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PubMed1999

Duplicate bladder exstrophy: a unique approach to initial repair.

OBJECTIVES: To describe a unique approach to the management of duplicate bladder exstrophy combining initial bladder closure and epispadias repair. Bladder exstrophy has been successfully managed by staged surgical repair with early bladder closure, subsequent epispadias repair, and, finally, bladder neck reconstruction. Duplicate bladder exstrophy is a rare variant of the exstrophy complex with fewer than 20 cases reported. METHODS: A male newborn presented with the appearance of both bladder exstrophy and a ruptured omphalocele. Repair of the omphalocele and bilateral orchiopexy was performed shortly after birth, but bladder closure was delayed until there was complete healing of the omphalocele defect, and the investigators believed the infant was ready for abdominal wall and bladder exstrophy closure. At age 8 months, bladder closure was performed with the intraoperative finding of a duplicate bladder lying posterior to the exstrophied bladder. The left ureter drained on the exstrophic bladder plate, and the right ureter drained into the posterior (internalized) duplicate bladder. After anterior innominate and vertical iliac osteotomies, the left ureter was reimplanted into the posterior bladder. A portion of the exstrophied bladder was then tubularized to construct a neourethra of the epispadic penis. RESULTS: The child has done well with an excellent cosmetic appearance of the abdominal wall and a straight phallus. The bladder subsequently required a Mitrofanoff-type continent stoma along with bladder augmentation, which was performed at the time of his Young-Dees-Leadbetter bladder neck reconstruction (age 3.5). The child is currently continent but requires intermittent clean catheterization through his appendicovesicostomy. CONCLUSIONS: The investigators report a unique and unexpected variant of bladder exstrophy and its successful management.

Bladder Exstrophy↗

PubMed2000

Complete duplication of the bladder, urethra, vagina, and uterus in girls.

UNLABELLED: OBJECTIVES. To present our experience with 3 girls with complete duplication of the bladder, urethra, vagina, and uterus, a very rare anomaly, and review published reports. Associated anomalies in these cases represent a wide spectrum. METHODS: We report 3 girls with complete duplication of the bladder, urethra, vagina, and uterus. The associated anomalies were different in each child. The first patient had a symphysis diastasis creating an abdominal hernia with two bladders dislocated into this space. The second patient had anal atresia with colon duplication. The third had cloacal exstrophy with one opened bladder and a second closed, with persistent urogenital sinus. Each patient was carefully evaluated, but the anatomy in 2 patients was not completely defined until surgical exploration. RESULTS: Each girl underwent surgical repair. In the first patient, iliac osteotomy, approximation of the symphysis pubis, and excision of the hernia was done. In the second, excision of the common wall between the two descending colons and posterior sagittal anorectoplasty were performed. In the third patient, staged reconstruction of the cloacal exstrophy with anastomosis of the bladders and vaginas was done. CONCLUSIONS: Complete duplication of the urogenital system in girls is associated with different anomalies. Which surgical procedures will be required depends on the multiple anatomic variables.

Abnormalities, Multiple↗

PubMed2001

The C. elegans zyg-1 gene encodes a regulator of centrosome duplication with distinct maternal and paternal roles in the embryo.

Centrosome duplication is a critical step in assembly of the bipolar mitotic spindle, but the molecular mechanisms regulating this process during the cell cycle and during animal development are poorly understood. Here, we report that the zyg-1 gene of Caenorhabditis elegans is an essential regulator of centrosome duplication. ZYG-1 is a protein kinase specifically required for daughter centriole formation that localizes transiently to centrosomes and acts at least one cell cycle prior to each spindle assembly event. In the embryo, ZYG-1 participates in a unique regulatory scheme whereby paternal ZYG-1 regulates duplication and bipolar spindle assembly during the first cell cycle, and maternal ZYG-1 regulates these processes thereafter. ZYG-1 is therefore a key molecular component of the centrosome/centriole duplication process.

Animals↗

PubMed1997

Partial duplication of the MLL gene in acute myelogenous leukemia without karyotypic aberration.

Partial duplication of the MLL gene is a recently characterized novel genetic mechanism for leukemogenesis. A close association with trisomy 11 has been observed. A case of acute myelogenous leukemia (AML) M6 without karyotypic abnormality was found to have rearrangement of the MLL gene. Southern analysis with an MLL exon 2 probe revealed partial duplication of the MLL gene, with a duplicated MLL transcript amplified by reverse transcription polymerase chain reaction (RT = PCR). The presence of trisomy 11 was excluded by fluorescence in situ hybridization (FISH). Few cases of AML with MLL gene duplication have been reported, and they showed involvement of the M1, M2, and M4 subtypes. This case is the first reported case with an M6 phenotype, and highlights the importance of investigating for MLL gene mutations in all subtypes of AML, as they may carry prognostic significance.

Aged↗

PubMed1997

Twenty-four-hour duplicate diet study 1994; nitrate and nitrite: method development and intake per person per day.

In spring and autumn of 1994 duplicates of 24-h diets were collected from 123 consumers (respondents). One goal of this study is to determine the amount of nitrite and nitrate in the duplicates of 24-h diets in order to establish the oral daily intake of these analytes. For this purpose a HPIC/UV method for the determination of nitrate and nitrite in duplicate diets was developed and validated. The mean intake of nitrate is 80 mg NO3- ion/person per day and the median intake of nitrite is 0.1 mg NO2- ion/person per day. The daily intake for nitrate as well nitrite is higher than found in the duplicate diets collected in the 1984/1985 study.

Adolescent↗

PubMed1995

Double duplication in a nonrotational colon. Study of a case associated with mucinous adenoma.

Duplications of gastrointestinal tract are unusual anomalies, especially in the colon. We report a case with two colonic duplications in a 20 year old woman who complained of recurrent backache associated with left lower quadrant abdominal pain. Neither physical examination nor laboratory test alterations were detected. Roentgenographic examination showed organic scolinosis, no intestinal gas and a mass with central hyperdensity and thickened wall in the descending colon area on the CT scan. Laparotomy was performed in which 22 cm of ascending colon and terminal ileum sited on left side, was excised. Pathological study revealed two unrelated and cystic duplications without communication to intestinal lumen. Their epithelial lining were of colonic or gastric types and showed a mucinous adenoma; the remaining layers were normal except for eosinophilic inflammatory infiltrate with Charcot-Leyden like crystaloids. In conclusion, we present a double spherical colonic duplication type I associated to a mucinous adenoma on a non-rotational ascending colon in a patient with organic scoliosis.

Adenoma↗

PubMed1997

Duplication and distribution of repetitive elements and non-unique regions in the human genome.

Genome mapping efforts and the initial sequencing of large segments of human DNA permit ongoing assessment of the patterns and extent of sequence duplication and divergence in the human genome. Initial sequence data indicate that the most highly repetitive sequences show isochore-related enrichment and clustering produced by successive insertional recombination and local duplication of particular repetitive elements. Regional duplication is also observed for a number of otherwise unique genomic sequences and thereby makes these segments become repetitive. The consequences of these duplication events are: (1) clustering of related genes, along with a variety of coregulatory mechanisms; and (2) recombinations between the nearby homologous sequences, which can delete genes in individuals and account for a significant fraction of human genetic disease.

Genetic Diseases, Inborn↗

PubMed2004

[Cystic mass of the pancreatic region associated with elevated CA 19-9 serum levels revealing a colonic duplication in an adult].

Intestinal duplications are rare embryologic malformations, especially in adults. We report a case of cystic duplication located near the pancreas revealed by unusual symptoms and associated with marked elevation of serum CA 19-9 levels. Although the physiopathology of the expression of CA 19-9 in duplications is unclear, this feature has been recently reported in adults and could be of interest in the diagnosis and management of intestinal duplications.

Abdominal Pain↗

PubMed1995

[Surgical treatment of duplication of the thumb. Apropos of 106 cases].

The surgical treatment of thumb duplication remains difficult, the sequelae usually observed are aesthetic (ungual dystrophy, hypoplastic pulp, clinodactyly) or functional (joint stiffness or instability). In order to clarify our therapeutic approach, we classify duplications into two types: proximal duplications (Wassel stage IV, V and VI) and distal duplications (Wassel stage I, II and III). Our experience is based on 106 cases operated over the last 15 years (1977). Our indications and operative techniques have progressed since 1988, in particular, we no longer perform Bilhaut-Cloquet operation, and prefer to perform the first operation before the age of one year. Resection of the hypoplastic supernumerary thumb. Preservation of the pulp skin to reconstitute the paronychium and pulp of the remaining thumb. Resection of supplementary joint facets. Meticulous repair of the capsulo-ligamentus apparatus by means of a capsulo-periosteal flap taken from the "sacrificed" thumb. Tendinous reequilibration and reinsertion of thenar muscles. We do not perform systematic subcapital osteotomy. When necessary, this procedure is performed during a complementary operation at the age of 2 to 3 years. Since the introduction of these technical modifications, our functional and aesthetic results have improved. Temporary overcorrection of the pulp is necessary. Parents must be advised that this deliberately hypertrophic appearance becomes normal with growth.

Dermatologic Surgical Procedures↗

PubMed2003

Dietary intake of platinum and gold by children from Germany using duplicate portion sampling.

The dietary intake of platinum and gold by 84 small children, 42 boys and 42 girls at the age of 14 to 83 months, with different food consumption behaviour living in urban and rural areas of Germany was measured by the duplicate method with a seven day sampling period from May to September 1998. The levels in the food duplicates were in the range of < 0.01 to 450 ng Pt/kg (dry weight) (median: 22) and < 0.14 to 28 microg Au/kg (dry weight) (median: 0.645). Related to the body weight, Pt was in the range of < 0.81 to 32 ng/(kg (body weight) x week) (median: 2.3) and Au was < 0.015 to 2.6 microg/(kg (body weight) x week) (median: 0.068). Children consuming exclusively products from the super market showed slightly higher Pt concentrations in the food duplicates and a higher dietary intake per body weight than children with food consumption including products from the family owned vegetable gardens or the surrounding area and/or products from domestic animals of the surrounding area. No influence of the food consumption behaviour was found for the concentrations in the food duplicates or the dietary intake of Au.

Body Weight↗

PubMed2001

Kinetics and regulation of de novo centriole assembly. Implications for the mechanism of centriole duplication.

BACKGROUND: Centriole duplication is a key step in the cell cycle whose mechanism is completely unknown. Why new centrioles always form next to preexisting ones is a fundamental question. The simplest model is that preexisting centrioles nucleate the assembly of new centrioles, and that although centrioles can in some cases form de novo without this nucleation, the de novo assembly mechanism should be too slow to compete with normal duplication in order to maintain fidelity of centriole duplication. RESULTS: We have measured the rate of de novo centriole assembly in vegetatively dividing cells that normally always contain centrioles. By using mutants of Chlamydomonas that are defective in centriole segregation, we obtained viable centrioleless cells that continue to divide, and find that within a single generation, 50% of these cells reacquire new centrioles by de novo assembly. This suggests that the rate of de novo assembly is approximately half the rate of templated duplication. A mutation in the VFL3 gene causes a complete loss of the templated assembly pathway without eliminating de novo assembly. A mutation in the centrin gene also reduced the rate of templated assembly. CONCLUSIONS: These results suggest that there are two pathways for centriole assembly, namely a templated pathway that requires preexisting centrioles to nucleate new centriole assembly, and a de novo assembly pathway that is normally turned off when centrioles are present.

Animals↗

PubMed2002

CP110, a cell cycle-dependent CDK substrate, regulates centrosome duplication in human cells.

Centrosome duplication and separation are linked inextricably to certain cell cycle events, in particular activation of cyclin-dependent kinases (CDKs). However, relatively few CDK targets driving these events have been uncovered. Here, we have performed a screen for CDK substrates and have isolated a target, CP110, which is phosphorylated by CDKs in vitro and in vivo. Human CP110 localizes to centrosomes. Its expression is strongly induced at the G1-to-S phase transition, coincident with the initiation of centrosome duplication. RNAi-mediated depletion of CP110 indicates that this protein plays an essential role in centrosome duplication. Long-term disruption of CP110 phosphorylation leads to unscheduled centrosome separation and overt polyploidy. Our data suggest that CP110 is a physiological centrosomal CDK target that promotes centrosome duplication, and its deregulation may contribute to genomic instability.

Amino Acid Motifs↗

PubMed2005

SAS-6 defines a protein family required for centrosome duplication in C. elegans and in human cells.

The mechanisms that ensure centrosome duplication are poorly understood. In Caenorhabditis elegans, ZYG-1, SAS-4, SAS-5 and SPD-2 are required for centriole formation. However, it is unclear whether these proteins have functional homologues in other organisms. Here, we identify SAS-6 as a component that is required for daughter centriole formation in C. elegans. SAS-6 is a coiled-coil protein that is recruited to centrioles at the onset of the centrosome duplication cycle. Our analysis indicates that SAS-6 and SAS-5 associate and that this interaction, as well as ZYG-1 function, is required for SAS-6 centriolar recruitment. SAS-6 is the founding member of an evolutionarily conserved protein family that contains the novel PISA motif. We investigated the function of the human homologue of SAS-6. GFP-HsSAS-6 localizes to centrosomes and its overexpression results in excess foci-bearing centriolar markers. Furthermore, siRNA-mediated inactivation of HsSAS-6 in U2OS cells abrogates centrosome overduplication following aphidicolin treatment and interferes with the normal centrosome duplication cycle. Therefore, HsSAS-6 is also required for centrosome duplication, indicating that the function of SAS-6-related proteins has been widely conserved during evolution.

Amino Acid Sequence↗

PubMed2003

Epsilon-tubulin is required for centriole duplication and microtubule organization.

Centrosomes nucleate microtubules and serve as poles of the mitotic spindle. Centrioles are a core component of centrosomes and duplicate once per cell cycle. We previously identified epsilon-tubulin as a new member of the tubulin superfamily that localizes asymmetrically to the two centrosomes after duplication. We show that recruitment of epsilon-tubulin to the new centrosome can only occur after exit from S phase and that epsilon-tubulin is associated with the sub-distal appendages of mature centrioles. Xenopus laevis epsilon-tubulin was cloned and shown to be similar to human epsilon-tubulin in both sequence and localization. Depletion of epsilon-tubulin from Xenopus egg extracts blocks centriole duplication in S phase and formation of organized centrosome-independent microtubule asters in M phase. We conclude that epsilon-tubulin is a component of the sub-distal appendages of the centriole, explaining its asymmetric localization to old and new centrosomes, and that epsilon-tubulin is required for centriole duplication and organization of the pericentriolar material.

Animals↗

PubMed2026

Persistent tic disorders are associated with 17q12 duplications.

Tourette Syndrome (TS) and Persistent Tic Disorder (PTD) are childhood-onset neuropsychiatric conditions with high heritability. Due to current sample size limitations, identifying TS/PTD risk genes has been challenging. This study addressed this issue by conducting a meta-analysis of microarray copy number variant (CNV) studies from three TS/PTD genomics consortia, supplemented with new data from 3291 cases. This approach more than doubled the sample size of previous TS/PTD CNV studies, with CNV calls generated from 5725 TS/PTD cases and 10,982 matched controls. The results confirmed that TS/PTD cases 1) have a higher burden of ultra-rare deletions overlapping loss-of-function intolerant genes (OR = 1.68, P = 9.3×10-5) and 2) are more likely to carry established neurodevelopmental CNVs (OR = 1.42, P = 3.9×10-2) compared to controls. Additionally, a novel, genome-wide significant CNV locus for TS/PTD was discovered, involving duplications at 17q12 (hg19 chr17:34.8 - 36.2 Mb). This locus is associated with a known duplication syndrome associated with variable neuropsychiatric traits, but has not been previously linked to tic disorders. Eight cases and one control carried the canonical ~1.4 Mb duplication at chr17:34.8-36.2 Mb, while one additional case had a smaller 110 kb duplication within this known CNV that included only one gene, ACACA (acetyl-CoA carboxylase, OR = 26.7, P = 5.69×10-7). Overall, this study provides further evidence that rare, genic CNVs play a substantial role in the genetic architecture of TS/PTD and identifies a new genome-wide significant association with this neurodevelopmental disorder.

Journal Article↗

PubMed1997

Internal tandem duplication of the FLT3 gene is preferentially seen in acute myeloid leukemia and myelodysplastic syndrome among various hematological malignancies. A study on a large series of patients and cell lines.

In this study, we examined a large number of patients to clarify the distribution and frequency of a recently described FLT3 tandem duplication among hematopoietic malignancies, including 112 acute myelocytic leukemia (AML), 55 acute lymphoblastic leukemia (ALL), 37 myelodysplastic syndrome (MDS), 20 chronic myelogenous leukemia (CML), 30 non-Hodgkin's lymphoma (NHL), 14 adult T cell leukemia, 15 chronic lymphocytic leukemia (CLL) and 38 multiple myeloma (MM). We also evaluated 71 cell lines derived from 11 AML, 31 ALL, two hairy cell leukemia, three acute unclassified leukemia, 10 CML, 12 NHL including six Burkitt's lymphoma, and two MM. Using genomic PCR of exon 11 coding for the juxtamembrane (JM) domain and first amino acids of the 5'-tyrosine kinase (TK) domain, this length mutation was found only in AML (22/112, 20%) and MDS (1/37). According to the FAB subclassification, they were 5/18 (28%) of M1, 4/29 (14%) of M2, 3/17 (18%) of M3, 6/24 (25%) of M4, 4/20 (20%) of M5 and 1/9 of refractory anemia with excess of blast in transformation. In the various cell lines examined, this abnormality was determined in only one derived from AML and never found in other hematological malignancies. The sequence analysis of the abnormal PCR products revealed that 23 of 24 showed internal tandem duplication with or without insertion of nucleotides. In one AML, insertion and deletion without duplication was determined. All 24 lengthened sequences were in-frame. Duplication takes place in the sequence coding for the JM domain and leaves the TK domain intact. In conclusion, we emphasize that the length mutation of FLT3 at JM/TK-I domains were restricted to AML and MDS. Since all these mutations resulted in in-frame, this abnormality might function for the proliferation of leukemic cells.

Acute Disease↗

PubMed2000

Deletion and tandem duplication of exons 2 - 7 in the epidermal growth factor receptor gene of a human malignant glioma.

The epidermal growth factor receptor (EGFR) gene is frequently amplified and rearranged in malignant gliomas with expression of oncogenic deletion mutants (DM). The most common mutant EGFRvIII, which contains a deletion of exons 2 - 7, is constitutively autophosphorylated and inefficiently downregulated. Other less common EGFR mRNA species in gliomas contain tandem duplication of exons, which encode the tyrosine kinase (TK) and calcium mediated receptor internalization (CAIN) domains of the molecule. We examined a panel of human malignant gliomas and found one tumor that expressed four related EGFR proteins, including 125-, 140-, 170-, and 180-kDa species. This tumor also contained four EGFR-related mRNA species, including both wild type EGFR and EGFRvIII transcripts. A third transcript contained a deletion of exons 2 - 7 and 12 - 13 corresponding to the 125-kDa protein. A fourth transcript contained an in-frame, tandem duplication of exons 2 - 7 (EGFR.TDM/2 - 7). The 180-kDa, tandem duplication mutant (TDM) exhibited enhanced basal phosphorylation and impaired downregulation. In contrast to the 140-kDa EGFRvIII; however, phosphorylation of the 180-kDa EGFR.TDM/2 - 7 was strongly induced by ligand. Expression of both deletion and tandem duplication mutants in the same tumor suggests that the mechanisms responsible for DM and TDM formation might be closely related. Oncogene (2000) 19, 4542 - 4548.

Central Nervous System Neoplasms↗

PubMed2002

Human papillomaviruses and centrosome duplication errors: modeling the origins of genomic instability.

The majority of human cancers are genomically unstable, often with gains or losses of whole chromosomes. In high-risk human papillomavirus (HPV)-associated cervical neoplasia, the two HPV-encoded oncoproteins E6 and E7 have been implicated in mitotic infidelity by their ability to induce centrosome-related mitotic disturbances. However, the mechanisms by which HPV E6 and E7 subvert centrosome homeostasis are strikingly different. Whereas the E7 oncoprotein rapidly drives centrosome duplication errors in cells that appear phenotypically normal, expression of the HPV E6 oncoprotein results in an accumulation of supernumerary centrosomes in multinucleated cells. The primary centrosome duplication defect in HPV E7 expressing cells may be linked to the ability of E7 to disrupt regulatory nodes that govern both the host cell division cycle machinery and the initiation of centrosome duplication. Most importantly, the E7 oncoprotein has been shown to dysregulate cdk2 activity, a major determinant for the initiation of centrosome duplication. HPV-induced centrosome abnormalities, multipolar mitoses, and aneuploidy often occur at early stages during cervical carcinogenesis and increase with malignant conversion. These findings suggest that HPV oncoprotein-induced chromosomal instability increases the risk for genetic changes that may ultimately facilitate carcinogenic progression.

Cell Transformation, Neoplastic↗