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PubMed2003

Biology and treatment of chronic lymphocytic leukemia.

Major advances have occurred in our understanding of the biology, immunology, and opportunities for treatment of chronic lymphocytic leukemia (CLL) in recent times. Surface antigen analysis has helped us define classical CLL and differentiate it from variants such as marginal zone leukemia, mantle cell leukemia, and prolymphocytic leukemia. An important observation has been that the B-cells in indolent types of CLL, which do not require therapy, have undergone somatic hypermutation and function as memory B-lymphocytes whereas those more likely to progress have not undergone this process. Section I by Dr. Nicholas Chiorazzi encompasses emerging elements of the new biology of CLL and will address the types of somatic hypermutation that occur in CLL cells and their correlation with other parameters such as telomere length and ZAP70 status. In addition he addresses the concept of which cells are proliferating in CLL and how we can quantitate the proliferative thrust using novel methods. The interaction between these parameters is also explored. Section II by Dr. Thomas Kipps focuses on immune biology and immunotherapy of CLL and discusses new animal models in CLL, which can be exploited to increase understanding of the disease and create new opportunities for testing the interaction of the CLL cells with a variety of elements of the immune system. It is obvious that immunotherapy is emerging as a major therapeutic modality in chronic lymphocytic leukemia. Dr. Kipps addresses the present understanding of the immune status of CLL and the role of passive immunotherapy with monoclonal antibodies such as rituximab, alemtuzumab, and emerging new antibodies. In addition the interaction between the CLL cells and the immune system, which has been exploited in gene therapy with transfection of CLL cells by CD40 ligand, is discussed. In Section III, Dr. Michael Keating examines the question "Do we have the tools to cure CLL?" and focuses on the fact that we now have three distinct modalities, which are able to achieve high quality remissions with polymerase chain reaction (PCR) negativity for the immunoglobulin heavy chain in CLL. These modalities include initial chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab, the use of alemtuzumab for marrow cytoreduction in minimal residual disease and allogeneic bone marrow transplants. The emergence of non-ablative marrow transplants in CLL has led to the broadening of the range of opportunities to treat older patients. The addition of rituximab to the chemotherapy preparative regimens appears to be a significant advance. The combination of our increased understanding of the biology, immune status, and therapy of CLL provides for the first time the opportunity for curative strategies.

Animals↗
PubMed2002

Etiology and significance of the optically clear nucleus.

Papillary thyroid carcinoma (PTC) is diagnosed in both cytology and surgical pathology specimens on the basis of distinct nuclear morphology, characterized by nuclear elongation, chromatin clearing, intranuclear grooves, and inclusions. Although these nuclear features are specific to papillary carcinoma, they can be mimicked in some benign conditions. The majority of PTC cases do not pose diagnostic problems. However, a distinct subset of cases has generated controversy among experts. These cases are follicular patterned tumors that show minimal nuclear changes in PTC. Several investigators have explored the role of immunohistochemical markers in the histologic diagnosis of PTC. Somatic rearrangements of the RET protooncogene are the most frequent genetic abnormality found in PTC. The frequency of these rearrangements has varied according to the geographic region, radiation exposure, and methodologies used and histologic variant of PTC. Recent studies have suggested that RET/PTC may be the cause of this specific nuclear change in PTC; however, the role of RET/PTC in tumor progression still needs to be defined.

Adenocarcinoma, Follicular↗
PubMed1999

Molecular analysis of single B cells from T-cell-rich B-cell lymphoma shows the derivation of the tumor cells from mutating germinal center B cells and exemplifies means by which immunoglobulin genes are modified in germinal center B cells.

T-cell-rich B-cell lymphoma (TCRBCL) belongs to the group of diffuse large cell lymphomas (DLL). It is characterized by a small number of tumor B cells among a major population of nonmalignant polyclonal T cells. To identify the developmental stage of the tumor progenitor cells, we micromanipulated the putative neoplastic large CD20(+) cells from TCRBCLs and amplified and sequenced immunoglobulin (Ig) V gene rearrangements from individual cells. In six cases, clonal Ig heavy, as well as light chain, gene rearrangements were amplified from the isolated B cells. All six cases harbored somatically mutated V gene rearrangements with an average mutation frequency of 15.5% for heavy (VH) and 5.9% for light (VL) chains and intraclonal diversity based on somatic mutation. These findings identify germinal center (GC) B cells as the precursors of the transformed B cells in TCRBCL. The study also exemplifies various means how Ig gene rearrangements can be modified by GC B cells or their malignant counterparts in TCRBCL: In one case, the tumor precursor may have switched from kappa to lambda light chain expression after acquiring a crippling mutation within the initially functional kappa light chain gene. In another case, the tumor cells harbor two in-frame VH gene rearrangements, one of which was rendered nonfunctional by somatic mutation. Either the tumor cell precursor entered the GC with two potentially functional in-frame rearrangements or the second VHDHJH rearrangement occurred in the GC after the initial in-frame rearrangement was inactivated by somatic mutation. Finally, in each of the six cases, at least one cell contained two (or more) copies of a clonal Ig gene rearrangement with sequence variations between these copies. The presence of sequence variants for V region genes within single B cells has so far not been observed in any other normal or transformed B lymphocyte. Fluorescence in situ hybridization (FISH) points to a generalized polyploidy of the tumor cells.

Adult↗
PubMed2002

I105V polymorphism and promoter methylation of the GSTP1 gene in prostate adenocarcinoma.

The GSTP1 gene encodes for an enzyme, glutathione S-transferase pi (GSTpi),involved in detoxification of carcinogens. An aminoacid substitution (I105V) in GSTP1 produces a variant enzyme with lower activity and less capability of effective detoxification. This variant GSTP*B allele has been associated with a propensity to develop several neoplasms. Because GSTP1 promoter hypermethylation and inactivation of GSTpi expression is a frequent alteration in prostate carcinoma, we hypothesized that this somatic epigenetic modification could obviate any reduced enzyme activity caused by the germ-line polymorphism. We tested for the GSTP1 genotype in a population of prostate cancer patients, and in a control group composed of patients with benign prostatic hyperplasia (BPH) and healthy blood donors. Tissue samples from the 105 prostate cancer cases (105 adenocarcinomas and 34 prostatic intraepithelial neoplasia lesions), and from 43 BPH patients were tested for GSTP1 hypermethylation by methylation-specific PCR. GSTpi protein expression was assessed by immunohistochemistry. No significant effect on prostate cancer risk was detectable for GSTP1 genotype compared with the control population (odds ratio, 1.02; 95% confidence interval, 0.59-1.75). Moreover, no association was found between this genotype and tumor or BPH methylation status. Patients with unmethylated carcinomas did not disclose significant differences in genotypic distribution compared with the control population. In adenocarcinoma, a strong association (P < 0.00001) between GSTP1 promoter hypermethylation and loss of GSTpi expression was observed; however, this trend was not retained in prostatic intraepithelial neoplasia or BPH lesions. Although the GSTP1 polymorphism is not associated with altered susceptibility to prostate cancer, somatic promoter hypermethylation is an effective, but not the only, cause of decreased GSTpi function.

Adenocarcinoma↗
PubMed1985

Mapping of transforming growth factor alpha gene on human chromosome 2 close to the breakpoint of the Burkitt's lymphoma t(2;8) variant translocation.

Transforming growth factors (TGFs) are defined as biologically active polypeptides which reversibly confer the transformed phenotype onto untransformed cultured cells. TGF-alpha shows sequence homology with epidermal growth factor and competes with epidermal growth factor for binding to the epidermal growth factor receptor, stimulating the phosphorylation of the receptor. TGF-alpha is secreted by many transformed cells and may be involved in embryonic development. A cloned human TGF-alpha gene was used to map the locus for the TGF-alpha precursor to the short arm of human chromosome 2, region 2p11----2p13, by Southern blotting techniques with DNA prepared from rodent X human somatic cell hybrids. These hybrids contained different subsets of human chromosomes and included a set with a translocation between human chromosomes 1 and 2 [t(1;2) (q32;q13)]. In situ hybridization of the TGF-alpha probe to normal human metaphase spreads confirmed these data and localized TGF-alpha more precisely to bands 2p11----2p13. Breakpoints in the variant Burkitt lymphoma translocation t(2;8) occur within these bands. Such a t(2;8) translocation could place TGF-alpha next to c-myc in band 8q24. The possibility is raised that TGF-alpha might contribute to tumor progression in these cases of Burkitt's lymphoma.

Burkitt Lymphoma↗
PubMed1998

Transcription and splicing patterns of M- and O-type P elements in drosophila bifasciata, D. helvetica, and scaptomyza pallida

RT-PCR was applied to analyze the splicing patterns of P-element-derived mRNAs in Drosophila bifasciata, D. helvetica, and Scaptomyza pallida. D. melanogaster was used as a control. The experiments revealed that P elements are transcribed in all species investigated. However, there are differences in the splicing patterns of IVS3, which has to be removed in order to produce transposase mRNA instead of repressor mRNA. These differences are observed among species as well as between the P element subfamilies, the M and the O type, which coexist in the genomes of D. bifasciata and S. pallida. In D. helvetica M-type transposase mRNA was found in the germline and repressor mRNA in the soma, as has been previously described for the canonical (M-type-related) P element of D. melanogaster. In contrast, in S. pallida only repressor mRNA of M-type elements was detected in all tissues. In D. bifasciata, M-type IVS3, although activated both in the soma and the germline, is never completely excised. Instead, two alternative double-spliced variants occur in which two small introns are removed within the IVS3 region. One of these variants codes for a protein 12 aa longer than the regular transposase. Taking these findings together, transposase production and transpositional activity of M-type elements seem to be limited to D. helvetica and D. melanogaster, whereas M-type elements have become immobile in D. bifasciata and S. pallida. Unlike the M type, the splicing of O-type transcripts in D. bifasciata and S. pallida follows the classical rules of tissue-specific P element regulation: transposase mRNA is produced exclusively in the germline whereas repressor mRNA is formed in somatic cells. Thus O-type elements are thought to be still transpositionally active in both species. This finding is in accordance with the postulated recent transfer of O-type elements between the gene pools of D. bifasciata and S. pallida. In addition, we were able to show that the IVS3 double-spliced variants of both P element types are produced regularily in all species of the genus Drosophila investigated so far, but not in S. pallida.

Journal Article↗
PubMed1986

Structure and genomic organization of proretrovirus-like elements partially eliminated from the somatic genome of Ascaris lumbricoides.

A clone containing a middle repetitive element next to satellite DNA has been isolated from a germ line genomic library of the chromatin eliminating nematode Ascaris lumbricoides var. suum. The structure of this element has been elucidated by comparison of several clones containing the element in different environments. It is flanked by 256-bp-long terminal repeats (LTRs) and has an internal region of approximately 7 kb. The nucleotide sequences of both the 5' and the 3' LTRs have been determined. The element has a strong structural similarity with retroviral proviruses and related mobile elements. It was therefore named 'Tas', for transposon-like element of Ascaris. Approximately 50 Tas copies are dispersed over approximately 20 different chromosomal sites. Their genomic distribution varies between individuals, indicating that Tas elements are mobile in the Ascaris genome. Two variant forms, Tas-1 and Tas-2, present in a ratio of approximately 2 to 1 in the germ line genome, have been characterized. They differ not only in their restriction pattern, but also in their elimination behaviour. While only about one-fourth of the Tas-1 elements are expelled from the somatic cell lineage, all Tas-2 copies are specifically eliminated and are thus confined to the germ line cells. We have demonstrated that a cloned representative of Tas-1 elements is expelled concomitantly with its flanking DNA sequences during the chromatin elimination process.

Animals↗
PubMed1986

DSM-III diagnoses in chronic pain. Confusion or clarity?

The assessment of patients with chronic pain is receiving increasing attention by psychiatrists. Recent publications have put forward the concept of the "pain-prone disorder" as a variant of depressive illness. This study describes a series of 50 consecutive patients with chronic pain in terms of the five axes of the DSM-III nosology. Diagnoses were made after a 90- to 120-minute psychiatric interview, and a check on diagnostic reliability was made on a small subsample. Psychological factors affecting physical condition were diagnosed in 34% and dysthymic disorder was diagnosed in 28%, while major depression, psychogenic pain disorder, somatization disorder, and anxiety disorders were each respectively diagnosed in 8%. Only 6% had no diagnosis on axis I and 4% had no diagnosis on axis III. Personality disorder was diagnosed in 40%, and traits of dependence, compulsiveness, and anxiety were common. Overall, the patients had experienced a high degree of psychosocial stress with fair to poor adaptive functioning. The notion of chronic pain as a variant of depressive disease is questioned on the basis of these findings. The author suggests that although pain-proneness is a useful psychodynamic concept, the case for its establishment as a new psychobiological disorder is not proven. Furthermore, the concepts of pain-proneness, depression, and psychogenic pain have become confused. The author argues that the current classification is adequate to deal with the varieties of depression associated with chronic pain and that psychogenic pain disorder should be remerged with conversion disorder for the sake of clarity.

Adolescent↗
PubMed1988

A variant nuclear protein in dedifferentiated hepatoma cells binds to the same functional sequences in the beta fibrinogen gene promoter as HNF-1.

Normal liver and differentiated hepatoma cell lines contain a nuclear factor, HNF-1, which binds functional sequences within the promoters of the alpha and beta chains of fibrinogen and alpha 1-antitrypsin. In UV cross-linking studies we find that HNF-1 has an apparent mol. wt of 92 kd in differentiated hepatocytes. Nuclear extracts from a dedifferentiated hepatoma cell line, Fao flC2 (C2), selected on the basis of morphological and biochemical dedifferentiation from Fao contains a protein, vHNF, which binds to the same DNA sequence motif as HNF-1 but has an apparent mol. wt of 72 rather than 92 kd. Mixing experiments indicate that this variant nuclear factor does not arise from HNF-1 by proteolysis. Reversion to the differentiated phenotype in C2-Rev7 (Rev7), selected by growth in glucose-free media, results in the re-expression of many liver-specific functions including the fibrinogen genes. In Rev7, HNF-1 is indistinguishable from that in the original differentiated cell line Fao. Transfection studies and nuclear run-on experiments indicate that reduced expression of fibrinogen RNA in C2 relative to Fao is related to reduced transcription. vHNF but not HNF-1 is present in somatic hybrids between fibroblasts and liver cells which show extinction of liver specific traits and it can also be detected in normal tissue, predominantly in lung nuclear extracts. Since vHNF and HNF-1 are not co-expressed yet correlate with the non-hepatic and hepatic phenotype, respectively, we suggest that the expression of these variant forms reflects determination events in establishing the hepatic phenotype.

Animals↗
PubMed1988

Antibody-forming capacity of B cell-deficient chickens reconstituted with limiting numbers of B cell precursors.

To examine the antibody-forming capacity of neonatally cyclophosphamide-treated chickens reconstituted with limiting numbers of B cell precursors, we analyzed their antibody responses to six unrelated antigens. Our results demonstrate that about 10 x 10(6) bursal cells are needed in this adoptive cell transfer model to restore normal immune competence to B cell-deficient birds. From our earlier data we know that with low repopulating cell numbers (less than 10 x 10(6) cells) developing bursal follicles are of clonal origin. Ten million cells repopulate about 40%, i.e. about 4 x 10(3) of the bursal lymphoid follicles. Assuming the clonal origin of the follicles these results imply that the B cell system of birds receiving this dose is derived from less than 5 x 10(3) precursor cells. At the lowest reconstituting dose (1.25 x 10(6) cells) most birds do not respond to the antigens studied. However, their B cell system is derived from only about 500 precursor cells. Because the antibody repertoire of a normal chicken was estimated to be at least 10(6) our results suggest that each precursor gives rise to a large number (greater than 200) of immunoglobulin V-region gene variants during its clonal proliferation in the bursa. Our results are thus consistent with the proposed "hyperconversion" mechanism of generation of antibody diversity in the chicken and provide quantitative data useful for estimating what such somatic modification rates might be.

Animals↗
PubMed1997

The vicinal chloroalcohols 1,3-dichloro-2-propanol (DC2P), 3-chloro-1,2-propanediol (3CPD) and 2-chloro-1,3-propanediol (2CPD) are not genotoxic in vivo in the wing spot test of Drosophila melanogaster.

In this study, the vicinal chloroalcohols 1,3-dichloro-2-propanol (DC2P), 3-chloro-1,2-propanediol (3CPD) and 2-chloro-1,3-propanediol (2CPD) were investigated for genotoxicity in the wing spot test of Drosophila. DC2P is an important starting material in many processes of synthesis in chemical industry. 3CPD as well as some related glycerol chlorohydrins were identified in protein hydrolysates industrially used for the production of food items such as seasonings, sauces and soups. The wing spot test is a somatic mutation and recombination test (SMART) and is a sensitive in vivo assay for the detection of mutagens and promutagens. The test was applied here in its standard version with normal bioactivation and in a variant with increased cytochrome P450-dependent bioactivation capacity. All three compounds were clearly non-genotoxic in these in vivo assays. The results are in agreement with recent findings which strongly suggest that positive genotoxicity results in in vitro testing of vicinal chloroalcohols such as DC2P are due to directly acting genotoxic intermediates arising from a chemical reaction with the culture medium rather than from enzymatic biotransformation.

Animals↗
PubMed2005

High frequency of somatic mitochondrial DNA mutations in human thyroid carcinomas and complex I respiratory defect in thyroid cancer cell lines.

Significant progress has been made to elucidate the molecular mechanisms that determine thyroid tumor development and progression. However, most investigations have mainly focused on the genetic alterations of nuclear DNA. The potential role of mitochondrial DNA (mtDNA) mutations in thyroid tumorigenesis is not well defined. In the present study, we investigated the frequency of mtDNA mutations in 24 thyroid tumor specimens (19 primary papillary thyroid carcinomas (PTC), one follicular thyroid carcinoma, and four multinodular hyperplasias) and four thyroid cancer cell lines by sequencing the entire coding regions of mitochondrial genome. Among the 19 PTC samples tested, seven (36.8%) had somatic mutations. Somatic mtDNA mutations were also detected in one of four multinodular hyperplasias examined. All the thyroid tumor cell lines carried sequence variations that change amino acid and have not been reported previously as normal sequence variants. Flow cytometry analysis of mitochondria respiratory function in the thyroid tumor cell lines revealed a severe defect in mitochondrial complex I activity. The majority of the mutations was involved in genes located in the complex I of the mitochondrial genome. The mutations were either A --> G or C --> T transitions, often resulting in a change of a moderately or highly conserved amino acid of their corresponding protein. These data suggest that mtDNA mutations may play an important role in the thyroid tumorigenesis. Given that mtDNA mutation is present in the benign multinodular hyperplasia, it might be involved in the early stage of tumor development.

Carcinoma↗
PubMed2003

Mutation analysis of the BRAF, ARAF and RAF-1 genes in human colorectal adenocarcinomas.

Colorectal cancer is a multi-step process characterized by a sequence of genetic alterations in cell growth regulatory genes, such as the adenomatous polyposis coli, KRAS, p53 and DCC genes. In the present study mutation analysis was performed with SSCA/direct sequencing of the hot-spot regions in exons 11 and 15 for the BRAF gene and exons 1-2 for the KRAS gene in 130 primary colorectal cancer tumors and correlated with clinico-pathological and mutational data. We also performed mutation analysis of the corresponding conserved regions in the ARAF and RAF-1 genes. Mutations in the BRAF and KRAS genes were found in 11.5 and 40% of the tumors, respectively. One germline exonic and nine germline intronic genetic variants were found in the ARAF and RAF-1 genes. All of the BRAF mutations were located in the kinase domain of the conserved region 3 in exon 15 of the BRAF gene. One novel somatic mutation was also identified in the BRAF gene. The majority of the BRAF mutations were found in colon compared with rectal tumors (P = 0.014). In agreement with others, a statistically significant correlation between BRAF mutations and microsatellite instability could be found. A negative correlation was also evident between mutations in the BRAF and KRAS genes, which supports earlier studies where somatic mutations in these genes are mutually exclusive. Collectively, our results provide support for the idea that activation of the MAP kinase pathway, especially via BRAF and KRAS mutations, is of critical importance for the development of colorectal cancer.

Adenocarcinoma↗
PubMed2005

Dynamic relocalization of hOGG1 during the cell cycle is disrupted in cells harbouring the hOGG1-Cys326 polymorphic variant.

Numerous lines of evidence support the role of oxidative stress in different types of cancer. A major DNA lesion, 8-oxo-7,8-dihydroguanine (8-oxoG), is formed by reactive oxygen species in the genome under physiological conditions. 8-OxoG is strongly mutagenic, generating G.C-->T.A transversions, a frequent somatic mutation in cancers. hOGG1 was cloned as a gene encoding a DNA glycosylase that specifically recognizes and removes 8-oxoG from 8-oxoG:C base pairs and suppresses G.C-->T.A transversions. In this study, we investigated the subcellular localization and expression of hOGG1 during the cell cycle. Northern blots showed cell-cycle-dependent mRNA expression of the two major hOGG1 isoforms. By using a cell line constitutively expressing hOGG1 fused to enhanced green fluorescence protein (EGFP), we observed a dynamic relocalization of EGFP-hOGG1 to the nucleoli during the S-phase of the cell cycle, and this localization was shown to be linked to transcription. A C/G change that results in an amino acid substitution from serine to cysteine in codon 326 has been reported as a genetic polymorphism and a risk allele for a variety of cancers. We investigated the cellular localization of the corresponding protein, hOGG1-Cys326, fused to EGFP and observed a dramatic effect on its localization that is explained by a change in the phosphorylation status of hOGG1.

Amino Acid Substitution↗
PubMed2006

Comparative effects of early postnatal ibuprofen and indomethacin on VEGF, IGF-I, and GH during rat ocular development.

PURPOSE: Ibuprofen and indomethacin are nonselective prostaglandin synthetase inhibitors that have been shown to improve oxygen-induced retinopathy in mice. Vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF)-I, and growth hormone (GH) are potent growth factors involved in retinal development. This study was conducted to examine and compare the effects of early postnatal ibuprofen and indomethacin on ocular and systemic VEGF, IGF-I, and GH during rat ocular development. METHODS: Newborn rats were treated with intraperitoneal injections of low and high doses of ibuprofen or indomethacin at birth (postnatal day [P]1) and on P2 and P3. A control group received equivalent volumes of saline. At P14, vitreous fluid, retinal homogenates, and serum were analyzed for VEGF, IGF-I, and GH protein levels. Retinal mRNA expression of VEGF splice variants (VEGF188, VEGF164, VEGF120), VEGF receptors (VEGFR-1, VEGFR-2, Npn-1, Npn-2), and pigment epithelium-derived factor (PEDF) were also examined. RESULTS: Animals treated with high-dose ibuprofen had significantly lower somatic growth and higher serum and vitreous IGF-I levels. High-dose ibuprofen decreased retinal VEGF levels and retinal VEGF164, VEGF120, and VEGFR-2 transcripts, resulting in a significant increase in the cecal period in 87% of rats at P14. Both indomethacin doses suppressed retinal VEGF164 transcripts without affecting VEGF receptors. CONCLUSIONS: Ibuprofen may be more effective than indomethacin for suppression of retinal VEGF signaling, suggesting a possible therapy for retinal neovascularization. However, deficits in somatic growth concurrent with higher systemic IGF-I levels suggests decreased IGF-I bioactivity. These adverse effects should be considered.

Animals↗
PubMed2004

High sensitivity scanning of colorectal tumors and matched plasma DNA for mutations in APC, TP53, K-RAS, and BRAF genes with a novel DHPLC fluorescence detection platform.

Tumor-associated DNA has been detected in plasma of colorectal cancer (CRC) patients using various techniques but with limited gene or mutation coverage. We report a highly sensitive scanning methodology for mutational assessment of the APC and TP53 genes, which typically pose an analytical challenge because of their significant genotypic heterogeneity as well as specific mutational scoring assays for K-RAS and BRAF. Plasma DNA isolated from 20 CRC patients were scanned for mutations in these targets without knowledge of the molecular or pathological analyses of the matched primary tumors. We chose mutation scanning technology and these molecular targets to provide a comprehensive screen for somatic mutations known to be associated with sporadic CRC. Mutations were identified with a novel denaturing high-performance liquid chromatography (DHPLC) platform that uses post-separation fluorescence technology to enable the detection of variants that represent <0.1% of the total analyzed DNA. Mutant allele specific amplification (MASA) followed by detection with the same platform was used to identify low-level target mutations (mutation scoring) in K-RAS codons 12, 13, and 61, and BRAF codon 599. Using this combined scanning and scoring approach, we were able to identify at least one mutational event in 20/20 (100%) CRC patients. The thoroughness of a mutation scanning and scoring panel may have important implications for CRC screening and disease monitoring during and following therapy.

Alleles↗
PubMed2005

Discordant MZ twins with cleft lip and palate: a model for identifying genes in complex traits.

Monozygotic (MZ) twins may be discordant for complex traits due to differential environmental exposure in utero, epigenetic variability in imprinting, X chromosome inactivation, or stochastic effects. Occasionally MZ twins may be discordant for chromosomal and single gene disorders due to somatic mosaicism. For complex traits, which are due to the interactive effects of multiple genes and environmental factors, the affected twin of a discordant MZ pair offers the possibility for identifying somatic mutations in candidate genes. DNA sequencing of candidate genes in discordant MZ twins can identify those rare etiologic mutational events responsible for the different phenotypes since the confounding effects of common single nucleotide polymorphisms are eliminated, as DNA sequences should be identical in MZ pairs. In this report we describe the extensive DNA sequencing of 18 candidate genes in a sample of MZ and dizygotic (DZ) twins with nonsyndromic cleft lip with or without cleft palate. We were unable to identify any somatic differences in approximately 34 Kb of DNA sequenced in 13 MZ pairs, for a total of approximately 900 Kb of sequence comparisons, supporting the hypothesis that nonetiologic posttwinning mutations are rare. While no etiologic variants were identified in this study, sequence comparisons of discordant MZ twins can serve as a tool for identifying etiologic mutations in clefting and other complex traits.

Cleft Lip↗
PubMedDate not supplied

[Clinical course of premature and newborn infants of mothers with HELLP syndrome].

The HELLP-syndrome is complicated by a maternal mortality of 3.5% and a perinatal mortality between 9.5 and 60%. It is a variant of severe preeclampsia which includes hemolysis, elevated liver enzymes and low platelets. It is described in the literature that neonates of mothers with HELLP-syndrome show characteristic symptoms especially thrombocytopenia, leukocytopenia and prenatal somatic dystrophy. In this retrospective investigation of 36 preterm and term infants of mothers with HELLP-syndrome we found the following results: 1. Thrombocytopenia was seen in 11% and leucocytopenia in 12% of the analysed cases. Anemia was seen in 10% of the analysed neonates. They needed transfusion of blood. The rate of prenatal somatic dystrophy was increased (58%). 2. Elevated blood pressure was observed in 29% of the neonates within the analysed interval. The time of artificial ventilation of preterm infants with maternal HELLP-syndrome was in 37% extended in comparison with infants without HELLP-syndrome in pregnancy. 3. The perinatal mortality was 8%. All observed infants during delivery and of the neonatal period in our collective survived.

Alanine Transaminase↗