Treatment of congenital convex pes valgus with navicular excision and subtalar arthroereisis: a case study.

This article presents a case study of a 4-year-old female with a delayed diagnosis of congenital convex pes valgus. The severe soft-tissue contractures and osseous abnormalities in this case necessitated excision of the navicular and subtalar arthroereisis in addition to standard soft-tissue releases in order to achieve and maintain adequate reduction. A review of the literature and a discussion of these adjunctive techniques is provided to examine the concepts relevant to treatment of this condition.

Phylogenetic analysis of T-Box genes demonstrates the importance of amphioxus for understanding evolution of the vertebrate genome.

The duplication of preexisting genes has played a major role in evolution. To understand the evolution of genetic complexity it is important to reconstruct the phylogenetic history of the genome. A widely held view suggests that the vertebrate genome evolved via two successive rounds of whole-genome duplication. To test this model we have isolated seven new T-box genes from the primitive chordate amphioxus. We find that each amphioxus gene generally corresponds to two or three vertebrate counterparts. A phylogenetic analysis of these genes supports the idea that a single whole-genome duplication took place early in vertebrate evolution, but cannot exclude the possibility that a second duplication later took place. The origin of additional paralogs evident in this and other gene families could be the result of subsequent, smaller-scale chromosomal duplications. Our findings highlight the importance of amphioxus as a key organism for understanding evolution of the vertebrate genome.

Necrotizing fasciitis in the lower extremity: a review and case presentation.

Necrotizing fasciitis is a rare but potentially fatal disease which is often confused with cellulitis. By examining the pathogenesis, clinical presentation, treatment, and a representative case study, this article proposes to lend a broader perspective to this infection. Emphasis is placed on the necessity of surgical debridement in combination with antibiotic therapy to minimize the possible morbidity associated with this condition.

tbx20, a new vertebrate T-box gene expressed in the cranial motor neurons and developing cardiovascular structures in zebrafish.

The T-box genes constitute a family of transcriptional regulator genes that have been implicated in a variety of developmental processes ranging from the formation of germ layers to the regionalization of the central nervous system. In this report we describe the cloning and expression pattern of a new T-box gene from zebrafish, which we named tbx20. tbx20 is an ortholog of two other T-box genes isolated from animals of different phyla - H15 of Drosophila melanogaster and tbx-12 of Caenorhabditis elegans, suggesting that the evolutionary origin of this gene predates the divergence between the protostomes and deuterostomes. During development, tbx20 is expressed in embryonic structures of both mesodermal and ectodermal origins, including the heart, cranial motor neurons, and the roof of the dorsal aorta.

The bHLH transcription factor hand2 plays parallel roles in zebrafish heart and pectoral fin development.

The precursors of several organs reside within the lateral plate mesoderm of vertebrate embryos. Here, we demonstrate that the zebrafish hands off locus is essential for the development of two structures derived from the lateral plate mesoderm - the heart and the pectoral fin. hands off mutant embryos have defects in myocardial development from an early stage: they produce a reduced number of myocardial precursors, and the myocardial tissue that does form is improperly patterned and fails to maintain tbx5 expression. A similar array of defects is observed in the differentiation of the pectoral fin mesenchyme: small fin buds form in a delayed fashion, anteroposterior patterning of the fin mesenchyme is absent and tbx5 expression is poorly maintained. Defects in these mesodermal structures are preceded by the aberrant morphogenesis of both the cardiogenic and forelimb-forming regions of the lateral plate mesoderm. Molecular analysis of two hands off alleles indicates that the hands off locus encodes the bHLH transcription factor Hand2, which is expressed in the lateral plate mesoderm starting at the completion of gastrulation. Thus, these studies reveal early functions for Hand2 in several cellular processes and highlight a genetic parallel between heart and forelimb development.

The evolution of paired appendages in vertebrates: T-box genes in the zebrafish.

The presence of two sets of paired appendages is one of the defining features of jawed vertebrates. We are interested in identifying genetic systems that could have been responsible for the origin of the first set of such appendages, for their subsequent duplication at a different axial level, and/or for the generation of their distinct identities. It has been hypothesized that four genes of the T-box gene family (Tbx2-Tbx5) played important roles in the course of vertebrate limb evolution. To test this idea, we characterized the orthologs of tetrapod limb-expressed T-box genes from a teleost, Danio rerio. Here we report isolation of three of these genes, tbx2, tbx4, and tbx5. We found that their expression patterns are remarkably similar to those of their tetrapod counterparts. In particular, expression of tbx5 and tbx4 is restricted to pectoral and pelvic fin buds, respectively, while tbx2 can be detected at the anterior and posterior margins of the outgrowing fin buds. This, in combination with conserved expression patterns in other tissues, suggests that the last common ancestor of teleosts and tetrapods possessed all four of these limb-expressed T-box genes (Tbx2-Tbx5), and that these genes had already acquired, and have subsequently maintained, their gene-specific functions. Furthermore, this evidence provides molecular support for the notion that teleost pectoral and pelvic fins and tetrapod fore- and hindlimbs, respectively, are homologous structures, as suggested by comparative morphological analyses.

An axonemal dynein at the Hybrid Sterility 6 locus: implications for t haplotype-specific male sterility and the evolution of species barriers.

Poor sperm motility characterized by a distinct aberration in flagellar waveform known as "curlicue" is a hallmark of t haplotype (t) homozygous male sterility. Previous studies have localized "curlicue" and a flagellar developmental defect, "whipless", to the Hybrid Sterility 6 locus (Hst6), between the markers Pim1 and Crya1. More recent heterospecific breeding experiments between Mus spretus (Spretus) and Mus musculus domesticus (Domesticus) have mapped the primary source(s) of both "curlicue" and "whipless" to a small sub-locus of Hst6, Curlicue a (Ccua). Here we report the complete physical isolation of the Ccua locus and the identification of a candidate gene for expression of both "whipless" and "curlicue" at its proximal end, an axonemal dynein heavy chain gene, Dnahc8, formerly mapped by interspecific backcross analysis near Pim1. Dnahc8 mRNA expression commences in the Domesticus wild-type testis just prior to flagellar assembly and is testis-specific in the adult male. However, expression of Dnahc8 is not readily evident in the testis of either Spretus or "whipless" animals (Domesticus males homozygous for the Spretus allele of Dnahc8). Our results argue that Dnahc8 is fundamental to flagellar organization and function in Domesticus, but not Spretus, and suggest that Dnahc8 is integral to both Hst6- and t-specific male infertility.

Mapping and expression analysis of the mouse ortholog of Xenopus Eomesodermin.

The T-box gene family has been conserved throughout metazoan evolution. The genes code for putative transcription factors which share a uniquely defining DNA binding domain, known as the T-box ([Bollag et al., 1994]). They are implicated in the control of diverse developmental processes by their highly specific expression patterns throughout gastrulation and organogenesis in mouse and other species ([Chapman et al., 1996]) ([Gibson-Brown et al., 1998]), and by mutations in T-box genes that have profound developmental effects ([Papaioannou, 1997]; [Chapman and Papaioannou, 1998]; [Papaioannou and Silver, 1998]). In this report, we describe the mapping and expression pattern of the mouse ortholog of a gene, Eomesodermin, first identified in Xenopus ([Ryan et al., 1996]). The mouse gene was previously reported ([Wattler et al., 1998]) under the name MmEomes. The gene maps to mouse chromosome 9 in a region syntenic with human chromosome 3p. Mouse eomesodermin is expressed in the trophoblast of the blastocyst and in its derivative, the chorionic ectoderm. At gastrulation, eomesodermin is expressed in the primitive streak and embryonic mesoderm as well, but this expression disappears prior to the end of gastrulation. Later, eomesodermin is expressed in the developing forebrain, in a pattern largely overlapping a closely related T-box gene, Tbr1 ([Bulfone et al., 1995]), and is also seen in a localized area of each limb.

Mapping and cloning recombinant breakpoints demarcating the hybrid sterility 6-specific sperm tail assembly defect.

Variants of the mouse t complex known as t haplotypes (t) express factors that perturb sperm differentiation, resulting in the non-Mendelian transmission of t from +/t heterozygous males and the sterility of t/t homozygous males. Previous studies of mice carrying heterospecific combinations of the t complex have revealed a 1-cM candidate locus, Hst6, for the distal-most of these factors, Tcd/Tcs2. Males heterozygous for the M. spretus allele of Hst6 and a t haplotype (Hst6(s)/t) are sterile, expressing an abnormality in sperm flagellar curvature ("curlicue") indistinguishable from one exhibited by sperm from t/t homozygotes. Hst6(s)/Hst6(s) males are also sterile; however, sperm produced by these males are completely immotile owing to the absence of assembled flagella. Recent studies have shown that the complete presentation of "curlicue" derives from expression of at least two factors within the locus, Curlicue a (Ccua) proximally and Curlicue b (Ccub) distally, with a factor affecting sperm-oolemma penetration, Stop1p, mapping between them. In the present report, we have examined expression of the Hst6-specific flagellar assembly phenotype in sperm from mice homozygous for M. spretus-M. m. domesticus recombinant Chr 17 homologs whose breakpoints map within the Hst6 locus. SSLP analysis of these homologs has demonstrated that the flagellar assembly defect maps to less than 0.2 cM between D17Mit61 and D17Mit135, coincident with Ccua. SSR content analysis of 23 BACs mapping to four contigs within the Hst6 locus has resulted in isolation of proximal and distal recombinant breakpoints circumscribing the flagellar assembly phenotype/Ccua factor. In addition, we have provided increased high-resolution mapping of the Stop1p and Ccub factors. These new data enhance our ability to isolate and characterize candidates for Tcd/Tcs2.

Transgenic N-myc mouse model for indolent B cell lymphoma: tumor characterization and analysis of genetic alterations in spontaneous and retrovirally accelerated tumors.

Little is known about stepwise deregulation of specific genes leading to lymphoid malignancy. Aberrant myc gene expression in transgenic mice is correlated with B cell lymphomagenesis. We generated a unique transgenic mouse model in which deregulated murine E mu-N-myc transgene expression leads to development of indolent B cell lymphoma. Tumor cells were monoclonal, morphologically mature and surface immunoglobulin expressing B cells. Tumors arose in a disease course and exhibited a cytoarchitectural appearance reminiscent of human follicular lymphoma. Yet tumor cells were staged as preB since they failed to rearrange the immunoglobulin light chain genes. Retroviral insertion mutagenesis analyses of adult transgenic mice infected as newborns with murine leukemia virus revealed decreased disease latency, increased lymphoma incidence and a histologically more mature tumor type. Proviral insertion sites were not equivalent when accelerated E mu-N-myc indolent lymphomas were compared to accelerated c-myc preB cell lymphomas. The bcl-2 gene was not disrupted in either spontaneous or provirally accelerated E mu-N-myc lymphomas. These findings suggest that tumor progression in N-myc-associated indolent B cell lymphoma can proceed along diverse pathways involving distinctly different combinations of deregulated and/or intact genes than those pathways described in highly aggressive forms of myc-related murine preB cell disease.

Sex-restricted non-Mendelian inheritance of mouse chromosome 11 in the offspring of crosses between C57BL/6J and (C57BL/6J x DBA/2J)F1 mice.

We report on the observation of sex-restricted, non-Mendelian inheritance over a region of mouse Chromosome (Chr) 11, occurring in the offspring of crosses between two commonly used Mus musculus-derived inbred strains, C57BL/6J and DBA/2J. In the surviving backcross progeny of reciprocal matings between (C57BL/6J x DBA/2J)F1 hybrids and the C57BL/6J parental strain, we observed the preferential appearance of C57BL/6J alleles along a region of Chr 11. The deviation from Mendelian predictions was observed only in female offspring from both reciprocal backcrosses, and not in males from either cross. The sex-specificity of the observed non-Mendelian inheritance points to an explanation based on embryonic or neonatal lethality. Our data add to previously obtained evidence for a Chr 11 locus or loci with sex-specific and allele-specific effects on viability.

Cloning, mapping, and expression analysis of TBX15, a new member of the T-Box gene family.

The T-box gene family has been conserved throughout metazoan evolution and codes for putative transcription factors that share a uniquely defining DNA-binding domain. We have previously uncovered six mouse T-box genes with discrete spatial and temporal patterns of expression during embryogenesis. Here, we report a novel mouse T-box gene, Tbx15. The Tbx15 gene produces a 3.7-kb transcript with an open reading frame coding for a polypeptide with 602 amino acid residues. Phylogenetic analysis places the Tbx15 gene into a T-box subfamily that also includes mouse Tbx1, Drosophila H15, and nematode Ce-tbx-12 genes. We have mapped mouse Tbx15 to chromosome 3, at a position 49 cM from the centromere. During development, Tbx15 transcripts are first detected at embryonic day 9.5. The gene is expressed primarily in the cranio-facial region and in the developing limbs. An isolated human homolog, TBX15, has been mapped by in situ hybridization to chromosomal band 1p13. TBX15 appears to be an excellent candidate for the dominantly expressed acromegaloid facial appearance syndrome, which also maps to the short arm of human chromosome 1 and, like TBX15, is expressed prominently in the eyebrow regions.

Expression of T-box genes Tbx2-Tbx5 during chick organogenesis.

T-box genes encode putative transcription factors implicated in diverse developmental processes (Papaioannou, V.E. and Silver, L.M., 1998. BioEssays 20, 9-19). We have previously reported the embryonic expression patterns of T-box genes in mice (Chapman, D.L., Garvey, N., Hancock, S., Alexiou, M., Agulnik, S.I., Gibson-Brown, J.J., Cebra-Thomas, J., Bollag, R.J., Silver, L.M., Papaioannou, V.E., 1996. Dev. Dyn. 206, 379-390; Chapman, D.L., Agulnik, I., Hancock, S., Silver, L.M. and Papaioannou, V.E., 1996. Dev. Biol. 180, 534-542; Gibson-Brown, J.J., Agulnik, S.I., Chapman, D.L., Alexiou, M., Garvey, N., Silver, L.M., Papaioannou, V.E., 1996. Mech. Dev. 56, 93-101). Four of these genes (Tbx2-Tbx5) are represented in the mouse genome as two cognate, linked gene pairs (Agulnik, S.I., Garvey, N., Hancock, S., Ruvinsky, I., Chapman, D.L., Agulnik, I., Bollag, R., Papaioannou, V.E., Silver, L.M., 1996. Genetics 144, 249-254), and have all been implicated in playing important roles in limb development (Gibson-Brown, J.J., Agulnik, S.I., Chapman, D.L., Alexiou, M., Garvey, N., Silver, L.M., Papaioannou, V.E., 1996. Mech. Dev. 56, 93-101). To investigate the role of these genes in limb development, we cloned the chicken orthologs and report functional studies, as well as patterns of expression in the developing limbs, elsewhere (Gibson-Brown, J.J., Agulnik, S.I., Silver, L.M., Niswander, L., Papaioannou, V.E., Development, in press). This report details the patterns of expression of Tbx2-Tbx5 in chick embryonic tissues other than the limbs.