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1.  WNT1 Mutations in Early-onset Osteoporosis and Osteogenesis Imperfecta 
The New England journal of medicine  2013;368(19):1809-1816.
SUMMARY
This report identifies human skeletal diseases associated with mutations in WNT1. In ten family members with dominantly inherited early-onset osteoporosis, a heterozygous missense variation c.652T>G (p.Cys218Gly) in WNT1 segregated with the disease, and a homozygous nonsense mutation (c.884C>A, p.Ser295*) was identified in two siblings with recessive osteogenesis imperfecta. In vitro, aberrant forms of WNT1 protein showed impaired capacity to induce canonical WNT signaling, their target genes, and mineralization. Wnt1 was clearly expressed in bone marrow, especially in B cell lineage and hematopoietic progenitors; lineage tracing identified expression in a subset of osteocytes, suggesting altered cross-talk of WNT signaling between hematopoietic and osteoblastic lineage cells in these diseases.
doi:10.1056/NEJMoa1215458
PMCID: PMC3709450  PMID: 23656646
2.  Mutations in LRP5 cause primary osteoporosis without features of OI by reducing Wnt signaling activity 
BMC Medical Genetics  2012;13:26.
Background
Primary osteoporosis is a rare childhood-onset skeletal condition whose pathogenesis has been largely unknown. We have previously shown that primary osteoporosis can be caused by heterozygous missense mutations in the Low-density lipoprotein receptor-related protein 5 (LRP5) gene, and the role of LRP5 is further investigated here.
Methods
LRP5 was analyzed in 18 otherwise healthy children and adolescents who had evidence of osteoporosis (manifested as reduced bone mineral density i.e. BMD, recurrent peripheral fractures and/or vertebral compression fractures) but who lacked the clinical features of osteogenesis imperfecta (OI) or other known syndromes linked to low BMD. Also 51 controls were analyzed. Methods used in the genetic analyses included direct sequencing and multiplex ligation-dependent probe amplification (MLPA). In vitro studies were performed using luciferase assay and quantitative real-time polymerase chain reaction (qPCR) to examine the effect of two novel and three previously identified mutations on the activity of canonical Wnt signaling and on expression of tryptophan hydroxylase 1 (Tph1) and 5-hydroxytryptamine (5-Htr1b).
Results
Two novel LRP5 mutations (c.3446 T > A; p.L1149Q and c.3553 G > A; p.G1185R) were identified in two patients and their affected family members. In vitro analyses showed that one of these novel mutations together with two previously reported mutations (p.C913fs, p.R1036Q) significantly reduced the activity of the canonical Wnt signaling pathway. Such reductions may lead to decreased bone formation, and could explain the bone phenotype. Gut-derived Lrp5 has been shown to regulate serotonin synthesis by controlling the production of serotonin rate-limiting enzyme, Tph1. LRP5 mutations did not affect Tph1 expression, and only one mutant (p.L1149Q) reduced expression of serotonin receptor 5-Htr1b (p < 0.002).
Conclusions
Our results provide additional information on the role of LRP5 mutations and their effects on the development of juvenile-onset primary osteoporosis, and hence the pathogenesis of the disorder. The mutations causing primary osteoporosis reduce the signaling activity of the canonical Wnt signaling pathway and may therefore result in decreased bone formation. The specific mechanism affecting signaling activity remains to be resolved in future studies.
doi:10.1186/1471-2350-13-26
PMCID: PMC3374890  PMID: 22487062
3.  How Stand Productivity Results from Size- and Competition-Dependent Growth and Mortality 
PLoS ONE  2011;6(12):e28660.
Background
A better understanding of the relationship between stand structure and productivity is required for the development of: a) scalable models that can accurately predict growth and yield dynamics for the world's forests; and b) stand management regimes that maximize wood and/or timber yield, while maintaining structural and species diversity.
Methods
We develop a cohort-based canopy competition model (“CAIN”), parameterized with inventory data from Ontario, Canada, to examine the relationship between stand structure and productivity. Tree growth, mortality and recruitment are quantified as functions of diameter and asymmetric competition, using a competition index (CAIh) defined as the total projected area of tree crowns at a given tree's mid-crown height. Stand growth, mortality, and yield are simulated for inventoried stands, and also for hypothetical stands differing in total volume and tree size distribution.
Results
For a given diameter, tree growth decreases as CAIh increases, whereas the probability of mortality increases. For a given CAIh, diameter growth exhibits a humped pattern with respect to diameter, whereas mortality exhibits a U-shaped pattern reflecting senescence of large trees. For a fixed size distribution, stand growth increases asymptotically with total density, whereas mortality increases monotonically. Thus, net productivity peaks at an intermediate volume of 100–150 m3/ha, and approaches zero at 250 m3/ha. However, for a fixed stand volume, mortality due to senescence decreases if the proportion of large trees decreases as overall density increases. This size-related reduction in mortality offsets the density-related increase in mortality, resulting in a 40% increase in yield.
Conclusions
Size-related variation in growth and mortality exerts a profound influence on the relationship between stand structure and productivity. Dense stands dominated by small trees yield more wood than stands dominated by fewer large trees, because the relative growth rate of small trees is higher, and because they are less likely to die.
doi:10.1371/journal.pone.0028660
PMCID: PMC3236764  PMID: 22174861
4.  Long-Term Clinical Outcome and Carrier Phenotype in Autosomal Recessive Hypophosphatemia Caused by a Novel DMP1 Mutation 
Journal of Bone and Mineral Research  2010;25(10):2165-2174.
Homozygous inactivating mutations in DMP1 (dentin matrix protein 1), the gene encoding a noncollagenous bone matrix protein expressed in osteoblasts and osteocytes, cause autosomal recessive hypophosphatemia (ARHP). Herein we describe a family with ARHP owing to a novel homozygous DMP1 mutation and provide a detailed description of the associated skeletal dysplasia and carrier phenotype. The two adult patients with ARHP, a 78-year-old man and his 66-year-old sister, have suffered from bone pain and lower extremity varus deformities since early childhood. With increasing age, both patients developed severe joint pain, contractures, and complete immobilization of the spine. Radiographs showed short and deformed long bones, significant cranial hyperostosis, enthesopathies, and calcifications of the paraspinal ligaments. Biochemistries were consistent with hypophosphatemia owing to renal phosphate wasting; markers of bone turnover and serum fibroblast growth factor 23 (FGF-23) levels were increased significantly. Nucleotide sequence analysis of DMP1 revealed a novel homozygous mutation at the splice acceptor junction of exon 6 (IVS5-1G > A). Two heterozygous carriers of the mutation also showed mild hypophosphatemia, and bone biopsy in one of these individuals showed focal areas of osteomalacia. In bone, DMP1 expression was absent in the homozygote but normal in the heterozygote, whereas FGF-23 expression was increased in both subjects but higher in the ARHP patient. The clinical and laboratory observations in this family confirm that DMP1 has an important role in normal skeletal development and mineral homeostasis. The skeletal phenotype in ARHP may be significantly more severe than in other forms of hypophosphatemic rickets. © 2010 American Society for Bone and Mineral Research.
doi:10.1002/jbmr.105
PMCID: PMC3153319  PMID: 20499351
hypophosphatemia; rickets; osteomalacia; skeletal dysplasia; DMP1; FGF-23
5.  Characterization of the Six Zebrafish Clade B Fibrillar Procollagen Genes, with Evidence for Evolutionarily Conserved Alternative Splicing within the pro-α1(V) C-propeptide 
Genes for tetrapod fibrillar procollagen chains can be divided into two clades, A and B, based on sequence homologies and differences in protein domain and gene structures. Although the major fibrillar collagen types I–III comprise only clade A chains, the minor fibrillar collagen types V and XI comprise both clade A chains and the clade B chains pro-α1(V), pro-α3(V), pro-α1(XI) and pro-α2(XI), in which defects can underlie various genetic connective tissue disorders. Here we characterize the clade B procollagen chains of zebrafish. We demonstrate that in contrast to the four tetrapod clade B chains, zebrafish have six clade B chains, designated here as pro-α1(V), proα3(V)a and b, pro-α1(XI)a and b, and pro-α2(XI), based on synteny, sequence homologies, and features of protein domain and gene structures. Spatiotemporal expression patterns are described, as are conserved and non-conserved features that provide insights into the function and evolution of the clade B chain types. Such features include differential alternative splicing of NH2-terminal globular sequences and the first case of a non-triple helical imperfection in the COL1 domain of a clade B, or clade A, fibrillar procollagen chain. Evidence is also provided for previously unknown and evolutionarily conserved alternative splicing within the pro-α1(V) C-propeptide, which may affect selectivity of collagen type V/XI chain associations in species ranging from zebrafish to human. Data presented herein provide insights into the nature of clade B procollagen chains and should facilitate their study in the zebrafish model system.
doi:10.1016/j.matbio.2010.01.006
PMCID: PMC2862785  PMID: 20102740
Collagen type V/XI; Clade B procollagen chains; Spatiotemporal expression; Intron/exon organization; Alternative splicing; Zebrafish
6.  What Must a Vocabulary Editing Interface Offer? 
Creating, modifying, and maintaining a vocabulary is a new task that more healthcare enterprises are having to take on. There are today essentially no readily available vocabulary editing systems. This poster sets out a basic list of editing functions that knowledge workers will require - a minimal functionality list. Functions are explained and illustrated.
PMCID: PMC2232096
16.  Factors predicting the outcome of primary clubfoot surgery 
Canadian Journal of Surgery  2006;49(2):123-127.
Background
We aimed to determine the rate of further surgery, the functional outcome and the factors associated with outcome after primary clubfoot surgery.
Method
We conducted a retrospective study of a cohort of all children who were less than 2 years of age at the time of surgery for idiopathic clubfoot deformity at the Hospital for Sick Children, Toronto, Ont., a tertiary care pediatric hospital. Of the 91 families who could be contacted, 63 agreed to return. The children's charts were reviewed, and their feet were given a Functional Rating System (FRS) score.
Results
Of the original operated population (n = 126), 75% were male and 41% had bilateral clubfoot. The average age at the time of surgery was 8 months, and the mean follow-up was 80.6 months. Further surgery was performed in 19% of cases. The mean FRS outcome score was 79. On average, the FRS score increased by 1.9 points as age at the time of surgery increased by 1 month. Only the presurgical talocalcaneal index was associated with the need for further surgery.
Conclusion
The need for further surgery was 19% overall. Children who had surgery closer to 12 months of age had better functional results. Therefore, surgery should probably be performed in the second, rather than the first, 6 months of life.
PMCID: PMC3207538  PMID: 16630424
17.  A novel COL1A1 mutation in infantile cortical hyperostosis (Caffey disease) expands the spectrum of collagen-related disorders 
Journal of Clinical Investigation  2005;115(5):1250-1257.
Infantile cortical hyperostosis (Caffey disease) is characterized by spontaneous episodes of subperiosteal new bone formation along 1 or more bones commencing within the first 5 months of life. A genome-wide screen for genetic linkage in a large family with an autosomal dominant form of Caffey disease (ADC) revealed a locus on chromosome 17q21 (LOD score, 6.78). Affected individuals and obligate carriers were heterozygous for a missense mutation (3040C↠T) in exon 41 of the gene encoding the α1(I) chain of type I collagen (COL1A1), altering residue 836 (R836C) in the triple-helical domain of this chain. The same mutation was identified in affected members of 2 unrelated, smaller families with ADC, but not in 2 prenatal cases and not in more than 300 chromosomes from healthy individuals. Fibroblast cultures from an affected individual produced abnormal disulfide-bonded dimeric α1(I) chains. Dermal collagen fibrils of the same individual were larger, more variable in shape and size, and less densely packed than those in control samples. Individuals bearing the mutation, whether they had experienced an episode of cortical hyperostosis or not, had joint hyperlaxity, hyperextensible skin, and inguinal hernias resembling symptoms of a mild form of Ehlers-Danlos syndrome type III. These findings extend the spectrum of COL1A1-related diseases to include a hyperostotic disorder.
doi:10.1172/JCI200522760
PMCID: PMC1087158  PMID: 15864348
18.  Quick and Accurate Monitoring Via Metaphor Graphics 
The present study addresses the use of one class of representation, metaphor graphics, as an aid to monitoring a rapidly changing data intensive situation, in this case a patient on a mechanical ventilator. Eight experts in the field of mechanical ventilation viewed summaries containing seven days of data related to a single patient and, as quickly as possible, decided whether the patient was steadily improving, steadily worsening, or was initially moving in one of these two directions but then reversed course. Accuracy was extremely high for both graphic and numerical versions of the summaries but graphic representation led to performance that was significantly faster, averaging half the time required for numeric representation. These findings complement and extend previous research showing that metaphoric graphic representation leads to Bayesian diagnostic reasoning that is extremely accurate but much faster than reasoning via numerical tables.
PMCID: PMC2245395
19.  Graphic Representation Can Lead To Fast and Accurate Bayesian Reasoning 
90 college student subjects participated in an experiment testing the effect of graphic representation on speed and accuracy of Bayesian reasoning. Five representation conditions were employed: a contingency table representation, three graphic representations, and a no-training control group. Tabular or graphic depictions were shown only as feedback and were not available as a student solved a problem. Control subjects remained inaccurate throughout the experiment, showing that practice alone is not sufficient to teach Bayesian reasoning. Subjects receiving graphic feedback were highly accurate and significantly faster than those in the contingency table condition. The reaction time findings are interpreted as evidence that a person using one of the present three graphic representations does not simply reduce the diagram to a contingency table representation as a substep in solving a Bayesian problem. Graphic repesentation seems to lead to a mental model that differs from the model prompted by tabular representation. Practically, the present findings suggest that a physician or nurse with no external aid can accurately diagram and solve a Bayesian diagnostic problem in about 30 seconds.
PMCID: PMC2245778
20.  Automatic Classification of Medical Text: The Influence of Publication Form1 
Previous research has shown that within the domain of medical journal abstracts the statistical distribution of words is neither random nor uniform, but is highly characteristic. Many words are used mainly or solely by one medical specialty or when writing about one particular level of description. Due to this regularity of usage, automatic classification within journal abstracts has proved quite successful. The present research asks two further questions. It investigates whether this statistical regularity and automatic classification success can also be achieved in medical textbook chapters. It then goes on to see whether the statistical distribution found in textbooks is sufficiently similar to that found in abstracts to permit accurate classification of abstracts based solely on previous knowledge of textbooks. 14 textbook chapters and 45 MEDLINE abstracts were submitted to an automatic classification program that had been trained only on chapters drawn from a standard textbook series. Statistical analysis of the properties of abstracts vs. chapters revealed important differences in word use. Automatic classification performance was good for chapters, but poor for abstracts.
PMCID: PMC2245267
21.  Distinguishing Man from Molecules: The Distinctiveness of Medical Concepts at Different Levels of Description 
A computer program was created to use information about the statistical distribution of words in journal abstracts to make probabilistic judgments about the level of description (e.g. molecular, cell, organ) of medical text. Statistical analysis of 7,409 journal abstracts taken from three medical journals representing distinct levels of description revealed that many medical words seem to be highly specific to one or another level of description. For example, the word adrenoreceptors occurred only in the American Journal of Physiology, never in Journal of Biological Chemistry or in Journal of American Medical Association. Such highly specific words occured so frequently that the automatic classification program was able to classify correctly 45 out of 45 test abstracts, with 100% confidence. These findings are interpreted in terms of both a theory of the structure of medical knowledge and the pragmatics of automatic classification.
PMCID: PMC2245044
22.  Patterns of Hierarchical Structure in the Medical Lexicon 
Concepts in basic and clinical medical science cover a wide range of levels of description, from the subatomic level to the level of the patient as a whole. Medical language may have usage regularities consistent with this hierarchical nature of medical knowledge. Preliminary studies of word occurrence in abstracts drawn from three medical journals representing three broadly defined levels of description (chemical system, physiologic system, and patient as a whole) demonstrated a nonuniform word usage, with many words unique to one or another journal. In this present study, word occurrence was examined in an expanded pool of medical text consisting of sixteen textbooks representing ten different levels of description: atom/ion, micromolecule, macromolecule, organelle, cell, tissue, organ, physiologic system, major body part (or multiple physiologic systems) and patient as a whole. Word usage was found to be nonuniform, with many words unique to specific levels. The presence of such usage regularities may provide a basis for facilitating the automatic classification and retrieval of medical text.
PMCID: PMC2245018
23.  Multiple epiphyseal dysplasia mutations in MATN3 cause misfolding of the A-domain and prevent secretion of mutant matrilin-3 
Human Mutation  2005;26(6):557-565.
Multiple epiphyseal dysplasia (MED) is a relatively common skeletal dysplasia that can present in childhood with a variable phenotype of short stature and pain and stiffness in the large joints, and often progresses to early-onset osteoarthritis in adulthood. Mutations in the matrilin-3 gene (MATN3) have recently been shown to underlie some forms of autosomal dominant MED. To date all MED mutations in matrilin-3 cluster in the single A-domain, suggesting that they may disrupt the structure and/or function of this important domain. To determine the effects of MATN3 mutations on the structure and function of matrilin-3 we expressed both normal and mutant matrilin-3 in mammalian cells. Wild-type (wt) matrilin-3 was efficiently secreted into conditioned medium, whereas mutant matrilin-3 was retained and accumulated within the cell. Furthermore, when the mutant A-domains were examined individually, they existed primarily in an unfolded conformation. Co-immunoprecipitation experiments demonstrated that the mutant A-domains were specifically associated with ERp72, a chaperone protein known to be involved in mediating disulfide bond formation. Light microscopy of cartilage from an MED patient with a MATN3 mutation showed the presence of intracellular material within the chondrocytes, whilst the overall matrix appeared normal. On electron micrographs, the inclusions noted at the light microscopy level appeared to be dilated cisternae of rough endoplasmic reticulum and immunohistochemical analysis confirmed that the retained protein was matrilin-3. In summary, the data presented in this paper suggest that MED caused by MATN3 mutations is the result of an intracellular retention of the mutant protein.
doi:10.1002/humu.20263
PMCID: PMC2726956  PMID: 16287128
cartilage; chondrodysplasias; matrilin-3; gene mutation; protein misfolding; chaperone protein; disease mechanism; multiple epiphyseal dysplasia

Results 1-23 (23)