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PubMed2001

Functional analysis of kinetochore assembly in Caenorhabditis elegans.

In all eukaryotes, segregation of mitotic chromosomes requires their interaction with spindle microtubules. To dissect this interaction, we use live and fixed assays in the one-cell stage Caenorhabditis elegans embryo. We compare the consequences of depleting homologues of the centromeric histone CENP-A, the kinetochore structural component CENP-C, and the chromosomal passenger protein INCENP. Depletion of either CeCENP-A or CeCENP-C results in an identical "kinetochore null" phenotype, characterized by complete failure of mitotic chromosome segregation as well as failure to recruit other kinetochore components and to assemble a mechanically stable spindle. The similarity of their depletion phenotypes, combined with a requirement for CeCENP-A to localize CeCENP-C but not vice versa, suggest that a key step in kinetochore assembly is the recruitment of CENP-C by CENP-A-containing chromatin. Parallel analysis of CeINCENP-depleted embryos revealed mitotic chromosome segregation defects different from those observed in the absence of CeCENP-A/C. Defects are observed before and during anaphase, but the chromatin separates into two equivalently sized masses. Mechanically stable spindles assemble that show defects later in anaphase and telophase. Furthermore, kinetochore assembly and the recruitment of CeINCENP to chromosomes are independent. These results suggest distinct roles for the kinetochore and the chromosomal passengers in mitotic chromosome segregation.

Animals↗
PubMed2002

CFC1 mutations in patients with transposition of the great arteries and double-outlet right ventricle.

Recent investigations identified heterozygous CFC1 mutations in subjects with heterotaxy syndrome, all of whom had congenital cardiac malformations, including malposition of the great arteries. We hypothesized that a subset of patients with similar types of congenital heart disease---namely, transposition of the great arteries and double-outlet right ventricle, in the absence of laterality defects---would also have CFC1 mutations. Our analysis of the CFC1 gene in patients with these cardiac disorders identified two disease-related mutations in 86 patients. The present study identifies the first autosomal single-gene defect for these cardiac malformations and indicates that some cases of transposition of the great arteries and double-outlet right ventricle can share a common genetic etiology with heterotaxy syndrome. In addition, these results demonstrate that the molecular pathway involving CFC1 plays a critical role in normal and abnormal cardiovascular development.

Base Sequence↗
PubMed2003

Localization of Pavarotti-KLP in living Drosophila embryos suggests roles in reorganizing the cortical cytoskeleton during the mitotic cycle.

Pav-KLP is the Drosophila member of the MKLP1 family essential for cytokinesis. In the syncytial blastoderm embryo, GFP-Pav-KLP cyclically associates with astral, spindle, and midzone microtubules and also to actomyosin pseudocleavage furrows. As the embryo cellularizes, GFP-Pav-KLP also localizes to the leading edge of the furrows that form cells. In mononucleate cells, nuclear localization of GFP-Pav-KLP is mediated through NLS elements in its C-terminal domain. Mutants in these elements that delocalize Pav-KLP to the cytoplasm in interphase do not affect cell division. In mitotic cells, one population of wild-type GFP-Pav-KLP associates with the spindle and concentrates in the midzone at anaphase B. A second is at the cell cortex on mitotic entry and later concentrates in the region of the cleavage furrow. An ATP binding mutant does not localize to the cortex and spindle midzone but accumulates on spindle pole microtubules to which actin is recruited. This leads either to failure of the cleavage furrow to form or later defects in which daughter cells remain connected by a microtubule bridge. Together, this suggests Pav-KLP transports elements of the actomyosin cytoskeleton to plus ends of astral microtubules in the equatorial region of the cell to permit cleavage ring formation.

Actomyosin↗
PubMed1998

Alloplastic and microvascular restoration of the mandible: a comparison study.

The evolution of mandibular reconstruction following composite resection is advanced by improved alloplastic prosthesis and reliable microvascular free tissue transfers. A 42-case, 6-year experience is presented using both methods at the University of California, San Francisco. The advantages and complications of both are discussed. The authors conclude that the success rate for lateral defect restoration is equivalent with either technique, and that the anterior defects are more reliably reconstructed with free tissue transfer. The advantage of microvascular flaps in the anterior defect must be gauged against the physical status of the patient, disease extent, and likelihood of dental rehabilitation by interosseous fixation.

Aged↗
PubMed2004

The activity of the Nodal antagonist Cerl-2 in the mouse node is required for correct L/R body axis.

Correct establishment of the left/right (L/R) body asymmetry in the mouse embryo requires asymmetric activation of the evolutionarily conserved Nodal signaling cascade in the left lateral plate mesoderm (L-LPM). Furthermore, the presence of Nodal in the node is essential for its own expression in the L-LPM. Here, we have characterized the function of cerl-2, a novel Nodal antagonist, which displays a unique asymmetric expression on the right side of the mouse node. cerl-2 knockout mice display multiple laterality defects including randomization of the L/R axis. These defects can be partially rescued by removing one nodal allele. Our results demonstrate that Cerl-2 plays a key role in restricting the Nodal signaling pathway toward the left side of the mouse embryo by preventing its activity in the right side.

Animals↗
PubMed1997

Effects of actinomycin D on developing hamster molar tooth germs in vitro.

The aim of this study was to evaluate the toxic effects of actinomycin D on the developing hamster tooth germ in organ culture. Hamster tooth germs during early secretory amelogenesis were exposed in vitro for 24 h to 10(-9) M-5 x 10(-5) M actinomycin D. Actinomycin D dose-dependently (> or = 10(-7) M) decreased the tooth germ dry weight but mineralization was affected only by doses > or = 10(-5) M. However, the uptakes of TCA-insoluble 32P and [3H]thymidine were significantly reduced dose-dependently from > or = 10(-8) M actinomycin D, indicating that the drug inhibits the synthesis of phosphate-containing macromolecules as well as DNA synthesis. Histologically, 10(-8) M actinomycin D was the lowest dose which was not toxic to any cell type in the developing tooth germ. At 10(-7) M actinomycin D, the most sensitive cells were the proliferating pre-odontoblasts followed by pre-ameloblasts; the mature secretory ameloblasts and odontoblasts appeared unaffected. Higher doses resulted in increased cytotoxicity to the secretory cells and, eventually, total degeneration of most cells. The data suggest that children treated for cancer during tooth development using anti-chemotherapy cocktails containing actinomycin D (serum levels > 10(-7) M) may develop defects later on in the mature dentition as a direct consequence of the toxicity of the drug to the tooth organ.

Ameloblasts↗
PubMed2003

Too much or too little: neonatal ocular misalignment frequency can predict later abnormality.

BACKGROUND: 214 orthoptists' infants have been followed for up to 15 years, relating neonatal misalignment (NMs) and first convergence onset to later childhood ocular abnormalities. NMs are shown in a companion paper to reflect the onset of first convergence, but if frequent or absent may predict a higher risk of refractive error and esodeviation. METHODS: In a prospective postal survey, orthoptist mothers observed their own infants during the first months of life and regularly reported ocular behaviour and alignment, visual development, and any subsequent ocular abnormalities. RESULTS: Later strabismus and refractive error were less common in infants who showed NMs occasionally compared with those who never or frequently did. There was a significant linear trend for fewer ocular abnormalities to be found in children with more frequent NMs (p<0.001). Hypermetropes were later to show first convergence than emmetropes or myopes (p = 0.006) CONCLUSIONS: NMs usually reflect an emerging and normally developing vergence system. This study suggests that delayed onset of convergence (and lack of NMs) is associated with later defects, especially hyperopia. Possible causal relations are discussed.

Age Factors↗
PubMed2002

The role of ZIC3 in vertebrate development.

ZIC3 is a C2H2 zinc finger transcription factor that is involved in early patterning of the vertebrate embryo. Human patients with mutations in the X-linked ZIC3 gene have a complex developmental phenotype that includes laterality defects, congenital heart disease, and lumbosacral and anal anomalies, including neural tube defects. Similar phenotypes are found in the bent tail (BN) mouse, a spontaneous mutation that is associated with a submicroscopic deletion of the ZIC3 locus, as well as in a ZIC3 null allele generated through homologous recombination. These findings suggest that ZIC3 plays important roles during development in establishing a proper left-right axis and in midline neural patterning. This review will summarize our current understanding of the role of ZIC3 in patterning of the vertebrate embryo, based on studies in model organisms such as Xenopus and the mouse. In addition, a comparison of ZIC3 with other vertebrate ZIC family members will be provided.

Animals↗
PubMed1984

The clinical features of isolated left circumflex coronary artery disease.

The clinical characteristics of 84 patients with isolated circumflex disease (greater than or equal to 70% luminal stenosis) were reviewed. A total of 66 patients had angina pectoris (mean duration 17.3 months), and 60 had suffered a myocardial infarction. Risk factors averaged 2.2 per patient. In the 84 patients there were 103 discrete circumflex stenoses; 51 stenoses were central (proximal circumflex, obtuse marginal, and intermediate branches), and 52 were peripheral (distal circumflex, posterolateral, and posterior descending branches); 48 were total and 55 were subtotal. Left ventricular function was normal in 21 patients and abnormal in 63 patients, but the mean left ventricular ejection fraction of the group was normal (59 +/- 12%). Eighty-two patients had abnormal electrocardiograms: there were Q waves in 25, RV pattern in 43, ST-T wave abnormalities in 19, left bundle branch block in two, and pacemaker rhythm in one. Inferior abnormalities on the electrocardiogram correlated with peripheral stenoses (p less than .02), and lateral abnormalities on the electrocardiogram correlated with central stenoses (p less than .01). The RV pattern of true posterior infarction was seen in both central and peripheral stenoses. In the 32 patients who underwent thallium scanning, lateral defects were more common with central stenoses, but posterolateral defects occurred similarly in central and peripheral stenoses. Prognosis was good. There were two deaths during the mean follow-up time of 17 months (range 1 to 49). The cumulative survival rate was 100% at 12 months, 97.5 +/- 2.9% at 24 months, and 97.5 +/- 3.6% at 30 months.

Adult↗
PubMed1993

Molecular basis for fibrinogen Dusart (A alpha 554 Arg-->Cys) and its association with abnormal fibrin polymerization and thrombophilia.

The molecular defect in the abnormal fibrinogen Dusart (Paris V) that is associated with thrombophilia was determined by sequence analysis of genomic DNA that had been amplified using the polymerase chain reaction. The propositus was heterozygous for a single base change (C-->T) in the A alpha-chain gene, resulting in the amino acid substitution A alpha 554 Arg-->Cys. Restriction analysis of the amplified DNA derived from the family members showed that his father and his two sons were also heterozygous. Electron microscopic studies on fibrin formed from purified fibrinogen Dusart demonstrated fibers that were much thinner than in normal fibrin. In contrast to the previously observed defective binding of plasminogen, the binding of thrombospondin to immobilized fibrinogen Dusart was similar to that of normal fibrinogen. Immunoblot analysis of plasma fibrinogen demonstrated that a substantial part of the fibrinogen Dusart molecules were disulfide-linked to albumin. The plasma of the affected family members also contained fibrinogen-albumin complexes. Furthermore, small amounts of high molecular weight complexes containing fibrinogen were detected in all the heterozygous individuals. These data indicate that the molecular abnormality in fibrinogen Dusart (A alpha 554 Arg-->Cys) results in defective lateral association of the fibrin fibers and disulfide-linked complex formation with albumin, and is associated with a family history of recurrent thrombosis in the affected individuals.

Adult↗
PubMed2006

Regulation of somitogenesis by Ena/VASP proteins and FAK during Xenopus development.

The metameric organization of the vertebrate body plan is established during somitogenesis as somite pairs sequentially form along the anteroposterior axis. Coordinated regulation of cell shape, motility and adhesion are crucial for directing the morphological segmentation of somites. We show that members of the Ena/VASP family of actin regulatory proteins are required for somitogenesis in Xenopus. Xenopus Ena (Xena) localizes to the cell periphery in the presomitic mesoderm (PSM), and is enriched at intersomitic junctions and at myotendinous junctions in somites and the myotome, where it co-localizes with beta1-integrin, vinculin and FAK. Inhibition of Ena/VASP function with dominant-negative mutants results in abnormal somite formation that correlates with later defects in intermyotomal junctions. Neutralization of Ena/VASP activity disrupts cell rearrangements during somite rotation and leads to defects in the fibronectin (FN) matrix surrounding somites. Furthermore, inhibition of Ena/VASP function impairs FN matrix assembly, spreading of somitic cells on FN and autophosphorylation of FAK, suggesting a role for Ena/VASP proteins in the modulation of integrin-mediated processes. We also show that inhibition of FAK results in defects in somite formation, blocks FN matrix deposition and alters Xena localization. Together, these results provide evidence that Ena/VASP proteins and FAK are required for somite formation in Xenopus and support the idea that Ena/VASP and FAK function in a common pathway to regulate integrin-dependent migration and adhesion during somitogenesis.

Animals↗
PubMed1999

Genes required for axon pathfinding and extension in the C. elegans nerve ring.

Over half of the neurons in Caenorhabditis elegans send axons to the nerve ring, a large neuropil in the head of the animal. Genetic screens in animals that express the green fluorescent protein in a subset of sensory neurons identified eight new sax genes that affect the morphology of nerve ring axons. sax-3/robo mutations disrupt axon guidance in the nerve ring, while sax-5, sax-9 and unc-44 disrupt both axon guidance and axon extension. Axon extension and guidance proceed normally in sax-1, sax-2, sax-6, sax-7 and sax-8 mutants, but these animals exhibit later defects in the maintenance of nerve ring structure. The functions of existing guidance genes in nerve ring development were also examined, revealing that SAX-3/Robo acts in parallel to the VAB-1/Eph receptor and the UNC-6/netrin, UNC-40/DCC guidance systems for ventral guidance of axons in the amphid commissure, a major route of axon entry into the nerve ring. In addition, SAX-3/Robo and the VAB-1/Eph receptor both function to prevent aberrant axon crossing at the ventral midline. Together, these genes define pathways required for axon growth, guidance and maintenance during nervous system development.

Animals↗
PubMed2006

Polycystin-2 immunolocalization and function in zebrafish.

Polycystin-2 functions as a cation-permeable transient receptor potential ion channel in kidney epithelial cells and when mutated results in human autosomal dominant polycystic kidney disease. For further exploration of the in vivo functions of Polycystin-2, this study examined its expression and function during zebrafish embryogenesis. pkd2 mRNA is ubiquitously expressed, and its presence in the larval kidney could be confirmed by reverse transcription-PCR on isolated pronephroi. Immunostaining with anti-zebrafish Polycystin-2 antibody revealed protein expression in motile kidney epithelial cell cilia and intracellular cell membranes. Intracellular localization was segment specific; in the proximal nephron segment, Polycystin-2 was localized to basolateral cell membranes, whereas in the caudal pronephric segment, Polycystin-2 was concentrated in subapical cytoplasmic vesicles. Polycystin-2 also was expressed in muscle cells and in a variety of sensory cells that are associated with mechanotransduction, including cells of the ear, the lateral line organ, and the olfactory placodes. Disruption of Polycystin-2 mRNA expression resulted in pronephric kidney cysts, body axis curvature, organ laterality defects, and hydrocephalus-defects that could be rescued by expression of a human PKD2 mRNA. In-frame deletions in the first extracellular loop and C-terminal phosphofurin acidic cluster sorting protein-1 (PACS-1) binding sites in the cytoplasmic tail caused Polycystin-2 mislocalization to the apical cell surface. Unlike zebrafish intraflagellar transport protein (IFT) mutants, cyst formation was not associated with cilia defects and instead correlated with reduced kidney fluid output, expansion of caudal duct apical cell membranes, and occlusion of the caudal pronephric nephron segment.

Amino Acid Sequence↗
PubMed1978

Herniated thoracic disc at T1-2 level associated with Horner's syndrome. Case report.

A case of symptomatic herniation at the first thoracic disc level is reported. The patient presented with hand weakness, Horner's syndrome, and pain radiating along the medial aspect of the upper extremity. Myelography demonstrated a smooth lateral defect at T1-2. Three sequestrated epidural disc fragments were removed with postoperatvie relief of pain. A slightly miotic pupil remains.

Adult↗
PubMed2026

A Novel Nonsense Variant in Ankyrin Repeat and Sterile Alpha Motif Domain-Containing 6 Promotes Polycystic Kidney Disease in Han:SPRD- Cy Rats and Its Homozygosity Is Prenatally Lethal.

KEY POINTS: A novel nonsense variant ( mcy ) in ankyrin repeat and sterile alpha motif domain-containing 6 ( Anks6 ) promotes rapid disease progression in the Han:SPRD- Cy rat carrying a missense variant in Anks6 . mcy-/- rats exhibit prenatal lethality characterized by laterality and cardiovascular abnormalities. These findings indicate that ANKS6 nonfunction in rats leads to prenatal lethality, whereas misfunction leads to polycystic kidney disease development. BACKGROUND: Polycystic kidney disease (PKD) encompasses a group of genetic disorders characterized by the proliferation of fluid-filled renal cysts, leading to progressive renal failure and death. A key feature of PKD is its variable expressivity across patients, even when caused by the same variant, highlighting the importance of genetic background in PKD expression. METHODS: We identified an ostensibly healthy Sprague Dawley rat line with a variant that modifies PKD expressivity in Han:SPRD- Cy rats (caused by a missense variant [p.Arg717Trp] in the ankyrin repeat and sterile alpha motif domain-containing 6 [ Anks6 ] gene), which we named mcy (modifier of Cy ). We used whole-genome sequencing and segregation analysis to identify the mcy variant, quantitative PCR and mRNA sequencing to evaluate its effects on gene expression, western blotting and immunohistochemistry to assess its protein consequences, and ultrasound and histology to examine its impact on rat embryonic development. RESULTS: We identified a nonsense variant in the Anks6 gene as the genetic basis of the mcy phenotype (c.1126G>T [p.Glu376X]). Although mcy+/- rats are ostensibly healthy and do not develop PKD, mcy-/- rats exhibit laterality defects and die prenatally at E16.5 because of apparent perturbations in cardiovascular development. Notably, mcy+/-Cy+/- rats develop PKD much more rapidly than Cy+/- rats, and in a timeframe consistent with Cy-/-rats . Transcripts with the mcy variant allele seem to undergo nonsense-mediated decay, and no ANKS6 protein is detected. However, gene expression patterns in the kidneys did not differ significantly between age-matched mcy+/+ and mcy+/- rats, indicating that ANKS6 insufficiency does not cause PKD. CONCLUSIONS: We identified a novel nonsense variant in Anks6 . The findings indicate that the absence of wild-type ANKS6 accelerates PKD development in the Han:SPRD- Cy rat and that complete ANKS6 deficiency prevents normal embryonic development in rats.

Animals↗
PubMed1990

[A case of hypopharyngeal stenosis caused by late radiation injuries--reconstruction of the hypopharynx with myomucosal tongue flap].

The authors reported a 47-year-old man with hypopharyngeal stenosis caused by late radiation injuries. At the age of ten he underwent irradiation (3000rads) to the neck because of the cervical lymphadenopathy. He had keroid skin change at the age of 19, hypothyroidism since 26, right cervical and brachial plexus neuropathy since 33, and paralysis and papilloma of right vocal cord at 34. And at the age of 41 he underwent tracheostomy owing to laryngeal stenosis. In November 1984 (at age 43) he felt abnormal sensation on the throat but had no dysphagia nor misdiglutition. On November 1987 he had difficulties of swallowing, and could not take anything but fluid. At that time he was diagnosed as hypopharyngeal stenosis. With steroids and antibiotics his difficulties of swallowing were reduced. He experienced the same difficulties on April 1988. Since December 1988 his dysphagia got worse and was not recovered with medication. On May 17 1989, laryngopharyngectomy was performed. At the level of cricoid cartilage hypopharynx was resected. As for the posterior wall, pharynx and cervical esophagus were fixed to prevertebral fascia and anastomosed with end-to-end. And antero-lateral defects were reconstructed with myomucosal tongue flap. Postoperatively he could eat orally. On the basis of the experience of this case and the review of the literature the authors conclude that myomucosal tongue flap is one of alternatives for hypopharyngeal reconstruction.

Constriction, Pathologic↗
PubMed1999

Mandibular reconstruction: free flap vs AO plate.

The purpose of this study was to compare the use of the AO reconstruction plate with immediate free vascularized bone graft mandibular reconstruction. From April 1989 to December 1993 we performed 13 cases of mandibular reconstruction. Reconstruction plates were used in 4 and immediate free bone grafts were used in 9 patients. The overall success rate for use of the plate was 2 of 4 (50%). In one of the plate failure patients, the plate was removed eight months postoperatively. She was able to wear a dental prosthesis. Cancer destruction and microvascular anastomosis of the first seven free flaps were performed by one surgical team. Only 4 free flaps were successful (success rate was 44%). We found that the use of AO plate with flap for lateral defect was relatively safe, simple, functional, time-saving, cosmetically acceptable and could be used successfully in post-operative irradiated patients. Success rate of the free flap was better with two surgical teams. The long-term result of the free flap was more reliable than the AO plate.

Adult↗
PubMed1999

Double layered autogenous vein graft patch reconstruction of the common carotid-internal jugular fistula caused by gunshot wound.

Hereby we present a case with a common carotid-internal jugular fistula caused by gunshot wound. The patient was a 32-year old male who had an entrance hole of a bullet on his right anterior cervical area, at the C4 level with a hematoma surrounding it. The exit hole could be detected at the sublingual area. By palpation a thrill and on auscultation a souffle was noted. Neither crepitation, nor any neurologic deficit or any symptom of Horner's syndrome was present. The emergency digital subtraction angiography (DSA) showed a fistulisation to internal jugular vein (IJV) approximately 0.5 cm below the common carotid artery (CCA) bifurcation level. During the operation a hematoma and a false aneurysm was observed on the CCA. Also, proximally to the bifurcation, a communication of CCA with IJV was noted. The wall of the JJV was rather thinned and the size of the vessel had considerably enlarged. Following the evacuation of the hematoma and debridement, the integration of the artery was achieved by placing a double layered autogenous vein graft patch over the 0.5 x 1.5 cm defect. The 0.3 x 1.5 cm defect laterally over the IJV was primarily sutured. The patient was discharged on the fifth day. The control DSA taken on the twelfth day showed a perfect integration of the vessels. We considered the case noticeable due to its rather rare incidence and the double layered autogen vein patch graft reconstruction.

Adult↗