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Commonly known as "Kissing Spines" (KS), the pathological mechanisms underlying impingement and overriding of spinous processes (ORSPs) in horses are poorly understood. Thoroughbreds, Warmbloods, and stock-type breeds, including Paint Horses and Quarter Horses are at increased risk for developing clinical signs of KS. A total of 155 stock-type and Warmblood horses presented at collaborating veterinary clinics and hospitals were examined using a strict clinical and radiographical phenotyping scheme to grade each horse from 0 for unaffected controls to 4 for severe KS. Following genotyping with the Illumina Equine SNP70 array (Illumina, Inc.) a Genome Wide Association Study (GWAS) using 61,229 filtered individual Single Nucleotide Polymorphisms (SNPs) was performed to the KS grade phenotype. Two significantly associated SNPs (BIEC2-668062 and BIEC2-668013) on chromosome 25 defined a ~1.4 Gb candidate region containing approximately 17 coding genes (EquCab3) and 195 ENSEMBL annotated variants. Investigation of the best associated SNP (BIEC2-668062) on chr25 demonstrates a significant correlation with an increase in one KS grade, on average, per A allele in this population. A significant effect of breed group, age, height or sex was not observed in this population. These preliminary results demonstrate the potential for KS diagnosis and preventative measures for WB/ST individuals supported by increased genetic risk for more severe KS grade. We propose further research including other affected breeds and evaluating causative variants, as well as the effect of BIEC2-668062 in these populations.

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The objective of this study was to compare the safety and efficacy of carboplatin plus epirubicin and paclitaxel (TEC) to carboplatin and paclitaxel (TC), in the treatment of epithelial ovarian, peritoneal, or tubal carcinoma. Between March 1999 and August 2001, 887 patients were randomized to receive six to nine cycles of paclitaxel (175 mg/m2, 3 h intravenously) followed by carboplatin (AUC 5, Calvert formula) with or without epirubicin (75 mg/m2 intravenously prior to paclitaxel), on a 3-weekly schedule. The primary endpoint was progression-free survival. Demographic information: Residual disease <1 cm was reported on 41% of patients. At the end of treatment, 65% in the TEC and 55% in the TC arm had achieved a clinical complete response, and 18 and 25% a clinical partial response resulting in an overall response rate of 83% in the TEC and 80% in the TC arm, whereas 7 and 9% had progressive disease, respectively. The three-drug combination produced a markedly higher myelotoxicity, resulting in a higher frequency of febrile neutropenia (12.5% of the TEC and 1.5% of the TC patients) and a higher number of dose reductions and treatment delays. Cycle prolongation above seven days was seen in 7 and 5% of cycles in the TEC and TC arm, respectively. Stomatitis > or = grade 3 was also higher with TEC (4% TEC and 0.5% TC). Reductions in left ventricular ejection fraction of more than 15% after six courses were slightly more common with the TEC regimen (3% versus 1.5%), but the difference was not statistically significant (P = 0.2). In conclusion, treatment with the TEC combination produced a higher rate of complete responses than treatment with the TC combination. Toxicity was manageable. Long-term survival data are awaited.

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The Caenorhabditis elegans genome contains three rac-like genes, ced-10, mig-2, and rac-2. We report that ced-10, mig-2 and rac-2 act redundantly in axon pathfinding: inactivating one gene had little effect, but inactivating two or more genes perturbed both axon outgrowth and guidance. mig-2 and ced-10 also have redundant functions in some cell migrations. By contrast, ced-10 is uniquely required for cell-corpse phagocytosis, and mig-2 and rac-2 have only subtle roles in this process. Rac activators are also used differentially. The UNC-73 Trio Rac GTP exchange factor affected all Rac pathways in axon pathfinding and cell migration but did not affect cell-corpse phagocytosis. CED-5 DOCK180, which acts with CED-10 Rac in cell-corpse phagocytosis, acted with MIG-2 but not CED-10 in axon pathfinding. Thus, distinct regulatory proteins modulate Rac activation and function in different developmental processes.

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As vulvovaginal disease are nog very common in prepubescent girls, it may seem reasonable to suspect sexual abuse when a small girl presents with complaints in the genital area. However, the very fact that there are visible changes suggests that it is no a case of sexual abuse, the signs of which are usually more subtle. To arrive at a correct diagnosis, and avoid unnecessary, traumatic investigation into the possibility of sexual abuse, it is essential that such patients be examined from the outset by physicians experienced in this field.

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Axon guidance receptors modulate the growth cone cytoskeleton through signaling pathways that are not well understood. Here, we describe the C. elegans unc-115 gene, which encodes a candidate cytoskeletal linker protein that acts in axon guidance. unc-115 mutants have defects in a subset of axons, particularly as the affected axons change environments during outgrowth. The unc-115 gene encodes a putative actin-binding protein that is similar to the human actin-binding protein abLIM/limatin; it has a villin headpiece domain and three LIM domains that could mediate protein interactions. unc-115 is expressed in neurons during their development and is required cell-autonomously in certain neurons for normal axon guidance. We propose that UNC-115 modulates the growth cone actin cytoskeleton in response to signals received by growth cone receptors.

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Mutation in the Caenorhabditis elegans gene osm-6 was previously shown to result in defects in the ultrastructure of sensory cilia and defects in chemosensory and mechanosensory behaviors. We have cloned osm-6 by transposon tagging and transformation rescue and have identified molecular lesions associated with five osm-6 mutations. The osm-6 gene encodes a protein that is 40% identical in amino acid sequence to a predicted mammalian protein of unknown function. We fused osm-6 with the gene for green fluorescent protein (GFP); the fusion gene rescued the osm-6 mutant phenotype and showed accumulation of GFP in ciliated sensory neurons exclusively. The OSM-6::GFP protein was localized to cytoplasm, including processes and dendritic endings where sensory cilia are situated. Mutations in other genes known to cause ciliary defects led to changes in the appearance of OSM-6::GFP in dendritic endings or, in the case of daf-19, reduced OSM-6::GFP accumulation. We conclude from an analysis of genetic mosaics that osm-6 acts cell autonomously in affecting cilium structure.

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Mutations in the mec-8 gene of Caenorhabditis elegans were previously shown to affect the functions of body wall muscle and mechanosensory and chemosensory neurons. Mutations in mec-8 also strongly enhance the mutant phenotype of specific mutations in unc-52, a gene that encodes, via alternative splicing of pre-mRNA, a set of basement membrane proteins, homologs of perlecan, that are important for body wall muscle assembly and attachment to basement membrane, hypodermis and cuticle. We have cloned mec-8 and found that it encodes a protein with two RNA recognition motifs, characteristic of RNA binding proteins. We have used reverse transcription-PCR and RNase protection experiments to show that mec-8 regulates the accumulation of a specific subset of alternatively spliced unc-52 transcripts. We have also shown with antibodies to UNC-52 that mec-8 affects the abundance of a subset of UNC-52 isoforms. We propose that mec-8 encodes a trans-acting factor that regulates the alternative splicing of the pre-mRNA of unc-52 and one or more additional genes that affect mechanosensory and chemosensory neuron function.

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Mutations in the Caenorhabditis elegans gene mec-8 were previously shown to cause defects in mechanosensation and in the structure and dye filling of certain chemosensory neurons. Using noncomplementation screens, we have identified eight new mec-8 alleles and a deficiency that uncovers the locus. Strong mec-8 mutants exhibit an incompletely penetrant cold-sensitive embryonic and larval arrest, which we have correlated with defects in the attachment of body muscle to the hypodermis and cuticle. Mutations in mec-8 strongly enhance the mutant phenotype of unc-52(viable) mutations; double mutants exhibit an unconditional arrest and paralysis at the twofold stage of embryonic elongation, a phenotype characteristic of lethal alleles of unc-52, a gene previously shown to encode a homolog of the core protein of heparan sulfate proteoglycan, found in basement membrane, and to be involved in the anchorage of myofilament lattice to the muscle cell membrane. We have identified and characterized four extragenic recessive suppressors of a mec-8; unc-52(viable) synthetic lethality. The suppressors, which define the genes smu-1 and smu-2, can weakly suppress all mec-8 mutant phenes. They also suppress the muscular dystrophy conferred by an unc-52(viable) mutation.

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The effects of the protein-synthesis inhibitor cycloheximide on 25-hydroxycholesterol-mediated suppression of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase mRNA levels were evaluated in the baby-hamster kidney cell line C100. Cells cultured in medium supplemented with delipidized fetal bovine serum and 25 microM lovastatin for 12-24 h had a 5-fold higher level of HMG-CoA reductase mRNA than cells grown in medium supplemented with non-delipidized fetal bovine serum (FBS). The higher level was due to increased transcription, as determined by run-on assays with isolated nuclei. Addition of 25-hydroxycholesterol to lovastatin-treated cells lowered HMG-CoA reductase mRNA levels within 4 h of treatment to those of cells grown in FBS-supplemented medium. This decrease was due in part to a decrease in gene transcription. Cycloheximide added in conjunction with 25-hydroxycholesterol to lovastatin-treated cells blocked the suppression of mRNA levels, but did not block oxysterol-mediated suppression of transcription. In addition, cycloheximide added to cells grown in FBS-supplemented medium rapidly increased mRNA levels by 10-fold relative to untreated cells, with no comparable increase in transcription. No comparable increase in either the mRNA level or rate of transcription for beta-actin was observed under such conditions. These results indicate that cycloheximide specifically stabilizes HMG-CoA reductase mRNA in the presence of oxysterols and suggests that continuous synthesis of a short lived protein regulator is required for oxysterol-mediated suppression of HMG-CoA reductase mRNA at a post-transcriptional level.

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The Abdominal-B (Abd-B) gene is one of three genes in the bithorax complex, a cluster of homeotic genes in Drosophila. During embryogenesis Abd-B is expressed in a complex pattern, producing four different transcript classes, each of which exhibits a unique spatial pattern of expression. Proper regulation of the class A transcripts is required for appropriate development of the fifth through eighth abdominal segments and is mediated, in part, by a 60-kb regulatory region located 3' of the gene. We have isolated a new mutation, designated Abd-BCorset, which is caused by a deletion that leaves 15 kb of the 3' regulatory sequences immediately adjacent to the gene, but removes 45 kb of the more distant 3' regulatory elements. This mutation produces an unexpected homeotic segmental transformation of the fourth through seventh abdominal segments, and has been analyzed by genetic and molecular techniques. In situ hybridization to Abd-BCorset embryos shows a uniform and moderate level of the Abd-B class A transcript in the posterior abdomen, rather than the normal graded pattern of expression. Our analysis of the Abd-BCorset mutation has prompted a model of the 3' regulatory region of Abd-B based on reiterated cell type-specific elements controlled by adjacent position-sensitive activating elements. The gradient of Abd-B expression normally observed in the posterior abdomen appears to be achieved by varying the number of reiterated elements that are active in each segment.

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