characterized by intensely pigmented cells arranged either in strands or clusters often forming the lining of small cleft-like or tubular spaces, or by alveolar structures surrounded by a fibrovascular stromal component. At ultrastructural level, the pigment corresponds to the cutaneous type of neural crest type of melanin. The histogenesis of these lesions and the classification of pigmented benign and malignant neuroectodermal tumors of the soft tissues are discussed especially taking into consideration the concept of the soft tissue variant of melanomas. The melanotic neuroectodermal tumor of infancy is a benign growth Only in very few cases a fatal outcome is reported in the literature. The melanotic neuroectodermal tumor of infancy must be distinguished from other types of benign and malignant neuroectodermal tumors. From histological point of view and with regard to its biological behaviour this lesion is a particular entity of pigmented neuroectodermal tumors of the soft tissues, and for subclassification the term melanotic progonoma should be maintained, too.

Female↗

PubMed1993

Iron protein succinylate: preclinical safety assessment.

In this brief review the preclinical safety studies on iron protein succinylate (synonym: ITF 282) are presented. Iron protein succinylate is an iron-protein complex, in which iron is present in ferric form. It has been developed for oral iron-supplementation therapy and is characterized by a very favorable tolerability profile. The acute toxicity of iron protein succinylate to rodents is very low, indicating a substantial margin of safety with respect to accidental child poisonings. In chronic toxicity studies of 52-week duration in rats and dogs, there were no findings of toxicological significance. In particular, there were no alterations in hematological parameters and no histopathological findings consistent with iron overload damage. Some deposition of iron was noted in the spleen and liver of the treated dogs. A series of reproductive toxicology studies were performed to assess the effects on fertility (in the rat), peri- and postnatal reproductive function (in the rat) and fetal toxicity (in the rat and the rabbit). Treatment with iron protein succinylate did not result in any adverse effect on reproductive performance nor did it affect the incidences of malformations, visceral and skeletal anomalies or skeletal variants. There was no evidence of mutagenic activity in a comprehensive series of in vitro and in vivo mutagenicity studies. No secondary pharmacological effects of the product were noted in a wide range of single and repeated administration studies. Overall, the available toxicology and safety profile of this product offers ample assurances of the safety of iron protein succinylate in clinical use.

Animals↗

PubMedDate not supplied

Low-grade sarcomas with CD34-positive fibroblasts and low-grade myofibroblastic sarcomas.

A subset of low-grade fibrosarcomas is composed of CD34-positive spindle cells. These include dermatofibrosarcoma, its morphologic variants, and its associated fibrosarcoma, solitary fibrous tumor, hemangiopericytoma and their malignant counterparts, and some cases of myxoinflammatory fibroblastic sarcoma. Dermatofibrosarcoma and related lesions are characterized by a t(17;22)(q22;q13) rearrangement resulting in fusion of the genes COL1A (17q21-22) and PDGFB1 (22q13). Solitary fibrous tumor displays varying cellularity and fibrosis and a peripheral hemangiopericytomatous pattern; most tumors formerly called hemangiopericytoma are now subsumed into the category of solitary fibrous tumor, although a few strictly defined examples are recognized; however, these are probably not composed of pericytes. Myofibroblastic malignancies are best identified by electron microscopy, with which varying degrees of differentiation, including the presence of fibronexus junctions, can be identified. Low-grade sarcomas showing myofibroblastic differentiation include myofibrosarcomas and inflammatory myofibroblastic tumors. Myofibrosarcomas are spindle cell neoplasms that occur in children or adults in the head and neck, trunk, and extremities as infiltrative neoplasms and that display a fascicular or fasciitis-like pattern with focal nuclear atypia and variable expression of myoid antigens. These sarcomas are prone to recurrence and a small number metastasize. Inflammatory myofibroblastic tumor (synonymous with inflammatory fibrosarcoma) is a neoplasm arising predominantly in childhood, and frequently in intraabdominal locations. It has spindle cells in fascicular, fasciitis-like and sclerosing patterns, with heavy chronic inflammation including abundant plasma cells. Many IMT have clonal chromosomal abnormalities involving 2p22-24, and fusion of the ALK gene with tropomyosin 3 (TPM3-ALK) or tropomyosin 4 (TPM4-ALK) is found in a subset.

Antigens, CD34↗

PubMed1980

Phaeomycotic cyst. A clinicopathologic study of twenty-five patients.

The clinical and pathologic features of 25 cases of phaeomycotic cyst, collected at the Armed Forces Institute of Pathology between 1959 and 1978, are described. Phaeomycotic cyst is infection of the deep dermis and subcutaneous tissue by dematiaceous (brown) fungi. Species of Phialophora were most frequently isolated from these lesions. Synonyms for phaeomycotic cyst are--among others--phaeomycosis and phaeosporotrichosis. Phaeohyphomycosis includes phaeomycotic cyst and some other mycoses. The term "phaeo" is derived from the Greek phi alpha iota omicron sigma, meaning grey or black, and refers to the brown color in vivo and in vitro of these fungi. Phialophora species are world-wide saprophytes, common in soil, decaying wood, and vegetation. They have low virulence and low pathogenicity, and are inoculated along with slivers whose retention is probably an important causal factor in establishing infection. Proliferation of the fungi provokes a mixed suppurative and granulomatous reaction which remains localized. Early the characteristic histopathologic picture is one of multiple stellate abscesses. These progress to a single circumscribed lesion with a central cavity filled with pus and surrounded by a fibrous wall. There are no systemic signs or symptoms, regional lymph nodes are not involved, nor has any patient had systemic spread. The infection is rare but tends to be more common in warm climates. No race, sex, or age group is predisposed, but patients with immune deficiency or debilitating disease are at increased risk. In older publications phaeomycotic cysts have been described as variants of chromomycosis, sporotrichosis, and mycetoma. Phaeomycotic cysts, however, do not provoke hyperplasia of the epidermis or ulceration--characteristic features of both chromomycosis and sporotrichosis, nor do phaeomycotic cysts form sinus tracts or contain grains--both typical features of mycetoma. The strictly localized abscess or "cyst" is the characteristic feature of phaeomycotic cysts.

Abscess↗

PubMed2001

Updated classification of papular mucinosis, lichen myxedematosus, and scleromyxedema.

Lichen myxedematosus (LM) is an idiopathic cutaneous mucinosis; its classification dates back to 1953, when Montgomery and Underwood distinguished 4 types of LM: a generalized lichenoid eruption, later called scleromyxedema, a discrete papular form, a localized or generalized lichenoid plaque form, and an urticarial plaque form. In the literature, the terms LM, papular mucinosis, and scleromyxedema have been often used indiscriminately as synonyms, but most reported cases of LM or papular mucinosis without indication of the subtype appear in fact to be cases of scleromyxedema. On the basis of personal experience, the anatomoclinical manifestations of published cases of LM, papular mucinosis, and scleromyxedema are reviewed to distinguish clearly between a generalized form with systemic, even lethal, manifestations and a localized form, which does not run a disabling course. LM includes two clinicopathologic subsets: a generalized papular and sclerodermoid form (also called scleromyxedema) and a localized papular form. Diagnosis of scleromyxedema should fulfill the following criteria: (1) generalized papular and sclerodermoid eruption; (2) mucin deposition, fibroblast proliferation, and fibrosis; (3) monoclonal gammopathy; and (4) the absence of thyroid disease. The criteria for localized LM are as follows: (1) papular or nodular/plaque eruption; (2) mucin deposition with variable fibroblast proliferation; and (3) the absence of both monoclonal gammopathy and thyroid disease. The localized form is subdivided into 5 subtypes: (1) a discrete papular form involving any site; (2) acral persistent papular mucinosis involving only the extensor surface of the hands and wrists; (3) self-healing papular mucinosis, of a juvenile and an adult type; (4) papular mucinosis of infancy, a pediatric variant of the discrete form or of acral persistent papular mucinosis; and (5) nodular form. A third group of atypical or intermediate forms, not meeting the criteria for either scleromyxedema or the localized form, includes cases of (1) scleromyxedema without monoclonal gammopathy, (2) localized forms with monoclonal gammopathy and/or systemic symptoms, (3) localized forms with mixed features of the 5 subtypes, and (4) not well-specified cases.

Diagnosis, Differential↗

PubMed1996

Hepatitis C in human immunodeficiency virus-coinfected patients: increased variability in the hypervariable envelope coding domain.

Patients coinfected with the hepatitis C virus (HCV) and the human immunodeficiency virus (HIV) were studied with regard to nucleotide sequence variability in the E2/NS1 first hypervariable region of the HCV genome. The nucleotide variability within individual patients was compared to patients infected only with HCV. The proportion of predicted synonymous and nonsynonymous amino acid changes, and the relationship to putative high-antigenicity sites, were evaluated in the hypervariable envelope domain. Ninety-one clones from 10 patients with HCV/HIV coinfection were sequenced, following polymerase chain reaction (PCR) amplification of the hypervariable region. The control HCV group included 53 clones from 7 patients. Sequence analysis encompassed the region coding for amino acids 384 to 414. Consensus sequences from each patient were used as the internal standard for nonsynonymous amino acid codon variability. Cumulative proportional comparison at each amino acid site revealed increased variability in HCV RNA from patients with HCV/HIV coinfection versus HCV alone (P < .05). The greatest variability was observed at amino acids 386, 397, 400, 402, 405, 407, and 414, with >l0 percent clonal variation at these sites. Jameson-Wolf plots were used to predict putative high-antigenicity domains. Nonsynonymous clonal variation resulted in alteration of putative antigenic sites within the hypervariable region. All clones had at least one high-probability site. Clones with unique predicted antigenic domains were observed more frequently in HIV/HCV coinfected patients, and, independent of viral titer, were consistent with increased sequence variability. These data suggest an accumulation of envelope variants in the HCV/HIV coinfected patients, which could be related to ineffective viral clearance, and may help explain prior reports of interferon (IFN) resistance in this patient group.

Adult↗

PubMed2007

Interaction analysis of the CBLB and CTLA4 genes in type 1 diabetes.

Gene-gene interaction analyses have been suggested as a potential strategy to help identify common disease susceptibility genes. Recently, evidence of a statistical interaction between polymorphisms in two negative immunoregulatory genes, CBLB and CTLA4, has been reported in type 1 diabetes (T1D). This study, in 480 Danish families, reported an association between T1D and a synonymous coding SNP in exon 12 of the CBLB gene (rs3772534 G>A; minor allele frequency, MAF=0.24; derived relative risk, RR for G allele=1.78; P=0.046). Furthermore, evidence of a statistical interaction with the known T1D susceptibility-associated CTLA4 polymorphism rs3087243 (laboratory name CT60, G>A) was reported (P<0.0001), such that the CBLB SNP rs3772534 G allele was overtransmitted to offspring with the CTLA4 rs3087243 G/G genotype. We have, therefore, attempted to obtain additional support for this finding in both large family and case-control collections. In a primary analysis, no evidence for an association of the CBLB SNP rs3772534 with disease was found in either sample set (2162 parent-child trios, P=0.33; 3453 cases and 3655 controls, P=0.69). In the case-only statistical interaction analysis between rs3772534 and rs3087243, there was also no support for an effect (1994 T1D affected offspring, and 3215 cases, P=0.92). These data highlight the need for large, well-characterized populations, offering the possibility of obtaining additional support for initial observations owing to the low prior probability of identifying reproducible evidence of gene-gene interactions in the analysis of common disease-associated variants in human populations.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Regulatory polymorphisms underlying complex disease traits.

There is growing evidence that genetic variation plays an important role in the determination of individual susceptibility to complex disease traits. In contrast to coding sequence polymorphisms, where the consequences of non-synonymous variation may be resolved at the level of the protein phenotype, defining specific functional regulatory polymorphisms has proved problematic. This has arisen for a number of reasons, including difficulties with fine mapping due to linkage disequilibrium, together with a paucity of experimental tools to resolve the effects of non-coding sequence variation on gene expression. Recent studies have shown that variation in gene expression is heritable and can be mapped as a quantitative trait. Allele-specific effects on gene expression appear relatively common, typically of modest magnitude and context specific. The role of regulatory polymorphisms in determining susceptibility to a number of complex disease traits is discussed, including variation at the VNTR of INS, encoding insulin, in type 1 diabetes and polymorphism of CTLA4, encoding cytotoxic T lymphocyte antigen, in autoimmune disease. Examples where regulatory polymorphisms have been found to play a role in mongenic traits such as factor VII deficiency are discussed, and contrasted with those polymorphisms associated with ischaemic heart disease at the same gene locus. Molecular mechanisms operating in an allele-specific manner at the level of transcription are illustrated, with examples including the role of Duffy binding protein in malaria. The difficulty of resolving specific functional regulatory variants arising from linkage disequilibrium is demonstrated using a number of examples including polymorphism of CCR5, encoding CC chemokine receptor 5, and HIV-1 infection. The importance of understanding haplotypic structure to the design and interpretation of functional assays of putative regulatory variation is highlighted, together with discussion of the strategic use of experimental tools to resolve regulatory polymorphisms at a transcriptional level. A number of examples are discussed including work on the TNF locus which demonstrate biological and experimental context specificity. Regulatory variation may also operate at other levels of control of gene expression and the modulation of splicing at PTPRC, encoding protein tyrosine phosphatase receptor-type C, and of translational efficiency at F12, encoding factor XII, are discussed.

Autoimmune Diseases↗

PubMed2002

Polymorphism and selection at the SerH immobilization antigen locus in natural populations of Tetrahymena thermophila.

The SerH locus of Tetrahymena thermophila is one of several paralogous loci with genes encoding variants of the major cell surface protein known as the immobilization antigen (i-ag). The locus is highly polymorphic, raising questions concerning functional equivalency and selective forces acting on its multiple alleles. Here, we compare the sequences and expression of SerH1, SerH3, SerH4, SerH5, and SerH6. The precursor i-ags are highly similar. They are rich in alanine, serine, threonine, and cysteine and they share nearly identical ER translocation and GPI addition signals. The locations of the 39 cysteines are highly conserved, particularly in the 3.5 central, imperfect tandem repeats in which 8 periodic cysteines punctuate alternating short and long stretches of amino acids. Hydrophobicity patterns are also conserved. Nevertheless, amino acid sequence identity is low, ranging from 60.7 to 82.9%. At the nucleotide level, from 9.7 to 26.7% of nucleotide sites are polymorphic in pairwise comparisons. Expression of each allele is regulated by temperature-sensitive mRNA stability. H mRNAs are stable at <36 degrees but are unstable at >36 degrees. The H5 mRNA, which is less affected by temperature, has a different arrangement of the putative mRNA destabilization motif AUUUA. Statistical analysis of SerH genes indicates that the multiple alleles are neutral. Significantly low ratios of the rates of nonsynonymous to synonymous amino acid substitutions suggest that the multiple alleles are subject to purifying (negative) selection enforcing constraints on structure.

Amino Acid Sequence↗

PubMed2006

Evolutionary anatomies of positions and types of disease-associated and neutral amino acid mutations in the human genome.

BACKGROUND: Amino acid mutations in a large number of human proteins are known to be associated with heritable genetic disease. These disease-associated mutations (DAMs) are known to occur predominantly in positions essential to the structure and function of the proteins. Here, we examine how the relative perpetuation and conservation of amino acid positions modulate the genome-wide patterns of 8,627 human disease-associated mutations (DAMs) reported in 541 genes. We compare these patterns with 5,308 non-synonymous Single Nucleotide Polymorphisms (nSNPs) in 2,592 genes from primary SNP resources. RESULTS: The abundance of DAMs shows a negative relationship with the evolutionary rate of the amino acid positions harboring them. An opposite trend describes the distribution of nSNPs. DAMs are also preferentially found in the amino acid positions that are retained (or present) in multiple vertebrate species, whereas the nSNPs are over-abundant in the positions that have been lost (or absent) in the non-human vertebrates. These observations are consistent with the effect of purifying selection on natural variation, which also explains the existence of lower minor nSNP allele frequencies at highly-conserved amino acid positions. The biochemical severity of the inter-specific amino acid changes is also modulated by natural selection, with the fast-evolving positions containing more radical amino acid differences among species. Similarly, DAMs associated with early-onset diseases are more radical than those associated with the late-onset diseases. A small fraction of DAMs (10%) overlap with the amino acid differences between species within the same position, but are biochemically the most conservative group of amino acid differences in our datasets. Overlapping DAMs are found disproportionately in fast-evolving amino acid positions, which, along with the conservative nature of the amino acid changes, may have allowed some of them to escape natural selection until compensatory changes occur. CONCLUSION: The consistency and predictability of genome-wide patterns of disease- associated and neutral amino acid variants reported here underscores the importance of the consideration of evolutionary rates of amino acid positions in clinical and population genetic analyses aimed at understanding the nature and fate of disease-associated and neutral population variation. Establishing such general patterns is an early step in efforts to diagnose the pathogenic potentials of novel amino acid mutations.

Amino Acid Substitution↗

PubMed2003

Association of molecular variants, haplotypes, and linkage disequilibrium within the human vitamin D-binding protein (DBP) gene with postmenopausal bone mineral density.

UNLABELLED: Possible contribution of vitamin D-binding protein (DBP) gene for determination of BMD was tested by characterizing 13 SNPs in 384 adult Japanese women. When the effect of a specific single SNP was tested, five SNPs (-39C>T, IVS1+827C>T, IVS1+1916C>T, IVS1-1154A>G, and IVS11+1097G>C) correlated with BMD significantly at various levels. The chromosomal dosage of one haplotype (T-C-C-G-T-C in -39C>T, IVS1+827C>T, IVS1+1916C>T, IVS1-1154A>G, D432E, and IVS11+1097G>C) displayed significant correlation with adjusted radial BMD (r = 0.15, p = 0.008; n = 331). Multiple regression analyses revealed a most significant correlation with the combination of IVS1+827C>T and D432E (r2 = 0.029, p = 0.005). These results indicate a complex combined effect of several SNPs within the DBP gene that might underlie susceptibility to low radial BMD and osteoporosis. INTRODUCTION: Osteoporosis results from the interplay of multiple environmental and genetic determinants. The gene encoding vitamin D-binding protein (DBP), a key factor for regulating calcium homeostasis through the vitamin D endocrine system, is a probable candidate for conferring susceptibility to osteoporosis. METHODS: To test a possible contribution of the DBP gene for determination of bone mineral density (BMD) of adult women, we have characterized 13 single nucleotide polymorphisms (SNPs) within the DBP gene in DNA from 384 adult Japanese women and attempted to correlate specific SNPs with BMD. RESULTS AND CONCLUSIONS: Sixteen major haplotypes accounted for 80% of the variations, indicating allelic complexity in this genomic region. Pairwise linkage disequilibrium (LD), measured by the D' and r2 statistics, demonstrated a general pattern of decline with increasing distance, but individual LD values within small genomic segments were diverse. Regression analysis for adjusted BMD revealed significant correlation with respect to five of them (-39C>T, IVS1+827C>T, IVS1+1916C>T, IVS1-1154A>G, and IVS11+1097G>C) at various levels. An intronic SNP (IVS11+1097G>C) with the highest significance of association (p = 0.006) showed significant LD with four SNPs located around the first exon (r2 values > 0.18, D' > 0.5). A non-synonymous coding SNP, D432E, showed a comparable level of correlation, but it was in a moderate LD only with IVS11+1097G>C. The chromosomal dosage of one haplotype (T-C-C-G-T-C in -39C>T, IVS1+827C>T, IVS1+1916C>T, IVS1-1154A>G, D432E and IVS11+1097G>C) estimated in each subject displayed significant correlation with adjusted radial BMD (r = 0.15, p = 0.008; n = 331). Furthermore, multiple regression analyses revealed that the most significant correlation was achieved for the combination of IVS1+827C>T and D432E (r2 = 0.029, p = 0.005). These results indicate a complex combined effect of several SNPs within the DBP gene that might underlie susceptibility to low radial BMD and osteoporosis.

Aged↗