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PubMed2004

Cited2 controls left-right patterning and heart development through a Nodal-Pitx2c pathway.

Malformations of the septum, outflow tract and aortic arch are the most common congenital cardiovascular defects and occur in mice lacking Cited2, a transcriptional coactivator of TFAP2. Here we show that Cited2(-/-) mice also develop laterality defects, including right isomerism, abnormal cardiac looping and hyposplenia, which are suppressed on a mixed genetic background. Cited2(-/-) mice lack expression of the Nodal target genes Pitx2c, Nodal and Ebaf in the left lateral plate mesoderm, where they are required for establishing laterality and cardiovascular development. CITED2 and TFAP2 were detected at the Pitx2c promoter in embryonic hearts, and they activate Pitx2c transcription in transient transfection assays. We propose that an abnormal Nodal-Pitx2c pathway represents a unifying mechanism for the cardiovascular malformations observed in Cited2(-/-) mice, and that such malformations may be the sole manifestation of a laterality defect.

Animals↗

PubMed2003

The left-right determinant Inversin is a component of node monocilia and other 9+0 cilia.

Inversin (Inv), a protein that contains ankyrin repeats, plays a key role in left-right determination during mammalian embryonic development, but its precise function remains unknown. Transgenic mice expressing an Inv and green fluorescent protein (GFP) fusion construct (Inv::GFP) were established to facilitate characterization of the subcellular localization of Inv. The Inv::GFP transgene rescued the laterality defects and polycystic kidney disease of Inv/Inv mice, indicating that the fusion protein is functional. In transgenic embryos, Inv::GFP protein was detected in the node monocilia. The fusion protein was also present in other 9+0 monocilia, including those of kidney epithelial cells and the pituitary gland, but it was not localized to 9+2 cilia. The N-terminal region of Inv (InvDeltaC) including the ankyrin repeats also localized to the node cilia and rescued the left-right defects of Inv/Inv mutants. Although no obvious abnormalities were detected in the node monocilia of Inv/Inv embryos, the laterality defects of such embryos were corrected by an artificial leftward flow of fluid in the node, suggesting that nodal flow is impaired by the Inv mutation. These results suggest that the Inv protein contributes to left-right determination as a component of monocilia in the node and is essential for the generation of normal nodal flow.

Animals↗

PubMed1976

Repair of large chest wall defects using pedicle flaps.

Three cases of chest wall resection illustrate the use of three different full thickness pedicle flaps which can be used to cover almost any area of the anterior chest wall. The medially based acromiothoracic flap was swung inferiorly to cover a lateral defect. Laterally based abdominal wall and axillary flaps were used to cover more medial defects. In case III bilateral axillary flaps were necessary to cover a huge central defect after resection of the anterior sternum and anterior cartilages of seven ribs for a sebaceous carcinoma.

Aged↗

PubMed2002

Gene-dosage-sensitive genetic interactions between inversus viscerum (iv), nodal, and activin type IIB receptor (ActRIIB) genes in asymmetrical patterning of the visceral organs along the left-right axis.

We have shown previously that mice deficient in the activin type IIB receptor (ActRIIB) exhibit right isomerism, which is characterized by mirror-image symmetrical right lungs, complex cardiac malformations, and hypoplasia of the spleen. These observations led us to hypothesize that the signaling of a TGF-beta family member by means of ActRIIB is necessary for the determination of the left-sidedness of the visceral organs. To test this hypothesis, we examined laterality defects in mice carrying mutations in both ActRIIB and inversus viscerum (iv) genes, because iv(-/-) mice display a spectrum of laterality defects, including situs inversus, right isomerism, and left isomerism. We found that all mice homozygous for both iv and ActRIIB mutations displayed the right isomerism. The phenotype of right isomerism in the double mutants was also more severe than that in ActRIIB(-/-) mice as shown by persistent left inferior vena cava, right atrial isomerism, and hypoplasia of spleen. Interestingly, the incidence of right isomerism also increased significantly in iv(-/-);ActRIIB(+/-) and iv(+/-);ActRIIB(-/-) mice compared with homozygous mice carrying either of single gene mutations. A mechanism of the genetic modulation between ActRIIB and iv genes may be that iv modulates the asymmetric expression of a TGF-beta family member that signals through activin type II receptors, ActRIIA and ActRIIB, to specify the "left-sidedness." Nodal is the most likely candidate. We show here that the penetrance and severity of the right isomerism is significantly elevated in nodal(+/-); ActRIIB(-/-) mice, compared with ActRIIB(-/-) mice. Furthermore, the chimeric mice derived from nodal(-/-) ES cells displayed right isomerism, indistinguishable from that in (iv(-/-);ActRIIB(-/-)) mice. We propose that iv functions to establish asymmetric expression of nodal in a gene-dosage-sensitive manner and that nodal signals through the activin type II receptors to specify the left-sidedness by means of a threshold mechanism.

Activin Receptors, Type II↗

PubMed1984

[Jejuno-ileal latero-lateral bypass. Defects of mechanical sutures].

In 6 of our patients operated upon for pathological obesity, complete recanalization of the jejunum closed by a mechanical suture upstreams of the jejuno-ileal latero-lateral anastomosis resulted in failure of the intestinal bypass. We have modified our technique and instead of closing the jejunum with a mechanical stapler we now divide it, then bury and attach together its two ends to avoid torsion and invagination. The operation is completed by creating an anti-reflux system at the terminal end of the excluded ileum.

Humans↗

PubMedDate not supplied

[Reconstruction of oropharyngeal defects with lateral arm flap].

The lateral arm flap, is a fasciocutaneous flap with great versatility, but underused in head and neck reconstruction. Its qualities include a intermediate thickness between the radial forearm flap and the pectoralis major, ideal to reconstruct oropharyngeal defect, a consistent vascular pedicle, a pliable soft tissue and a low donor site morbidity. Use of this flap does not require the sacrificing of a major feeding vessel to the arm. We have chosen this technique to reconstruct four cases with surgical defects in oral cavity and oropharynx. The anatomic and functional results have been satisfactory and the complications rate is comparable to other microvascular techniques. We think that the lateral arm free flap is a useful reconstructive technique in specific areas of head and neck.

Adult↗

PubMed2006

Mutations in the EGF-CFC gene cryptic are an infrequent cause of congenital heart disease.

Cryptic (CFC1), a member of the epidermal growth factor-Cripto/FRL-1/Cryptic (EGF-CFC) gene family, is involved in the evolutionarily conserved establishment of left-right lateral asymmetry. Inactivation of Cfc1 in mice results in laterality defects and complex cardiac malformations. Similarly, mutations in the human CFC1 gene have been identified in patients with heterotaxy syndrome. The cardiac defects in humans resemble those in mice lacking Cfc1. We postulated that some patients with isolated cardiac malformations could also have mutations in the CFC1 gene. Our analysis of the CFC1 gene in 167 patients with congenital heart disease revealed a novel A145T missense variant in 3 patients with type II atrial septal defect. Furthermore, we found the previously characterized R78W polymorphism in another patient with type II atrial septal defect. However, the A145T sequence alteration was also identified in 3 controls, suggesting that this variant is a polymorphism. We conclude that CFC1 variants could be a rare cause of congenital heart disease in patients without laterality defects.

Epidermal Growth Factor↗

PubMed1999

Multiple left-right asymmetry defects in Shh(-/-) mutant mice unveil a convergence of the shh and retinoic acid pathways in the control of Lefty-1.

Asymmetric expression of Sonic hedgehog (Shh) in Hensen's node of the chicken embryo plays a key role in the genetic cascade that controls left-right asymmetry, but its involvement in left-right specification in other vertebrates remains unclear. We show that mouse embryos lacking Shh display a variety of laterality defects, including pulmonary left isomerism, alterations of heart looping, and randomization of axial turning. Expression of the left-specific gene Lefty-1 is absent in Shh(-/-) embryos, suggesting that the observed laterality defects could be the result of the lack of Lefty-1. We also demonstrate that retinoic acid (RA) controls Lefty-1 expression in a pathway downstream or parallel to Shh. Further, we provide evidence that RA controls left-right development across vertebrate species. Thus, the roles of Shh and RA in left-right specification indeed are conserved among vertebrates, and the Shh and RA pathways converge in the control of Lefty-1.

Animals↗

PubMed2004

Long term results of reconstruction plates in lateral mandibular defects. Revision of nine cases.

OBJECTIVE: Although microsurgical bone transplant is still the gold standard, mandibular reconstruction plates (MRP) were for several years considered a fast and safe way to restore mandibular continuity without using a bone graft. New plate designs with locking screws have been recently introduced, and these may overcome some of the complications related to previous designs. We review the results of mandibular reconstruction plates in our institution from 1991 to 1995. METHODS: The records of nine cancer patients who underwent lateral mandibular resections (with preservation of both condyle and symphysis) followed by reconstruction with a mandibular reconstruction plate, were retrospectively reviewed. Patients were treated between 1991 and 1995 with regular Synthes and Leibinger plates (without locking screws). Immediately after tumour resection, the bone defect was reconstructed with an MRP without bone grafting. Three cases required soft tissue coverage: two flaps and one buccal fat pad flap. RESULTS: There was immediate orocervical fistula in six cases, one of which required surgical closure; and late complications were common. One patient died due to distant metastasis 13 months after surgery without symptoms related to the plate. The remaining eight patients had their plates removed at between 9 and 52 months after reconstruction, due to screw loosening (four cases), plate exposure (one case), or both (three cases). CONCLUSION: Lateral mandibular reconstruction with non-locking screws and regular profile plates is no longer recommended. New plates with improved designs are currently available. Their low profile and locking screws are the usual characteristics of these new plates. More clinical experience is necessary before plate reconstruction can be recommended over microvascular bone transfer.

Aged↗

PubMed2006

Reconstruction of large defects postmandibulectomy for oral cancer using plates and myocutaneous flaps: a long-term follow-up.

A series of 28 consecutive cases of mandibular reconstruction by means of reconstructive plates and myocutaneous flaps were reviewed. In all cases mandibular resection was indicated for treatment of squamous cell carcinoma of the oral cavity: 25 pelviglossomandibulectomies (resulting in large defects from the angle of the mandible), 2 Commando operations (resulting in lateral defects) and 1 anterior sectional mandibulectomy (resulting in an anterior defect). Tumour stages were T1-T2 (4 cases) and T3-T4 (24 cases). Success was defined as plate maintenance 6 months' postoperatively/postradiotherapy. The overall success rate was 32.2%. Lateral-centre-lateral (L-C-L) defects had 32% success, L (lateral) defects had 50% success and in the single case of a C (centre) defect, the plate was not maintained. Stainless steel reconstruction plates showed a similar success rate as titanium plates (30% versus 34%). In cases not submitted to radiotherapy there were more maintained plates than in cases that received radiotherapy (45.5% versus 23.6%). Reconstruction plates are not effective in bridging large defects of the resected mandible. Only in selected cases that are not eligible for microvascular free flaps should plates and myocutaneous flaps be considered as an option for mandibular reconstruction.

Adolescent↗

PubMed2002

A protein disulfide isomerase expressed in the embryonic midline is required for left/right asymmetries.

Although the vertebrate embryonic midline plays a critical role in determining the left/right asymmetric development of multiple organs, few genes expressed in the midline are known to function specifically in establishing laterality patterning. Here we show that a gene encoding protein disulfide isomerase P5 (PDI-P5) is expressed at high levels in the organizer and axial mesoderm and is required for establishing left/right asymmetries in the zebrafish embryo. pdi-p5 was discovered in a screen to detect genes down-regulated in the zebrafish midline mutant one-eyed pinhead and expressed predominantly in midline tissues of wild-type embryos. Depletion of the pdi-p5 product with morpholino antisense oligonucleotides results in loss of the asymmetric development of the heart, liver, pancreas, and gut. In addition, PDI-P5 depletion results in bilateral expression of all genes known to be expressed asymmetrically in the lateral plate mesoderm and the brain during embryogenesis. The laterality defects caused by pdi-p5 antisense treatment arise solely due to loss of the PDI-P5 protein, as they are reversed when treated embryos are supplied with an exogenous source of the PDI-P5 protein. Thus the spectrum of laterality defects resulting from depletion of the PDI-P5 protein fully recapitulates that resulting from loss of the midline. As loss of PDI-P5 does not appear to interfere with other aspects of midline development or function, we propose that PDI-P5 is specifically involved in the production of midline-derived signals required to establish left/right asymmetry.

Animals↗

PubMed2006

Prognosis as a determinant of free flap utilization for reconstruction of the lateral mandibular defect.

BACKGROUND: The purpose of this study was to determine whether patients with a poor prognosis for survival were more likely to undergo reconstruction with a pectoralis flap versus a free flap and whether the use of a pectoralis flap offered any perioperative advantage, such as a reduction in medical complications. METHODS: Fifty-five consecutive patients who underwent immediate reconstruction after a lateral mandibulectomy were retrospectively reviewed. RESULTS: Age >or=70 years (p = .03), moderate or severe comorbidity (p = .02), and involvement of the base of tongue by tumor (p = .04) were significantly associated with decreased utilization of a free flap (n = 36). Comorbidity was the main determinant of medical complications (p = .001) and length of hospital stay (p = .03). CONCLUSIONS: Expectations of prognosis bias the surgeon's decision regarding flap selection. Reconstruction with a pectoralis flap does not necessarily contribute toward the desired outcome of reduced medical complications. Any functional comparison between reconstructive groups needs to account for those differences in health status and prognosis that might explain any observed postoperative differences.

Age Factors↗

PubMed2005

Lack of a laterality phenotype in Pkd1 knock-out embryos correlates with absence of polycystin-1 in nodal cilia.

The invariant asymmetric placement of thoracic and abdominal organs in the vertebrates is controlled by the left-asymmetric activity of the Nodal signaling cascade during embryogenesis. In the mouse embryo asymmetric induction of nodal is thought to be dependent on functional monocilia on the ventral node cells and on the Pkd2 gene, which encodes the calcium channel polycystin-2 (PC2). In humans mutations in PKD2 and PKD1 give rise to polycystic kidney disease. The PC1 and PC2 proteins are thought to function as part of a multifactorial complex. Localization of both proteins to the primary renal cilium suggested a function on cilia of the ventral node. Here we investigated Pkd1 knock-out embryos for laterality defects and found wild-type organ morphogenesis and normal expression of nodal and Pitx2. While PC2 localized to nodal cilia, no ciliary localization of PC1 was detected in mouse embryos. This finding was confirmed in an archetypical mammalian blastodisc, the rabbit embryo. Thus, absence of PC1 localization to cilia corresponded with a lack of laterality defects in Pkd1 knock-out embryos. Our results demonstrate a PC1-independent function of PC2 in left-right axis formation, and indirectly support a ciliary role of PC2 in this process.

Animals↗

PubMed2005

Evidence of functional redundancy between MID proteins: implications for the presentation of Opitz syndrome.

Opitz G/BBB syndrome (OS) is a congenital defect characterized by hypertelorism and hypospadias, but additional midline malformations are also common in OS patients. X-linked OS is caused by mutations in the ubiquitin ligase MID1. In chick, MID1 is involved in left-right determination: a mutually repressive relationship between Shh and cMid1 in Hensen's node plays a key role in establishing the avian left-right axis. We have utilized our existing knowledge of the molecular basis of avian L/R determination to investigate the possible existence of functional redundancy between MID1 and its close homologue MID2. The expression of cMid2 overlaps with that of cMid1 in the node, and we demonstrate that MID2 can both mimic MID1 function as a right side determinant and rescue the laterality defects caused by knocking down endogenous MID proteins in the node. Our results show that MID2 is able to compensate for an absence in MID1 during chick left-right determination and may explain why OS patients do not suffer laterality defects despite the association between midline and L/R development. The demonstration of functional redundancy between MID1 and MID2 in the node provides supports for the hypothesis that partial functional redundancy between MID proteins in other developing structures contributes to the wide variability of OS phenotype.

Abnormalities, Multiple↗

PubMed1999

Paravaginal defect repair in the treatment of female stress urinary incontinence and cystocele.

OBJECTIVES: To assess the functional and anatomic results of the paravaginal defect repair (PVdR) in women with stress urinary incontinence (SUI) due to bladder neck hypermobility (BNH) and cystocele. METHODS: Fifty-two consecutive patients with a mean age of 61 years underwent PVdR for the treatment of SUI associated with BNH and varying degrees of vaginal prolapse. Twenty-five patients underwent PVdR alone (group 1), and 27 underwent PVdR in association with a rectus muscle sling (group 2) for the treatment of intrinsic sphincter deficiency. All patients had SUI and lateral defect cystocele (paravaginal defect). Associated vaginal and pelvic floor defects included rectocele in 34, vault prolapse in 24, and enterocele in 18; these defects were repaired simultaneously and had an equal distribution among the two groups. RESULTS: At a mean follow-up of 17 months, the cure rate (defined as no pads and no leakage) was 79% (group 1, 72%; group 2, 85%). When expanded to include substantially improved (1 pad/day or less), the success rate was 88% (group 1, 84%; group 2, 93%). Recurrent vaginal prolapse occurred in 8 patients, 6 of whom had PVdR alone. For those patients with failure, time to recurrence of incontinence was 15 and 23 months in groups 1 and 2, respectively. CONCLUSIONS: PVdR restores the normal lateral attachment of the pubocervical fascia to the arcus tendineous fascia pelvis of the pelvic sidewall and provides anatomic repair of lateral defect cystoceles. In women with anatomic SUI, PVdR restores continence by alleviating BNH and should be used in conjunction with a sling procedure in those with intrinsic sphincter deficiency.

Adult↗

PubMedDate not supplied

Polysplenia and situs inversus in siblings. Case reports.

Heterotaxy syndromes, otherwise laterality defects, are variations from anatomic left-right asymmetry. Situs inversus is the complete reversal of the normal situs, still situs ambiguus is the randomisation of the normal organ position. Situs ambiguus may be manifested as asplenia or polysplenia syndrome. Normal situs and both types of the heterotaxy syndromes may appear among some affected families, whereas the different situs are rarely expressed in the same family. We describe an autosomal-recessive inherited familial heterotaxy syndrome with two affected siblings - one of whom has situs inversus, and the other with polysplenia syndrome. The polysplenia syndrome was diagnosed by fetal echocardiography. Since the chromosomal or molecular diagnosis of laterality defects are accessible only in X-linked heterotaxy syndromes, the fetal echocardiography is the earliest available diagnostic method in this field. Therefore, fetal echocardiography has great importance for affected families.

Fatal Outcome↗

PubMed2003

Horizontal advancement flap for symmetric reconstruction of small to medium-sized cutaneous defects of the lateral nasal supratip.

BACKGROUND: Aesthetic repair of small cutaneous defects of the nose is a common challenge for the dermatologic surgeon because nonmelanoma cancers occur frequently in this location. OBJECTIVE: Our aim was to devise a simple flap for repair of small to medium-sized defects of the lateral nasal supratip. METHODS: The mechanics of the proposed horizontal advancement ("east-west") flap are described. Patient selection, flap design, and flap mechanics are discussed. The benefits and limitations of this repair are compared with those of alternative closures. RESULTS: The horizontal-advancement flap is an easily visualized, constructed, and executed flap that permits repair of small to moderately sized lateral nasal supratip defects without inducing asymmetry of the nasal architecture. The flap is well camouflaged in skin lines, the ala and nares are not distorted, and the large, untwisted pedicle contributes to flap viability. Large defects and defects far lateral to the midline may not be amenable to this repair. CONCLUSIONS: In selected patients with small to medium-sized lateral nasal supratip defects, the horizontal advancement flap is a simple, reliable, and aesthetically pleasing reconstruction option.

Humans↗

PubMed1992

Cytogenetics of epithelial malignant lesions.

Chromosomal abnormalities have been believed to be responsible for neoplastic transformation and tumor growth for a long time. The confirming observations are of two types: (1) primary cytogenetic alterations that are responsible for tumor initiation and (2) secondary abnormalities that are acquired late and are associated with tumor growth, heterogeneity, and metastasis. Primary chromosomal abnormalities (such as the 13q deletion in retinoblastoma, 11p deletion in Wilms' tumor, 3p anomalies in renal cell carcinoma, and 5q deletion in colorectal carcinomas) first were identified in lymphocyte cultures as constitutional defects. Later, similar types of defects were observed as tumor-specific aberrations from patients whose lymphocytes otherwise had normal chromosomes. Recently, it has become clear that classes of known cancer-related genes (dominant protooncogenes and recessive tumor-suppressor or anti-oncogenes) are located at those hot spots that are involved in neoplasia-associated chromosomal alterations. In breast carcinoma, such a specific chromosomal alteration has not been identified conclusively in lymphocyte cultures, although chromosome 1 alterations have been observed in cell lines, directly processed effusions, and primary breast tumors. Lymphocyte cultures; primary tumors; and established cell lines from breast carcinomas, colorectal carcinomas, and renal cell carcinomas were analyzed to identify (1) primary chromosomal alterations precisely and (2) secondary cytogenetic defects that are associated with these most common solid adult neoplasms. Peripheral blood analysis indicated that chromosomes 1, 17, and 18 in breast carcinomas; chromosomes 3 and 14 in renal cell carcinomas; and chromosomes 5, 12, and 17 in colorectal carcinomas were involved nonrandomly in structural anomalies in a small number of lymphocyte cells (1-4%). These chromosomal aberrations were considered primary defects because of their involvement as marker formations in tumor cells; other structural and numeric abnormalities also were found. These results indicate that lymphocyte chromosomal analysis might identify those at high risk for breast, colorectal, and renal cell carcinomas, among other malignant lesions. Such identifications could facilitate early selection for primary and secondary cancer prevention or interventional trials.

Chromosome Aberrations↗