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Case Report: Tourette Syndrome and Klippel-Feil Anomaly in a Child with Chromosome 22q11 Duplication(2009)Journal ArticleThis is the first case description of the association of Klippel-Feil Syndrome (KFS), Tourette Syndrome (TS), Motor Stereotypies, and Obsessive Compulsive Behavior, with chromosome 22q11.2 Duplication Syndrome (22q11DupS). Neuropsychiatric symptoms in persons with 22q11.2 deletion, including obsessive compulsiveness, anxiety, hyperactivity, and one prior case report of TS, have been attributed to low copy number effects on Catechol-O-Methyltransferase (COMT). However, the present unique case of 22q11DupS and TS suggests a more complex relationship involving another gene(s) at or near this locus.
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(2009)Journal ArticleBone morphogenetic protein-13 (BMP-13) plays an important role in skeletal development. In the light of a recent report that mutations in the BMP-13 gene are associated with spine vertebral fusion in Klippel-Feil syndrome, we hypothesized that BMP-13 signaling is crucial for regulating embryonic endochondral ossification. In this study, we found that BMP-13 inhibited the osteogenic differentiation of human bone marrow multipotent mesenchymal stromal cells (BM MSCs) in vitro. The endogenous BMP-13 gene expression in MSCs was examined under expansion conditions. The MSCs were then induced to differentiate into osteoblasts in osteo-inductive medium containing exogenous BMP-13. Gene expression was analysed by real-time PCR. Alkaline phosphatase (ALP) expression and activity, proteoglycan (PG) synthesis and matrix mineralization were assessed by cytological staining or ALP assay. Results showed that endogenous BMP-13 mRNA expression was higher than BMP-2 or -7 during MSC growth. BMP-13 supplementation strongly inhibited matrix mineralization and ALP activity of osteogenic differentiated MSCs, yet increased PG synthesis under the same conditions. In conclusion, BMP-13 inhibited osteogenic differentiation of MSCs, implying that functional mutations or deficiency of BMP-13 may allow excess bone formation. Our finding provides an insight into the molecular mechanisms and the therapeutic potential of BMP-13 in restricting pathological bone formation.
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(2008)Journal ArticleBone morphogenetic proteins are a diverse group of morphogens with influences not only on bone tissue, as the nomenclature suggests, but on multiple tissues in the body and often at crucial and influential periods in development. The purpose of this review is to identify and discuss current knowledge of one vertebrate BMP, Bone Morphogenetic Protein 13 (BMP13), from a variety of research fields, in order to clarify BMP13's functional contribution to developing and maintaining healthy tissues, and to identify potential future research directions for this intriguing morphogen. BMP13 is highly evolutionarily conserved (active domain >95%) across diverse species from Zebrafish to humans, suggesting a crucial function. In addition, mutations in BMP13 have recently been associated with Klippel-Feil Syndrome, causative of numerous skeletal and developmental defects including spinal disc fusion. The specific nature of BMP13's crucial function is, however, not yet known. The literature for BMP13 is focused largely on its activity in the healing of tendon-like tissues, or in comparisons with other BMP family molecules for whom a clear function in embryo development or osteogenic differentiation has been identified. There is a paucity of detailed information regarding BMP13 protein activity, structure or protein processing. Whilst some activity in the stimulation of osteogenic or cartilaginous gene expression has been reported, and BMP13 expression is found in post natal cartilage and tendon tissues, there appears to be a redundancy of function in the BMP family, with several members capable of stimulating similar tissue responses. This review aims to summarise the known or potential role(s) for BMP13 in a variety of biological systems.
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(2000)Journal Article
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(2005)Journal ArticleNitric oxide (NO) is a signaling molecule synthesized from l-arginine by nitric oxide synthases (NOSs). NOS isoforms are either constitutive (endothelial NOS [eNOS] and neuronal NOS [nNOS]) or inducible NOS (iNOS). Previously, our group has reported that NO is expressed during and modulates fracture healing. In this study, we evaluated the specific contribution of iNOS to fracture healing by using iNOS gene therapy in iNOS-deficient mice. Twelve-week-old female wild-type mice and iNOS-KO mice had a right femoral midshaft osteotomy fixed with an intramedullary 0.5-mm-diameter needle. A gelatine sponge was implanted across the fracture site. The gelatine sponge received either Ad5-CMViNOS (in iNOS-deficient mice; n = 16) or Ad5-CMVempty (in wild-type mice; n = 15, and iNOS-deficient mice; n = 15) at a dose of 107 pfu. Mice were sacrificed at day 14, and their right and left hind limbs were harvested. Cross-sectional area (CSA) was determined by measuring the callus diameter across the mediolateral and anteroposterior plane using a vernier caliper. Specimens were loaded to failure torsionally in a biaxial INSTRON testing system, and maximum torque, torsional stiffness, and maximal and total energy were determined.Deletion of the iNOS gene decreased the total and maximum energy absorption of the healing femoral fracture by 30% and by 70% (P P = 0.01) in comparison to iNOS(-/-) mice that did not receive the iNOScDNA. There were no significant differences in the biomechanical properties of intact femora.These data indicate that iNOS is important in mouse fracture healing. However, the clinical utility of NOS gene therapy to enhance fracture healing will need further evaluation.
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(2009)Journal ArticleIn normal healthy-weight humans, women have a higher percentage body fat than men, a difference that commences at puberty and continues throughout adult life, suggesting that the mechanism is related to sex steroids. The first half of pregnancy is also a stage of body fat gain in women. From an energy balance point, there is no explanation why women should be fatter than men, as the latter consume more calories proportionately. Moreover, women store fat in early pregnancy when caloric intake does not significantly change. The aim of this review is to focus on evidence supporting one mechanism that may account for these findings. That is, oestrogen reduces postprandial fatty acid oxidation leading to an increase in body fat which may account for the greater fat mass observed in women compared with men and the fat gain in early pregnancy. Therefore, female puberty and early pregnancy could be seen as states of efficient fat storage of energy in preparation for fertility, foetal development and lactation providing an obvious biological advantage. Further research into this mechanism of fat storage may provide further insights into the regulation of body fat.
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(2009)Journal ArticleLittle is known about the associations between adiponectin and its oligomeric isoforms with female sex steroids, and the relevance of these relationships to insulin sensitivity in women. In a cross-sectional study of 32 healthy women (12 premenopausal, 10 postmenopausal, and 10 early pregnant), we investigated the correlations of total adiponectin and the high–, medium–, and low–molecular weight oligomers (HMW, MMW, and LMW, respectively) with estrogen, progesterone, adiposity, and insulin resistance. Fat mass and serum concentrations of estradiol, progesterone, insulin, glucose, and total and isoform adiponectin were measured. The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. Serum concentrations of total and HMW adiponectin were highest in postmenopausal women and lowest in pregnant women. Concentrations of the MMW and LMW isoforms were not significantly different between the 3 groups. Total adiponectin, HMW adiponectin, and MMW adiponectin were negatively associated with estradiol and progesterone; but no associations between the LMW isoform and female sex steroids were observed. Fat mass and HOMA-IR were highest in pregnant women and lowest in premenopausal women. The HOMA-IR was positively associated with fat mass, estradiol, and progesterone, and negatively associated with total, HMW, and MMW adiponectin. Multivariate stepwise regression analysis revealed that fat mass explained 34% of the variance in HOMA-IR and that total and isoform adiponectin contributed an additional 10% to 15%. In the multivariate linear regression analysis, there were significant interactions of estradiol and progesterone with adiponectin or fat mass in the associations with HOMA-IR. In conclusion, there are strong negative associations of serum adiponectin and some of its isoforms with estradiol and progesterone. Female sex steroids are likely to affect insulin sensitivity through modulation of adiponectin and body fat.
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(2008)Journal ArticleBackground: Professionalism is comprised of a set of values and behaviours that underpin the social contract between the public and the medical profession. Medical errors are reported to result in significant morbidity and mortality and are in-part related to underdeveloped professionalism. Aims: The aim was to determine whether specific aspects of professionalism were underdeveloped in medical students. Method: A questionnaire with 24 vignettes was taken by Year 2, 4, and 6 medical students and their responses were compared to responses from practicing Medical Academics. Results: Second, fourth and sixth Year medical students' responses differed from Academics in two aspects of professionalism, firstly, high ethical and moral standards and secondly, humanistic values such as integrity and honesty. Only Year 2 medical students' responses were different from Academics when it came to responsibility and accountability. Conclusions: Certain aspects of professionalism seem to be underdeveloped in medical students. These aspects of professionalism may need to be targeted for teaching and assessment in order that students develop as professionally responsible practitioners. In turn, students with well-developed professionalism may be less involved in medical error, and if involved they may have the personal values which can help them deal with error more honestly and effectively.
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