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PubMed2006

Syndrome stability and psychological predictors of symptom severity in idiopathic environmental intolerance and somatoform disorders.

BACKGROUND: Previous studies suggest that idiopathic environmental intolerance (IEI) is a variant of somatoform disorders (SFDs) or the so-called functional somatic syndromes. Little is known, however, about the stability and the psychological predictors of IEI. METHOD: This prospective study examined the 1-year stability of somatic symptoms and IEI features in three diagnostic groups: 49 subjects with IEI, 43 subjects with SFD but without IEI, and 54 subjects (control group, CG) with neither IEI nor SFD. The predictive value of typical psychological predictors for somatization was tested using zero-order correlations and multiple linear regression analyses. RESULTS: Somatic symptoms and IEI features proved to be temporally stable over the 1-year follow-up period. The SFD and IEI groups scored significantly higher than CG on all measures of somatic symptoms and on questionnaires assessing psychological predictors for somatization. Measures of trait negative affectivity (NA), somatic symptom attribution and somatosensory amplification predicted somatic symptom severity within the IEI and SFD groups, both at baseline and 1 year later. The strongest predictors of IEI complaints in the IEI group were somatic attributions, followed by prominent cognitions of environmental threat and a tendency to focus on unpleasant bodily sensations and to consider them as pathological. CONCLUSIONS: IEI and SFD are highly stable conditions. In both SFD and IEI, NA and the processes of symptom perception, interpretation and attribution contribute substantially to the persistence of typically somatoform symptoms and IEI complaints. Treatment of IEI and SFD should address these psychological factors and mechanisms.

Adult↗
PubMedDate not supplied

Diagnosis of ataxia telangiectasia with the glycophorin A somatic mutation assay.

There are no widely applied definitive laboratory tests for the diagnosis of ataxia telangiectasia (AT). We, and others, have previously reported significantly elevated levels of in vivo somatic mutation in blood samples from known AT patients, observations that might form the basis for a useful prospective laboratory test for confirmation of a clinical diagnosis of AT. In the present case, a 4 1/2-year-old black female was suspected of having AT based on ataxic gait and chronic upper respiratory infections. Blood work-up showed low IgG2 and elevated alpha-fetoprotein (AFP), consistent with the AT phenotype. Her peripheral blood karyotype was normal, however, with no spontaneous breakage observed among 100 solid stained metaphases. Lymphocytes from AT patients often show elevated levels of chromosome rearrangement, especially at sites of immunoglobulin and T-cell receptor genes. Therefore, a blood sample was analyzed with the glycophorin A (GPA) in vivo somatic mutation assay. The GPA assay detects and quantifies the phenotypically variant erythrocytes resulting from loss of heterozygosity for the MN blood group. The patient had a 10-fold increased frequency of variant erythrocytes with a phenotype consistent with simple loss of the N allele, which is characteristic of AT. In addition, the variant cell distribution for this patient showed three other, more qualitative hallmarks of AT: a normal frequency of allele loss and duplication events, a unique ridge of cells of intermediate phenotype between the normal and mutant peaks, and evidence of similar ongoing mutational loss of the M allele. Together with clinical data, these distinctive qualitative and quantitative features of the GPA assay allow for a diagnosis of AT with a projected accuracy of 95%. Therefore, we suggest that the GPA assay, which can be performed on < 1 ml of blood and completed in less than a day, be considered as a confirmatory laboratory test for a clinical diagnosis of AT.

Agammaglobulinemia↗
PubMed1975

200 infertile males: correlation of chromosome, histological, endocrine and clinical studies.

Somatic and meiotic chromosomes have been studied prospectively in 200 subfertile males. The results have been correlated with clinical, seminal and endocrinological features, with histological findings in testicular biopsies and with response to conventional treatment. Somatic chromosome abnormalities were found in 3-5% of cases and variants of the Y chromosome were found in 10-5%. Definite abnormalities in meiotic chromosomes were observed in 20% of these patients, including supernumerary chromosomes, low chiasma frequency and asynapsis, and translocations. Many of these abnormalities occurred as mosaics, presumably a result of meiotic mutation. In 4 cases, a previously unrecognised abnormality in pachynemas has been defined. Absence of meiosis was found in 12% of cases, which correlated well with the histological findings of germinal cell aplasia and elevated urinary FSH levels.

Chromosome Aberrations↗
PubMed1993

Extinction of insulin-like growth factor II gene expression in intratypic hybrids of rat liver cells.

The expression of the developmentally regulated insulin-like growth factor II (IGF-II) gene has been studied in somatic cell hybrids derived from rat liver cells. BRL3A cells, dedifferentiated variants of rat hepatocytes, producing high levels of IGF-II, were fused to BRL30E or FAO cells of the same embryonic lineage but not expressing detectable levels of IGF-II mRNA. We report here that the IGF-II gene is subject to extinction, since its specific RNA levels are decreased both in heterokaryons and stable cell hybrids. Transcriptional analysis in isolated nuclei from parental and hybrid cells showed that the IGF-II gene is transcribed at a similar rate in all cell types. Likewise, the stability of IGF-II cytoplasmic mRNA was equivalent in the high-expressing parental cells and in the hybrids. In contrast, the distribution of IGF-II mRNA between the nuclear and the cytoplasmic compartments differed markedly in parental and hybrid cell lines. The data presented show that the expression of the IGF-II gene is subject to a dominant negative control and suggest that the phenomenon involves mechanisms that operate at the posttranscriptional level.

Animals↗
PubMed1998

The role of 5-HT2C receptors in affective disorders.

5-HT(2C) receptors are predominantly localised in the brain and their dysregulation may contribute to particular symptoms of anxiety and depression. The marked affinity of several clinically established psychotropic agents sites (e.g., tricyclic antidepressants, clozapine, fluoxetine) for 5-HT(2C) receptor has generated interest in the therapeutic potential of selective, high affinity 5-HT(2C) receptor ligands. Like the selective serotonin re-uptake inhibitor (SSRI) fluoxetine, high affinity selective agonists such as Ro 60-0175 and Ro 60-0332 have potent in vivo activity in animal models suggestive of therapeutic action against depression, obsessive-compulsive disorder (OCD) and panic disorders. In contrast, 5-HT(2C) receptor antagonists such as SB-200646A or SB-221284 show signs of anxiolytic-like activity in tests for conditioned and phobic-like anxiety in rodents whereas they are inactive in tests indicative of antidepressant, antiOCD and antipanic activity. These results are consistent with an important hypothesis proposing that 5-HT has a complex, dual action on the neural mechanism of anxiety by either facilitating or inhibiting different kinds of anxiety in different brain regions. They also suggest that 5-HT(2C) receptor subtypes play an important role in the therapeutic properties of SSRIs. Certain 5-HT(2C) receptor antagonists may possess negative efficacy at 5-HT(2C) receptors and, as inverse agonists, may control constitutive receptor activity possibly characterising some psychopathological states. Receptor variants exist in the human population and indicate possible associations between somatic mutations in the 5-HT(2C) receptor and psychopathology or response to drug treatment. Selective 5-HT(2C) receptor ligands may offer innovative and improved therapeutic opportunities for the biological treatment of specific aspects of psychiatric syndromes.

Journal Article↗
PubMed1988

The number of clonal precursors of the follicular epithelium in the mouse ovary.

The number of clonal precursors of granulosa cells in mouse ovarian follicles has been estimated using a technique based on the phenomenon of random X-chromosome inactivation of somatic cells and the use of an X-linked alloenzyme variant of the glycolytic enzyme PGK-1. The granulosa cells of follicles were oligoclonal in origin and founded by a small number of cells (about 5) which was consistent with histological observations. When the analysis was extended to two subcompartments of the follicle, the mural and cumulus granulosa cells, the results indicated that the cumulus and mural granulosa cells had a common origin.

Animals↗
PubMed2001

Combinatorial events in generation of antibody diversity.

Combinatorial association of immunoglobulin gene elements is the most important process in the creation of extreme diversity of antibody molecules. The recombination of germ-line variable gene elements V, D, and J can potentially generate approximately 6000 variable genes of human heavy chains. As joining of these elements is imprecise and is occurring with nucleotide additions or deletions, the created diversity is in fact much higher. The assembled variable genes can be revised and edited resulting in a change of their affinity and even specificity. Due to somatic hypermutation, the affinity of synthesized antibody increases even more. Another variant of combinatorial recombination is joining of complete variable genes with one of the several constant genes and the formation of various immunoglobulin isotypes with different effector functions but with the same antibody specificity. Consequently, these processes not only develop the antibody repertoire but also solve some other problems of the adaptive immune response.

Animals↗
PubMed1996

A case of unrelenting pursuit of castration.

OBJECTIVE: Explore the limitations of the classification of body dysmorphic disorder. CLINICAL PICTURE: A chinese male relentlessly pursued castration to relieve painful erections which were never substantiated. The testes and corporaspongiosum had been removed. No psychotic symptom was prominent. TREATMENT: Cognitive therapy and psychotropics were tried. OUTCOME: The remaining corpora cavernosa was removed subsequently. CONCLUSION: The distorted somatic perception and secondary cognitive amplification (painful erections) could represent a variant of body dysmorphic disorder involving internal body image; diagnostic classifications should accommodate such a category.

Adult↗
PubMed2002

A new transthyretin variant Leu55Gln in a patient with systemic amyloidosis.

We report a 40-year-old woman with a new transthyretin (TTR) variant, glutamine replacing leucine at residue 55 (Leu55Gln), who showed progressive somatic and autonomic neuropathy, glaucoma, and vitreous opacities. Symptoms of glaucoma appeared prior to the onset of the neuropathy. Sural nerve biopsy revealed amyloid deposition in the endoneurium, and immunohistochemical analysis was positive with anti-human TTR. Sequencing of the patient's DNA revealed the substitution of A for T at the second position of codon 55 of the TTR gene indicating an amino acid change from leucine to glutamine.

Amyloidosis↗
PubMed2006

[Non-specific X-linked mental retardation].

INTRODUCTION: Non-specific mental retardation is defined by the absence of somatic, neurological, biochemical or behavioural features that characterise a particular clinical variant and accounts for a large percentage of cases of X-linked mental retardation (XLMR). Genetic linkage studies showed it to have a high rate of genetic heterogeneity. DEVELOPMENT: To date, genetic linkage studies or the characterisation of chromosomal rearrangement in patients have allowed 22 different genes to be identified. Some of the most notable of these are the genes responsible for syndromic forms, such as RPS6KA3, ARX, JARID1C, XNP or MeCP2, in which the mildest mutations, with a certain amount of functional activity, cause non-specific retardation. The proteins these genes code for are directly or indirectly involved in regulating the expression of other genes. Moreover, genes such as OPHN1, PAK3, ARHGEF6, FGD1 or TM4SF2 code for proteins that interact with rho GTPases, and play a role in the transmission of signals that regulate the development of axons and dendrites. Other types of functions of the known genes include establishing and modulating synapses (DLG3, IL1RAPL, NLGN4X, GDI1), regulating transcription (ZNF41, ZNF81, PQBP1) translation (FTSJ1), and fatty acid metabolism (FACL4), etc. CONCLUSIONS: Each gene that has been identified only accounts for a minor fraction of the total amount of XLMR, and even if taken together they still do not explain half the cases of non-specific XLMR. The number of XLMR genes is expected to rise in coming years with the development of new techniques that will facilitate diagnosis and genetic counselling in the relatively near future.

Chromosome Mapping↗
PubMed1980

[Psychopathologic disorders in burns].

Psychopathological disturbances in 149 patients with burn disease are described during all stages of the disorder. Certain correlations with the period of burn disease, the depth and affected surface, somatic disturbances, premorbid personality traits, sex and age were demonstrated. Different variants of psychopathological disturbances and their traits in burn trauma in the acute period of burn disease are described. Variants of such disorders persisted in patients with burn encephalopathy in the late period of the disease from one to 20 years.

Acute Disease↗
PubMed1995

Progression of hormone-dependent adenocarcinoma cells to hormone-independent spindle carcinoma cells in vitro in a clonal spontaneous rat mammary tumor cell line.

A hormone-dependent, clonal carcinoma cell line, designated RM22-F5, was derived from a malignant mammary mixed tumor spontaneously arising in an outbred old female Wistar rat. These cells expressed keratin and desmosomal protein and formed epithelial monolayers in a growth factor and hormone-supplemented medium (LHC-8) containing 10% fetal bovine serum (E-type cells). Cells subcultured for 6 to 8 passages in RPMI 1640 medium containing 10% fetal bovine serum without supplements appeared to be fibroblastic and expressed vimentin (F-type cells). The shift to a fibroblast-like morphology was associated with a more malignant phenotype which included rapid, hormone-independent growth and invasive sarcoma-like character in nude mice. F-type cells were no longer able to express their original epithelial phenotype in LHC-8 medium. Cytogenetic analysis revealed that both E- and F-type cells had essentially the same karyotype. Analysis of PCR-amplified DNA further demonstrated a point mutation of the H-ras-1 gene at codon 12 and loss of the normal H-ras-1 allele in both cell types. Genetic tagging of E-type cells with the neomycin-resistance gene resulted in the generation of F-type cells with neomycin resistance in RPMI 1640 medium, suggesting that F-type cells are a malignant variant of E-type cells arising during in vitro culture. Somatic cell fusion between E- and F-type cells revealed that with most hybrid clones tested, the fibroblast-like phenotype was greatly suppressed. These results suggest that an irreversible phenotypic transition, representative of tumor progression from hormone-dependent adenocarcinoma to more malignant hormone-independent spindle carcinoma cells, is a recessive event and may involve loss of a suppressor function.

Adenocarcinoma↗
PubMed1997

A novel, testis-specific mRNA transcript encoding an NH2-terminal truncated nitric-oxide synthase.

mRNA diversity represents a major theme of neuronal nitric-oxide synthase (nNOS) gene expression in somatic cells/tissues. Given that gonads often express unique and biologically informative variants of complex genes, we determined whether unique variants of nNOS are expressed in the testis. Analysis of cDNA clones isolated from human testis identified a novel, testis-specific nNOS (TnNOS) mRNA transcript. A predicted 3294-base pair open reading frame encodes an NH2-terminal truncated protein of 1098 amino acids. Measurement of calcium-activated L-[14C]citrulline formation and nitric oxide release in CHO-K1 cells stably transfected with the TnNOS cDNA indicates that this protein is a calcium-dependent nitric-oxide synthase with catalytic activity comparable to that of full-length nNOS. TnNOS transcripts exhibit novel 5' mRNA sequences encoded by two unique exons spliced to exon 4 of the full-length nNOS. Characterization of the genomic structure indicates that exonic regions used by the novel TnNOS are expressed from intron 3 of the NOS1 gene. Although lacking canonical TATA and CAAT boxes, the 5'-flanking region of the TnNOS exon 1 contains multiple putative cis-regulatory elements including those implicated in testis-specific gene expression. The downstream promoter of the human nNOS gene, which directs testis-specific expression of a novel NH2-terminal truncated nitric-oxide synthase, represents the first reported example in the NOS gene family of transcriptional diversity producing a variant NOS protein.

Alternative Splicing↗
PubMed1983

The human phosphoserine phosphatase gene (PSP) is mapped to chromosome 7 by somatic cell genetic analysis.

Human phosphoserine phosphatase (E.C. 3.1.3.3) (PSP), a phosphohydrolase, participates in the biosynthesis of serine from carbohydrates (Moro-Furlani et al., 1980). Starch gel electrophoresis has identified isoenzymes and rare allelic variants. More common electrophoretic variation is thought to be due to secondary nongenetic modification. Using starch gel electrophoresis of interspecific somatic cell hybrids, we have been able to assign the gene for this enzyme to human chromosome 7.

Animals↗
PubMed2006

Genetic and epigenetic analysis of CHEK2 in sporadic breast, colon, and ovarian cancers.

PURPOSE: Germ-line variants in CHEK2 have been associated with increased breast, thyroid, prostate, kidney, and colorectal cancer risk; however, the prevalence of somatic inactivation of CHEK2 in common cancer types is less clear. The aim of this study was to determine if somatic mutation and/or epigenetic modification play a role in development of sporadic breast, colon, or ovarian cancers. EXPERIMENTAL DESIGN: We undertook combined genetic and epigenetic analysis of CHEK2 in sporadic primary breast, ovarian, and colon tumors [all exhibiting chromosome 22q loss of heterozygosity (LOH)] and cancer cell lines. Expression of Chk2 was assessed by immunohistochemistry in 119 ovarian tumors. RESULTS: Two novel germ-line variants were identified; however, none of the primary tumors harbored somatic mutations. Two CpG clusters previously implicated in CHEK2 silencing were investigated for evidence of hypermethylation. No methylation was detected at the distal CpG island. The proximal CpG cluster was methylated in all tumor and normal DNA, suggesting that this might not represent a true CpG island and is not relevant in the control of CHEK2 expression. Twenty-three percent of ovarian tumors were negative for Chk2 protein by immunohistochemistry, but there was no significant correlation between LOH across the CHEK2 locus and intensity of Chk2 staining (P = 0.12). CONCLUSIONS: LOH across the CHEK2 locus is common in sporadic breast, ovarian, and colorectal cancers, but point mutation or epigenetic inactivation of the retained allele is uncommon. Loss of Chk2 protein in ovarian cancer was not associated with allelic status, suggesting that inactivation does not occur as a consequence of haploinsufficiency.

Alleles↗
PubMed1995

Identification of polymorphisms and sequence variants in the human homologue of the mouse natural resistance-associated macrophage protein gene.

The most common mycobacterial disease in humans is tuberculosis, and there is evidence for genetic factors in susceptibility to tuberculosis. In the mouse, the Bcg gene controls macrophage priming for activation and is a major gene for susceptibility to infection with mycobacteria. A candidate gene for Bcg was identified by positional cloning and was designated "natural resistance-associated macrophage protein gene" (Nramp1), and the human homologue (NRAMP1) has recently been cloned. Here we report on (1) the physical mapping of NRAMP1 close to VIL in chromosome region 2q35 by PCR analysis of somatic cell hybrids and YAC cloning and (2) the identification of nine sequence variants in NRAMP1. Of the four variants in the coding region, there were two missense mutations and two silent substitutions. The missense mutations were a conservative alanine-to-valine substitution at codon 318 in exon 9 and an aspartic acid-to-asparagine substitution at codon 543 in the predicted cytoplasmic tail of the NRAMP1 protein. A microsatellite was located in the immediate 5' region of the gene, three variants were in introns, and one variant was located in the 3' UTR. The allele frequencies of each of the nine variants were determined in DNA samples of 60 Caucasians and 20 Asians. In addition, we have physically linked two highly polymorphic microsatellite markers, D2S104 and D2S173, to NRAMP1 on a 1.5-Mb YAC contig. These molecular markers will be useful to assess the role of NRAMP1 is susceptibility to tuberculosis and other macrophage-mediated diseases.

Alleles↗
PubMed1979

6-Thioguanine resistant peripheral blood lymphocytes in humans following psoralen, long-wave ultraviolet light (PUVA) therapy.

A recently described method that enumerates variant 6-thioguanine resistant peripheral blood lymphocytes present in vivo in man as a potential marker of somatic cell mutations occurring in vivo was used to study 18 psoriatic patients receiving PUVA therapy, 16 conventinally treated psoriatic patients, 10 vitiligo patients receiving PUVA therapy and 7 untreated individuals with vitiligo. Variant lymphocyte frequencies determined for these individuals were compared with those determined for groups of 10 concurrent and 63 cumulative healthy control individuals. Variant frequencies were elevated in psoriatic and vitiligo patients receiving PUVA therapy and in conventionally-treated psoriatic patients. They were not elevated over control values in untreated vitiligo patients.

Adult↗