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Geneticist, Pediatrician
16 years of experience
Accepting new patients

Credentials

Education ?

Medical School Score Rankings
University of Michigan Medical School (1996)
  •  
Top 25%

Awards & Distinctions ?

Associations
American Board of Pediatrics
American Board of Medical Genetics

Affiliations ?

Dr. Martin is affiliated with 3 hospitals.

Hospital Affiliations

Score

Rankings

  • University of Michigan Hospitals & Health Centers
    1500 E Medical Center Dr, Ann Arbor, MI 48109
    •  
    Top 25%
  • C.S. Mott Children's Hospital
    1500 E Medical Center Dr, Ann Arbor, MI 48109
  • University of Michigan Health System
  • Publications & Research

    Dr. Martin has contributed to 170 publications.
    Title Mature Middle and Inner Ears Express Chd7 and Exhibit Distinctive Pathologies in a Mouse Model of Charge Syndrome.
    Date April 2012
    Journal Hearing Research
    Excerpt

    Heterozygous mutations in the gene encoding chromodomain-DNA-binding-protein 7 (CHD7) cause CHARGE syndrome, a multiple anomaly condition which includes vestibular dysfunction and hearing loss. Mice with heterozygous Chd7 mutations exhibit semicircular canal dysgenesis and abnormal inner ear neurogenesis, and are an excellent model of CHARGE syndrome. Here we characterized Chd7 expression in mature middle and inner ears, analyzed morphological features of mutant ears and tested whether Chd7 mutant mice have altered responses to noise exposure and correlated those responses to inner and middle ear structure. We found that Chd7 is highly expressed in mature inner and outer hair cells, spiral ganglion neurons, vestibular sensory epithelia and middle ear ossicles. There were no obvious defects in individual hair cell morphology by prestin immunostaining or scanning electron microscopy, and cochlear innervation appeared normal in Chd7(Gt)(/+) mice. Hearing thresholds by auditory brainstem response (ABR) testing were elevated at 4 and 16 kHz in Chd7(Gt)(/+) mice, and there were reduced distortion product otoacoustic emissions (DPOAE). Exposure of Chd7(Gt)(/+) mice to broadband noise resulted in variable degrees of hair cell loss which inversely correlated with severity of stapedial defects. The degrees of hair cell loss and threshold shifts after noise exposure were more severe in wild type mice than in mutants. Together, these data indicate that Chd7(Gt)(/+) mice have combined conductive and sensorineural hearing loss, correlating with changes in both middle and inner ears.

    Title Genome Sequence and Analysis of the Tuber Crop Potato.
    Date August 2011
    Journal Nature
    Excerpt

    Potato (Solanum tuberosum L.) is the world's most important non-grain food crop and is central to global food security. It is clonally propagated, highly heterozygous, autotetraploid, and suffers acute inbreeding depression. Here we use a homozygous doubled-monoploid potato clone to sequence and assemble 86% of the 844-megabase genome. We predict 39,031 protein-coding genes and present evidence for at least two genome duplication events indicative of a palaeopolyploid origin. As the first genome sequence of an asterid, the potato genome reveals 2,642 genes specific to this large angiosperm clade. We also sequenced a heterozygous diploid clone and show that gene presence/absence variants and other potentially deleterious mutations occur frequently and are a likely cause of inbreeding depression. Gene family expansion, tissue-specific expression and recruitment of genes to new pathways contributed to the evolution of tuber development. The potato genome sequence provides a platform for genetic improvement of this vital crop.

    Title Multiple Recurrent De Novo Cnvs, Including Duplications of the 7q11.23 Williams Syndrome Region, Are Strongly Associated with Autism.
    Date August 2011
    Journal Neuron
    Excerpt

    We have undertaken a genome-wide analysis of rare copy-number variation (CNV) in 1124 autism spectrum disorder (ASD) families, each comprised of a single proband, unaffected parents, and, in most kindreds, an unaffected sibling. We find significant association of ASD with de novo duplications of 7q11.23, where the reciprocal deletion causes Williams-Beuren syndrome, characterized by a highly social personality. We identify rare recurrent de novo CNVs at five additional regions, including 16p13.2 (encompassing genes USP7 and C16orf72) and Cadherin 13, and implement a rigorous approach to evaluating the statistical significance of these observations. Overall, large de novo CNVs, particularly those encompassing multiple genes, confer substantial risks (OR = 5.6; CI = 2.6-12.0, p = 2.4 × 10(-7)). We estimate there are 130-234 ASD-related CNV regions in the human genome and present compelling evidence, based on cumulative data, for association of rare de novo events at 7q11.23, 15q11.2-13.1, 16p11.2, and Neurexin 1.

    Title Bone Properties Surrounding Hydroxyapatite-coated Custom Osseous Integrated Dental Implants.
    Date January 2011
    Journal Journal of Biomedical Materials Research. Part B, Applied Biomaterials
    Excerpt

    Calcium phosphate (hydroxyapatite or HA) coatings have been applied to Custom Osseous Integrated Implants (COIIs) to improve the quality of the bone-implant integration, yet little is known concerning the biomechanical properties of bone surrounding the HA-coated implants in humans over the long term. The purpose of this study was to characterize the mechanical and histomorphometric properties of the bone along the implant interface. Specimens were prepared from three similar mandibular implants that were functional in three female patients for about 11 years. Histomorphometric analyses showed bone-implant contact averaging 75% for all specimens. Area coverage of residual HA-coating ranged from 52 to 70%. When compared with previous studies, these results show a relatively high percentage of residual HA after a decade in vivo. Nanoindentation showed similar average values of hardness and modulus (p = 0.53 and p = 0.56, respectively) comparing bone adjacent to residual HA-coating and regions where the coating was absent. The elastic modulus was significantly lower for bone near the bone-implant interface (<200 μm) as compared with bone distant (>1000 μm) from the interface (p = 0.05), thereby reflecting different properties of the bone near these interfaces. Backscattered electron imaging showed darker gray levels which indicated decreased mineral content in bone adjacent to the implant, consistent with the nanoindentation results.

    Title Chd7 Functions in the Nucleolus As a Positive Regulator of Ribosomal Rna Biogenesis.
    Date December 2010
    Journal Human Molecular Genetics
    Excerpt

    De novo mutation of the gene encoding chromodomain helicase DNA-binding protein 7 (CHD7) is the primary cause of CHARGE syndrome, a complex developmental disorder characterized by the co-occurrence of a specific set of birth defects. Recent studies indicate that CHD7 functions as a transcriptional regulator in the nucleoplasm. Here, we report based on immunofluorescence and western blotting of subcellular fractions that CHD7 is also constitutively localized to the nucleolus, the site of rRNA transcription. Standard chromatin immunoprecipitation (ChIP) assays indicate that CHD7 physically associates with rDNA, a result that is also observable upon alignment of whole-genome CHD7 ChIP coupled with massively parallel DNA sequencing data to the rDNA reference sequence. ChIP-chop analyses demonstrate that CHD7 specifically associates with hypomethylated, active rDNA, suggesting a role as a positive regulator of rRNA synthesis. Consistent with this hypothesis, siRNA-mediated depletion of CHD7 results in hypermethylation of the rDNA promoter and a concomitant reduction of 45S pre-rRNA levels. Accordingly, cells overexpressing CHD7 show increased levels of 45S pre-rRNA compared with control cells. Depletion of CHD7 also reduced cell proliferation and protein synthesis. Lastly, compared with wild-type ES cells, the levels of 45S pre-rRNA are reduced in both Chd7(+/-) and Chd7(-/-) mouse ES cells, as well as in Chd7(-/-) whole mouse embryos and multiple tissues dissected from Chd7(+/-) embryos. Together with previously published studies, these results indicate that CHD7 dually functions as a regulator of both nucleoplasmic and nucleolar genes and provide a novel avenue for investigation into the pathogenesis of CHARGE syndrome.

    Title Chromatin Remodeling in Development and Disease: Focus on Chd7.
    Date November 2010
    Journal Plos Genetics
    Title Chromodomain Proteins in Development: Lessons from Charge Syndrome.
    Date October 2010
    Journal Clinical Genetics
    Excerpt

    In humans, heterozygous mutations in the adenosine triphosphate-dependent chromatin remodeling gene CHD7 cause CHARGE syndrome, a common cause of deaf-blindness, balance disorders, congenital heart malformations, and olfactory dysfunction with an estimated incidence of approximately 1 in 10,000 newborns. The clinical features of CHARGE in humans and mice are highly variable and incompletely penetrant, and most mutations appear to result in haploinsufficiency of functional CHD7 protein. Mice with heterozygous loss of function mutations in Chd7 are a good model for CHARGE syndrome, and analyses of mouse mutant phenotypes have begun to clarify a role for CHD7 during development and into adulthood. Chd7 heterozygous mutant mice have postnatal delayed growth, inner ear malformations, anosmia/hyposmia, and craniofacial defects, and Chd7 homozygous mutants are embryonic lethal. A central question in developmental biology is how chromodomain proteins like CHD7 regulate important developmental processes, and whether they directly activate or repress downstream gene transcription or act more globally to alter chromatin structure and/or function. CHD7 is expressed in a wide variety of tissues during development, suggesting that it has tissue-specific and developmental stage-specific roles. Here, we review recent and ongoing analyses of CHD7 function in mouse models and cell-based systems. These studies explore tissue-specific effects of CHD7 deficiency, known CHD7 interacting proteins, and downstream target sites for CHD7 binding. CHD7 is emerging as a critical regulator of important developmental processes in organs affected by human CHARGE syndrome.

    Title Prophossi: Automating Expert Validation of Phosphopeptide-spectrum Matches from Tandem Mass Spectrometry.
    Date September 2010
    Journal Bioinformatics (oxford, England)
    Excerpt

    Complex patterns of protein phosphorylation mediate many cellular processes. Tandem mass spectrometry (MS/MS) is a powerful tool for identifying these post-translational modifications. In high-throughput experiments, mass spectrometry database search engines, such as MASCOT provide a ranked list of peptide identifications based on hundreds of thousands of MS/MS spectra obtained in a mass spectrometry experiment. These search results are not in themselves sufficient for confident assignment of phosphorylation sites as identification of characteristic mass differences requires time-consuming manual assessment of the spectra by an experienced analyst. The time required for manual assessment has previously rendered high-throughput confident assignment of phosphorylation sites challenging.

    Title The Atp-dependent Chromatin Remodeling Enzyme Chd7 Regulates Pro-neural Gene Expression and Neurogenesis in the Inner Ear.
    Date September 2010
    Journal Development (cambridge, England)
    Excerpt

    Inner ear neurogenesis is positively regulated by the pro-neural bHLH transcription factors Ngn1 and NeuroD, but the factors that act upstream of this regulation are not well understood. Recent evidence in mouse and Drosophila suggests that neural development depends on proper chromatin remodeling, both for maintenance of neural stem cells and for proper neuronal differentiation. Here, we show that CHD7, an ATP-dependent chromatin remodeling enzyme mutated in human CHARGE syndrome, is necessary for proliferation of inner ear neuroblasts and inner ear morphogenesis. Conditional deletion of Chd7 in the developing otocyst using Foxg1-Cre resulted in cochlear hypoplasia and complete absence of the semicircular canals and cristae. Conditional knockout and null otocysts also had reductions in vestibulo-cochlear ganglion size and neuron number in combination with reduced expression of Ngn1, Otx2 and Fgf10, concurrent with expansion of the neural fate suppressor Tbx1 and reduced cellular proliferation. Heterozygosity for Chd7 mutations had no major effects on expression of otic patterning genes or on cell survival, but resulted in decreased proliferation within the neurogenic domain. These data indicate that epigenetic regulation of gene expression by CHD7 must be tightly coordinated for proper development of inner ear neuroblasts.

    Title Duplication 16p11.2 in a Child with Infantile Seizure Disorder.
    Date August 2010
    Journal American Journal of Medical Genetics. Part A
    Excerpt

    Submicroscopic recurrent 16p11.2 rearrangements are associated with several neurodevelopmental disorders, including autism, mental retardation, and schizophrenia. The common 16p11.2 region includes 24 known genes, of which 22 are expressed in the developing human fetal nervous system. As yet, the mechanisms leading to neurodevelopmental abnormalities and the broader phenotypes associated with deletion or duplication of 16p11.2 have not been clarified. Here we report a child with spastic quadriparesis, refractory infantile seizures, severe global developmental delay, hypotonia, and microcephaly, and a de novo 598 kb 16p11.2 microduplication. Family history is negative for any of these features in parents and immediate family members. Sequencing analyses showed no mutations in DOC2A, QPRT, and SEZ6L2, genes within the duplicated 16p11.2 region that have been implicated in neuronal function and/or seizure related phenotypes. The child's clinical course is consistent with a rare seizure disorder called malignant migrating partial seizure disorder of infancy, raising the possibility that duplication or disruption of genes in the 16p11.2 interval may contribute to this severe disorder.

    Title Molecular and Phenotypic Aspects of Chd7 Mutation in Charge Syndrome.
    Date April 2010
    Journal American Journal of Medical Genetics. Part A
    Excerpt

    CHARGE syndrome [coloboma of the eye, heart defects, atresia of the choanae, retardation of growth and/or development, genital and/or urinary abnormalities, and ear abnormalities (including deafness)] is a genetic disorder characterized by a specific and a recognizable pattern of anomalies. De novo mutations in the gene encoding chromodomain helicase DNA binding protein 7 (CHD7) are the major cause of CHARGE syndrome. Here, we review the clinical features of 379 CHARGE patients who tested positive or negative for mutations in CHD7. We found that CHARGE individuals with CHD7 mutations more commonly have ocular colobomas, temporal bone anomalies (semicircular canal hypoplasia/dysplasia), and facial nerve paralysis compared with mutation negative individuals. We also highlight recent genetic and genomic studies that have provided functional insights into CHD7 and the pathogenesis of CHARGE syndrome.

    Title The Phosphoproteome of Bloodstream Form Trypanosoma Brucei, Causative Agent of African Sleeping Sickness.
    Date November 2009
    Journal Molecular & Cellular Proteomics : Mcp
    Excerpt

    The protozoan parasite Trypanosoma brucei is the causative agent of human African sleeping sickness and related animal diseases, and it has over 170 predicted protein kinases. Protein phosphorylation is a key regulatory mechanism for cellular function that, thus far, has been studied in T.brucei principally through putative kinase mRNA knockdown and observation of the resulting phenotype. However, despite the relatively large kinome of this organism and the demonstrated essentiality of several T. brucei kinases, very few specific phosphorylation sites have been determined in this organism. Using a gel-free, phosphopeptide enrichment-based proteomics approach we performed the first large scale phosphorylation site analyses for T.brucei. Serine, threonine, and tyrosine phosphorylation sites were determined for a cytosolic protein fraction of the bloodstream form of the parasite, resulting in the identification of 491 phosphoproteins based on the identification of 852 unique phosphopeptides and 1204 phosphorylation sites. The phosphoproteins detected in this study are predicted from their genome annotations to participate in a wide variety of biological processes, including signal transduction, processing of DNA and RNA, protein synthesis, and degradation and to a minor extent in metabolic pathways. The analysis of phosphopeptides and phosphorylation sites was facilitated by in-house developed software, and this automated approach was validated by manual annotation of spectra of the kinase subset of proteins. Analysis of the cytosolic bloodstream form T. brucei kinome revealed the presence of 44 phosphorylated protein kinases in our data set that could be classified into the major eukaryotic protein kinase groups by applying a multilevel hidden Markov model library of the kinase catalytic domain. Identification of the kinase phosphorylation sites showed conserved phosphorylation sequence motifs in several kinase activation segments, supporting the view that phosphorylation-based signaling is a general and fundamental regulatory process that extends to this highly divergent lower eukaryote.

    Title Defects in Neural Stem Cell Proliferation and Olfaction in Chd7 Deficient Mice Indicate a Mechanism for Hyposmia in Human Charge Syndrome.
    Date July 2009
    Journal Human Molecular Genetics
    Excerpt

    Mutations in CHD7, a chromodomain gene, are present in a majority of individuals with CHARGE syndrome, a multiple anomaly disorder characterized by ocular Coloboma, Heart defects, Atresia of the choanae, Retarded growth and development, Genital hypoplasia and Ear anomalies. The clinical features of CHARGE syndrome are highly variable and incompletely penetrant. Olfactory dysfunction is a common feature in CHARGE syndrome and has been potentially linked to primary olfactory bulb defects, but no data confirming this mechanistic link have been reported. On the basis of these observations, we hypothesized that loss of Chd7 disrupts mammalian olfactory tissue development and function. We found severe defects in olfaction in individuals with CHD7 mutations and CHARGE, and loss of odor evoked electro-olfactogram responses in Chd7 deficient mice, suggesting reduced olfaction is due to a dysfunctional olfactory epithelium. Chd7 expression was high in basal olfactory epithelial neural stem cells and down-regulated in mature olfactory sensory neurons. We observed smaller olfactory bulbs, reduced olfactory sensory neurons, and disorganized epithelial ultrastructure in Chd7 mutant mice, despite apparently normal functional cilia and sustentacular cells. Significant reductions in the proliferation of neural stem cells and regeneration of olfactory sensory neurons in the mature Chd7(Gt/+) olfactory epithelium indicate critical roles for Chd7 in regulating neurogenesis. These studies provide evidence that mammalian olfactory dysfunction due to Chd7 haploinsufficiency is linked to primary defects in olfactory neural stem cell proliferation and may influence olfactory bulb development.

    Title Jalview Version 2--a Multiple Sequence Alignment Editor and Analysis Workbench.
    Date June 2009
    Journal Bioinformatics (oxford, England)
    Excerpt

    Jalview Version 2 is a system for interactive WYSIWYG editing, analysis and annotation of multiple sequence alignments. Core features include keyboard and mouse-based editing, multiple views and alignment overviews, and linked structure display with Jmol. Jalview 2 is available in two forms: a lightweight Java applet for use in web applications, and a powerful desktop application that employs web services for sequence alignment, secondary structure prediction and the retrieval of alignments, sequences, annotation and structures from public databases and any DAS 1.53 compliant sequence or annotation server. Availability: The Jalview 2 Desktop application and JalviewLite applet are made freely available under the GPL, and can be downloaded from www.jalview.org.

    Title The Bouquet of Grapevine (vitis Vinifera L. Cv. Cabernet Sauvignon) Flowers Arises from the Biosynthesis of Sesquiterpene Volatiles in Pollen Grains.
    Date June 2009
    Journal Proceedings of the National Academy of Sciences of the United States of America
    Excerpt

    Terpenoid volatiles are important information molecules that enable pollinators to locate flowers and may protect reproductive tissues against pathogens or herbivores. Inflorescences of grapevine (Vitis vinifera L.) are composed of tiny green flowers that produce an abundance of sesquiterpenoid volatiles. We demonstrate that male flower parts of grapevines are responsible for sesquiterpenoid floral scent formation. We describe temporal and spatial patterns of biosynthesis and release of floral volatiles throughout the blooming of V. vinifera L. cv. Cabernet Sauvignon. The biosynthesis of sesquiterpene volatiles, which are emitted with a light-dependent diurnal pattern early in the morning at prebloom and bloom, is localized to anthers and, more specifically, within the developing pollen grains. Valencene synthase (VvValCS) enzyme activity, which produces the major sesquiterpene volatiles of grapevine flowers, is present in anthers. VvValCS transcripts are most abundant in flowers at prebloom stages. Western blot analysis identified VvValCS protein in anthers, and in situ immunolabeling located VvValCS protein in pollen grains during bloom. Histochemical staining, as well as immunolabeling analysis by fluorescent microscopy and transmission electron microscopy, indicated that VvValCS localizes close to lipid bodies within the maturing microspore.

    Title Free Testosterone Levels, Attentional Control, and Processing Speed Performance in Aging Men.
    Date April 2009
    Journal Neuropsychology
    Excerpt

    Psychometric measures of processing speed are strong predictors of cognitive functioning with aging; however, the neurobiological mechanisms underlying this association remain unclear. Recently, the authors reported a negative association between calculated free testosterone levels (cEFT) and processing speed in men aged between 50 and 70 years (Martin, Wittert, Burns, & McPherson, 2008). Ex-Gaussian decomposition of reaction time (RT) distributions allows for the robust estimation of skew in the distribution, which may reflect poorer attentional control. In a reanalysis of data from this previous study, the authors examined the associations between age, cEFT levels, and ex-Gaussian parameters derived from four RT tasks as predictors of cognitive functioning performance in 96 middle-to-older aged men. Results indicated that cEFT levels were significantly associated with increased skew in the RT distribution (i.e., the exponential portion) but not with the estimates derived from the Gaussian portion of the curve. Further, path analysis across the entire data set showed that this association was a strong predictor of processing speed performance. Taken together these results suggest that cEFT levels moderate cognitive functioning performance in males via attentional control processes.

    Title A Novel Chromosome 19p13.12 Deletion in a Child with Multiple Congenital Anomalies.
    Date April 2009
    Journal American Journal of Medical Genetics. Part A
    Excerpt

    We describe a patient with multiple congenital anomalies including deafness, lacrimal duct stenosis, strabismus, bilateral cervical sinuses, congenital cardiac defects, hypoplasia of the corpus callosum, and hypoplasia of the cerebellar vermis. Mutation analysis of EYA1, SIX1, and SIX5, genes that underlie otofaciocervical and/or branchio-oto-renal syndrome, was negative. Pathologic diagnosis of the excised cervical sinus tracts was revised on re-examination to heterotopic salivary gland tissue. Using high resolution chromosomal microarray analysis, we identified a novel 2.52 Mb deletion at 19p13.12, which was confirmed by fluorescent in situ hybridization and demonstrated to be a de novo mutation by testing of the parents. Overall, deletions of chromosome 19p13 are rare.

    Title Kinomer V. 1.0: a Database of Systematically Classified Eukaryotic Protein Kinases.
    Date March 2009
    Journal Nucleic Acids Research
    Excerpt

    The regulation of protein function through reversible phosphorylation by protein kinases and phosphatases is a general mechanism controlling virtually every cellular activity. Eukaryotic protein kinases can be classified into distinct, well-characterized groups based on amino acid sequence similarity and function. We recently reported a highly sensitive and accurate hidden Markov model-based method for the automatic detection and classification of protein kinases into these specific groups. The Kinomer v. 1.0 database presented here contains annotated classifications for the protein kinase complements of 43 eukaryotic genomes. These span the taxonomic range and include fungi (16 species), plants (6), diatoms (1), amoebas (2), protists (1) and animals (17). The kinomes are stored in a relational database and are accessible through a web interface on the basis of species, kinase group or a combination of both. In addition, the Kinomer v. 1.0 HMM library is made available for users to perform classification on arbitrary sequences. The Kinomer v. 1.0 database is a continually updated resource where direct comparison of kinase sequences across kinase groups and across species can give insights into kinase function and evolution. Kinomer v. 1.0 is available at http://www.compbio.dundee.ac.uk/kinomer/.

    Title Deafness: Lack of Regulation Encourages Hair Cell Growth.
    Date February 2009
    Journal Gene Therapy
    Title A Novel Short Splice Variant of the Tumour Suppressor Lkb1 is Required for Spermiogenesis.
    Date November 2008
    Journal The Biochemical Journal
    Excerpt

    LKB1 was discovered as a tumour suppressor mutated in Peutz-Jeghers syndrome, and is a gene involved in cell polarity as well as an upstream protein kinase for members of the AMP-activated protein kinase family. We report that mammals express two splice variants caused by alternate usage of 3'-exons. LKB1(L) is the previously described form, while LKB1(S) is a novel form in which the last 63 residues are replaced by a unique 39-residue sequence lacking known phosphorylation (Ser(431)) and farnesylation (Cys(433)) sites. Both isoforms are widely expressed in rodent and human tissues, although LKB1(S) is particularly abundant in haploid spermatids in the testis. Male mice in which expression of Lkb1(S) is knocked out are sterile, with the number of mature spermatozoa in the epididymis being dramatically reduced, and those spermatozoa that are produced have heads with an abnormal morphology and are non-motile. These results identify a previously undetected variant of LKB1, and suggest that it has a crucial role in spermiogenesis and male fertility.

    Title Branchiootorenal Syndrome and Oculoauriculovertebral Spectrum Features Associated with Duplication of Six1, Six6, and Otx2 Resulting from a Complex Chromosomal Rearrangement.
    Date November 2008
    Journal American Journal of Medical Genetics. Part A
    Excerpt

    We report on a 26-month-old boy with developmental delay and multiple congenital anomalies, including many features suggestive of either branchiootorenal syndrome (BOR) or oculoauriculovertebral spectrum (OAVS). Chromosomal microarray analysis (CMA) initially revealed a copy-number gain with a single BAC clone (RP11-79M1) mapping to 14q23.1. FISH analysis showed that the third copy of this genomic region was inserted into the long arm of one chromosome 13. The same pattern was also seen in the chromosomes of the father, who has mental retardation, short stature, hypernasal speech, and minor craniofacial anomalies, including tall forehead, and crowded dentition. Subsequent whole genome oligonucleotide microarray analysis revealed an approximately 11.79 Mb duplication of chromosome 14q22.3-q23.3 and a loss of an approximately 4.38 Mb sequence in 13q21.31-q21.32 in both the propositus and his father and FISH supported the apparent association of the two events. Chromosome 14q22.3-q23.3 contains 51 genes, including SIX1, SIX6, and OTX2. A locus for branchiootic syndrome (BOS) has been mapped to 14q21.3-q24.3, and designated as branchiootic syndrome 3 (BOS3). Interestingly, mutations in SIX1 have been reported in patients with BOR/BOS3. We propose that the increased dosage of SIX1, SIX6, or OTX2 may be responsible for the BOR and OAVS-like features in this family.

    Title Bridging the Divide: Openness in Adoption and Postadoption Psychosocial Adjustment Among Birth and Adoptive Parents.
    Date October 2008
    Journal Journal of Family Psychology : Jfp : Journal of the Division of Family Psychology of the American Psychological Association (division 43)
    Excerpt

    Using 323 matched parties of birth mothers and adoptive parents, this study examined the association between the degree of adoption openness (e.g., contact and knowledge between parties) and birth and adoptive parents' postadoption adjustment shortly after the adoption placement (6 to 9 months). Data from birth fathers (N = 112), an understudied sample, were also explored. Openness was assessed by multiple informants. Results indicated that openness was significantly related to satisfaction with adoption process among adoptive parents and birth mothers. Increased openness was positively associated with birth mothers' postplacement adjustment, as indexed by birth mothers' self-reports and the interviewers' impression of birth mothers' adjustment. Birth fathers' report of openness was associated with their greater satisfaction with the adoption process and better postadoption adjustment.

    Title Cre Fate Mapping Reveals Lineage Specific Defects in Neuronal Migration with Loss of Pitx2 Function in the Developing Mouse Hypothalamus and Subthalamic Nucleus.
    Date August 2008
    Journal Molecular and Cellular Neurosciences
    Excerpt

    Establishment of neuronal diversity is a central topic in developmental neurobiology. Prior studies implicated Pitx2, a paired-like homeodomain transcription factor, in mouse subthalamic nucleus neuronal development, but precise stages of neuronal differentiation affected (migration, axon outgrowth, fate specification) and underlying mechanisms were unknown. Here we report lineage tracing experiments using Pitx2(cre/+), Pitx2(cre/null), and conditional nuclear lacZ reporter mice to track embryonic Pitx2 expressing neurons. Migration of subthalamic nucleus and hypothalamic neurons was severely arrested in Pitx2(cre/null) embryos, and subclasses of subthalamic nucleus neurons identified by Lmx1b, Foxp1, and Foxp2-gene expression revealed differing sensitivities to Pitx2 dosage. Interestingly, embryonic subthalamic nucleus development was unaffected in Lmx1b null mice, suggesting that Pitx2 and Lmx1b act via independent genetic pathways. These data provide the first direct evidence for Pitx2-dependent neuronal migration in the developing hypothalamus, and demonstrate that complex transcriptional networks regulate regional specialization of distinct hypothalamic and subthalamic nucleus neurons.

    Title Taro: a Target Optimisation System for Structural Biology.
    Date August 2008
    Journal Nucleic Acids Research
    Excerpt

    TarO (http://www.compbio.dundee.ac.uk/taro) offers a single point of reference for key bioinformatics analyses relevant to selecting proteins or domains for study by structural biology techniques. The protein sequence is analysed by 17 algorithms and compared to 8 databases. TarO gathers putative homologues, including orthologues, and then obtains predictions of properties for these sequences including crystallisation propensity, protein disorder and post-translational modifications. Analyses are run on a high-performance computing cluster, the results integrated, stored in a database and accessed through a web-based user interface. Output is in tabulated format and in the form of an annotated multiple sequence alignment (MSA) that may be edited interactively in the program Jalview. TarO also simplifies the gathering of additional annotations via the Distributed Annotation System, both from the MSA in Jalview and through links to Dasty2. Routes to other information gateways are included, for example to relevant pages from UniProt, COG and the Conserved Domains Database. Open access to TarO is available from a guest account with private accounts for academic use available on request. Future development of TarO will include further analysis steps and integration with the Protein Information Management System (PIMS), a sister project in the BBSRC 'Structural Proteomics of Rational Targets' initiative.

    Title Endogenous Testosterone Levels, Mental Rotation Performance, and Constituent Abilities in Middle-to-older Aged Men.
    Date May 2008
    Journal Hormones and Behavior
    Excerpt

    Evidence from both human and animal studies suggests that gonadal steroids, such as testosterone, exert activational effects on adult spatial behavior. Endogenous testosterone levels decline gradually but variably as men age; it remains to be shown whether these decreases are associated with age-related declines in visuo-spatial performance or constituent abilities indicative of generalized age-related cognitive decline. Ninety-six healthy, community dwelling men aged between 38 and 69 years completed the Vandenberg and Kuse Mental Rotation Test (MRT) together with a battery of tests including processing speed, executive function, perceptual discrimination, working memory, and reaction time measures. Significant main effects of tertiles of calculated free testosterone levels (cEFT) were found on composite measures of processing speed, executive function, and perceptual discrimination ability in a subset of men aged over 50 years in age and crystallized intelligence controlled analyses; higher cEFT levels were associated with poorer performance. Hierarchical multiple regression and path analyses on the whole data set showed that cEFT levels negatively moderated processing speed performance, which in turn predicted both working memory and MRT performance with aging. Together these data suggest that age-related declines in endogenous testosterone levels in healthy middle-to-older aged men are not associated with generalized age-related cognitive decline.

    Title Characterization of Progenitor Domains in the Developing Mouse Thalamus.
    Date January 2008
    Journal The Journal of Comparative Neurology
    Excerpt

    To understand the molecular basis of the specification of thalamic nuclei, we analyzed the expression patterns of various transcription factors and defined progenitor cell populations in the embryonic mouse thalamus. We show that the basic helix-loop-helix (bHLH) transcription factor Olig3 is expressed in the entire thalamic ventricular zone and the zona limitans intrathalamica (ZLI). Next, we define two distinct progenitor domains within the thalamus, which we name pTH-R and pTH-C, located caudal to the ZLI. pTH-R is immediately caudal to the ZLI and expresses Nkx2.2, Mash1, and Olig3. pTH-C is caudal to pTH-R and expresses Ngn1, Ngn2, and Olig3. Short-term lineage analysis of Olig3-, Mash1-, Ngn1-, and Ngn2-expressing progenitor cells as well as tracing the Pitx2 cell lineage suggests that pTH-C is the only major source of thalamic nuclei containing neurons that project to the cerebral cortex, whereas pTH-R and ZLI are likely to produce distinct postmitotic populations outside of the cortex-projecting part of the thalamus. To determine if pTH-C is composed of subdomains, we characterized expression of the homeodomain protein Dbx1 and the bHLH protein Olig2. We show that Dbx1 is expressed in caudodorsal-high to rostroventral-low gradient within pTH-C. Analysis of heterozygous Dbx1(nlslacZ) knockin mice demonstrated that Dbx1-expressing progenitors preferentially give rise to caudodorsal thalamic nuclei. Olig2 is expressed in an opposite gradient within pTH-C to that of Dbx1. These results establish the molecular heterogeneity within the progenitor cells of the thalamus, and suggest that such heterogeneity contributes to the specification of thalamic nuclei.

    Title Defects in Vestibular Sensory Epithelia and Innervation in Mice with Loss of Chd7 Function: Implications for Human Charge Syndrome.
    Date December 2007
    Journal The Journal of Comparative Neurology
    Excerpt

    CHD7 is a chromodomain gene mutated in CHARGE syndrome, a multiple anomaly condition characterized by ocular coloboma, heart defects, atresia of the choanae, retarded growth and development, genital hypoplasia, and ear defects including deafness and semicircular canal dysgenesis. Mice with heterozygous Chd7 deficiency have circling behavior and semicircular canal defects and are an excellent animal model for exploring the pathogenesis of CHARGE features. Inner ear vestibular defects have been characterized in heterozygous Chd7-deficient embryos and early postnatal mice, but it is not known whether vestibular defects persist throughout adulthood in Chd7-deficient mice or whether the vestibular sensory epithelia and their associated innervation and function are intact. Here we describe a detailed analysis of inner ear vestibular structures in mature mice that are heterozygous for a Chd7-deficient, gene-trapped allele (Chd7(Gt/+)). Chd7(Gt/+) mice display variable asymmetric lateral and posterior semicircular canal malformations, as well as defects in vestibular sensory epithelial innervation despite the presence of intact hair cells in the target organs. These observations have important functional implications for understanding the clinical manifestations of CHD7 mutations in humans and for designing therapies to treat inner ear vestibular dysfunction.

    Title Steroids on the Job: an Emerging Problem.
    Date October 2007
    Journal Occupational Health & Safety (waco, Tex.)
    Title Loss of Chd7 Function in Gene-trapped Reporter Mice is Embryonic Lethal and Associated with Severe Defects in Multiple Developing Tissues.
    Date October 2007
    Journal Mammalian Genome : Official Journal of the International Mammalian Genome Society
    Excerpt

    CHD7 is a novel chromodomain gene mutated in 60%-80% of humans with CHARGE syndrome, a multiple congenital anomaly condition characterized by ocular coloboma, heart defects, atresia of the choanae, retarded growth and development, genital hypoplasia, and characteristic ear abnormalities including deafness. Phenotypic features of CHARGE are highly variable and incompletely penetrant. To explore developmental roles of CHD7, we generated mice carrying the Chd7(Gt) allele from a Chd7-deficient, gene-trapped lacZ reporter ES cell line. RT-PCR of embryo RNA demonstrated significantly reduced levels of wild-type transcript in Chd7(Gt/Gt) embryos. Chd7(Gt/Gt) embryos survive only up to embryonic day 10.5 (E10.5). Chd7(Gt/+) male and female mice are viable, small, and exhibit variable degrees of head-bobbing and circling, consistent with vestibular dysfunction. Paint-filling of E16.5 heterozygous inner ears revealed defects of the semicircular canals. The pattern of beta-galactosidase activity in Chd7(Gt/+) embryos mimics Chd7 mRNA expression in wild-type embryos, confirming the fidelity of the lacZ reporter. We observed tissue-specific beta-galactosidase in the E12.5 and E14.5 Chd7(Gt/+) brain, pituitary, ear, heart, and craniofacial structures, indicating survival of Chd7(Gt/+) cells in CHARGE-relevant organs. These studies demonstrate the utility of Chd7(Gt) as a reporter-tagged loss-of-function allele for future studies exploring developmental mechanisms of Chd7 deficiency.

    Title Draft Genome of the Filarial Nematode Parasite Brugia Malayi.
    Date September 2007
    Journal Science (new York, N.y.)
    Excerpt

    Parasitic nematodes that cause elephantiasis and river blindness threaten hundreds of millions of people in the developing world. We have sequenced the approximately 90 megabase (Mb) genome of the human filarial parasite Brugia malayi and predict approximately 11,500 protein coding genes in 71 Mb of robustly assembled sequence. Comparative analysis with the free-living, model nematode Caenorhabditis elegans revealed that, despite these genes having maintained little conservation of local synteny during approximately 350 million years of evolution, they largely remain in linkage on chromosomal units. More than 100 conserved operons were identified. Analysis of the predicted proteome provides evidence for adaptations of B. malayi to niches in its human and vector hosts and insights into the molecular basis of a mutualistic relationship with its Wolbachia endosymbiont. These findings offer a foundation for rational drug design.

    Title The 20th International Mammalian Genome Conference Meeting Report.
    Date August 2007
    Journal Mammalian Genome : Official Journal of the International Mammalian Genome Society
    Title Testosterone and Cognitive Function in Ageing Men: Data from the Florey Adelaide Male Ageing Study (famas).
    Date July 2007
    Journal Maturitas
    Excerpt

    OBJECTIVES: Recent evidence suggests that declining testosterone levels in ageing males may be associated with both normal and pathological cognitive ageing. The aim of the present analyses was to investigate whether endogenous gonadal steroid levels in males mediate or moderate the associations between age and performance on neuropsychological measures of verbal memory, executive function, and processing speed. METHODS: A cross-sectional analysis of the baseline data from 1046 community-dwelling men aged 35-80 years participating in the Florey Adelaide Male Ageing Study (FAMAS). Multiply adjusted analyses included participants' history of medical conditions, anthropometric measurements, medication use, smoking status, alcohol use and mood. Hormone measurements included total testosterone (TT), bioavailable testosterone (BT), calculated free testosterone (cEFT), oestradiol (E2), sex hormone binding globulin (SHBG), follicle stimulating hormone (FSH), and lutenising hormone (LH). Neuropsychological tests included the Fuld Object Memory Evaluation (FOME), Trails A and Trails B. RESULTS: In multiply adjusted analyses, higher cEFT and TT levels were associated with both poorer verbal memory and executive function performance and faster processing speed. cEFT levels were found to moderate the relationship between age and verbal memory performance quadratically and to mediate the relationship between age and processing speed. CONCLUSION: The results from this study suggest that higher levels of endogenous testosterone, particularly in the elderly, may have deleterious effects on cognitive functioning in men.

    Title Gonadal Steroids and Visuo-spatial Abilities in Adult Males: Implications for Generalized Age-related Cognitive Decline.
    Date June 2007
    Journal The Aging Male : the Official Journal of the International Society for the Study of the Aging Male
    Excerpt

    The relationship between the gonadal steroids, testosterone and estrogen, and individual and group differences in performance on some cognitive tasks remains unclear but sex differences favoring males on some tests of visuo-spatial ability are large and robust. This aim of this review is to assess evidence for both organizational and activational effects of gonadal steroids as the principle cause of sex difference in visuo-spatial ability. Additionally, the implications of this relationship are discussed in the context of decreasing levels of gonadal steroids in aging males and psychological theories of generalized age-related cognitive decline. Based upon human and non-human research gonadal steroids have organizational effects on visuo-spatial ability in adulthood. Activational effects of gonadal steroids on visuo-spatial ability appear most dominant in older men and are necessary for maintaining optimal visuo-spatial ability; randomized clinical trials show that testosterone supplementation improves performance. Additionally, decreasing gonadal steroid levels in aging males may contribute to generalized age-related cognitive decline. Future supplementation studies in men should attempt to control for constituent abilities related to visuo-spatial task performance, and investigate interactions between dosage levels and baseline gonadal status. Further future animal research is required to investigate changes in gonadal steroid levels and their relationship to neurotransmitter systems, neural plasticity, and behavioral correlates.

    Title Idiopathic Primary Chylopericardium in a Dog.
    Date January 2007
    Journal Journal of the American Veterinary Medical Association
    Excerpt

    CASE DESCRIPTION: A 7-year-old spayed female Labrador Retriever was evaluated because of pericardial effusion. CLINICAL FINDINGS: The dog had a history of decreased appetite and exercise intolerance of 3 days' duration. Thoracic radiography performed by the referring veterinarian revealed a large cardiac silhouette. Heart sounds were muffled. Echocardiographic findings were indicative of severe pericardial effusion with cardiac tamponade; no pleural effusion was identified. Pericardiocentesis yielded a considerable amount of chylous fluid. A diagnosis of chylopericardium in the absence of pleural effusion was made. TREATMENT AND OUTCOME: Conservative management was not effective, and subtotal pericardectomy and thoracic duct ligation were recommended. Surgery was postponed by the owners for 25 days, at which time the dog had both chylopericardium and chylothorax. The dog underwent subtotal pericardectomy and thoracic duct ligation; to delineate the thoracic duct, intraoperative lymphangiography was performed by injection of a radiopaque contrast agent directly into a mesenteric lymph node and subsequent injection of methylene blue solution into another mesenteric lymph node. Surgical treatment resulted in complete resolution of the clinical signs and pleural effusion. CLINICAL RELEVANCE: To the authors' knowledge, this is the first report of the development of chylopericardium prior to development of chylothorax in a dog. Treatment with thoracic duct ligation and pericardectomy resulted in complete resolution of the effusion and clinical signs.

    Title Cytolytic T-cell Clones Define Hla-a2-restricted Human Cutaneous Melanoma Peptide Epitopes: Correlation with T-cell Receptor Usage.
    Date October 2006
    Journal The Cancer Journal from Scientific American
    Excerpt

    PURPOSE: We studied the T-cell receptor alpha chain and beta chain variable region usage in HLA-A2-restricted and melanoma-specific T lymphocytes and correlated such T-cell receptor usage with HLA-A2-presented peptide-specific T-cell recognition. MATERIALS AND METHODS: Tumor-infiltrating lymphocytes were isolated from a metastatic melanoma lesion and cloned by limiting dilution. Clonal and oligoclonal tumor-infiltrating lymphocytes were analyzed for major histocompatibility complex class I--presented melanoma peptide recognition by using acid-eluted and high-performance liquid chromatography--fractionated melanoma peptides presented by HLA-A2 as targets. The T-cell receptor variable regions of the alpha and beta chains of each individual T-cell clone or oligoclonal T-cell population were analyzed by mRNA extraction and reverse transcribed cDNA by polymerase chain reaction using a panel of T-cell receptor alpha and beta variable region specific primers. RESULTS: We demonstrated that individual T-cell clones are capable of recognizing peptides within multiple high-performance liquid chromatography fractions containing melanoma epitopes, and that individual high-performance liquid chromatography fractions containing melanoma epitopes can be recognized by T-cell clones exhibiting limited usage of the T-cell receptor alpha and beta variable region chains. DISCUSSION: These results confirm the heterogeneity of T-cell-defined melanoma antigens in a single individual and suggest the possibility of developing novel antimelanoma therapeutic reagents using either peptides (as immunogens) or the T-cell receptors themselves (as gene therapy when introduced into lymphoid effectors).

    Title Nestin-cre Mediated Deletion of Pitx2 in the Mouse.
    Date September 2006
    Journal Genesis (new York, N.y. : 2000)
    Excerpt

    Nestin-Cre mice are widely used to generate gene deletions in the developing brain. Surprisingly, fewNestin-Cre lines have been characterized for their temporal and brain region-specific recombination. In addition, some Nestin-Cre lines express Cre outside the central nervous system, making it difficult to choose appropriate lines for targeting genes with brain region-restricted expression. Here we describe the properties of a Nestin-Cre transgenic line and its use for conditional deletions of Pitx2, a paired-like homeodomain transcription factor. We report that Nestin-Cre conditional Pitx2 mutant mice have ocular and craniofacial defects consistent with the role of human PITX2 in Rieger syndrome. Conditional mutants exhibit defects in midbrain neuronal development similar to those in Pitx2 homozygous null embryos, but lack the abnormalities in subthalamic nucleus neurons that occur with complete loss of Pitx2 function. These data indicate that normal differentiation of midbrain neurons depends upon adequate Pitx2 function during the period of active neurogenesis.

    Title Video Capsule Endoscopy: Clinical Relevance of Capsule Endoscopy Findings.
    Date July 2006
    Journal The American Surgeon
    Excerpt

    Video capsule endoscopy (VCE) is a novel diagnostic tool for noninvasively visualizing the lumen of the entire small intestine. It is especially useful in identifying the source of obscure small intestinal bleeding. However, VCE is not always optimal for localizing small bowel lesions. Several studies show VCE to be markedly superior to standard diagnostic techniques although the true clinical relevance of many of the capsule endoscopic findings remain unknown. We present two case reports of VCE findings that resulted in surgical intervention but were found to be benign lesions on definitive pathological examination. The actual clinical relevance of many of the lesions found on VCE thus remains to be demonstrated.

    Title Multifocal Osteoma Cutis in a Golden Retriever.
    Date June 2006
    Journal The Canadian Veterinary Journal. La Revue Vétérinaire Canadienne
    Excerpt

    A 10-year-old, spayed female, obese golden retriever, presented for immune-mediated thrombocytopenia, was successfully managed with the administration of vincristine and prednisone. However, 6 mo after discontinuing corticosteroid therapy because of suspected iatrogenic hyperglucocorticoidism, the patient was presented with multiple, firm, bilaterally symmetric, dermal masses composed histologically of differentiated cortical bone.

    Title Identification of Multiple Distinct Snf2 Subfamilies with Conserved Structural Motifs.
    Date June 2006
    Journal Nucleic Acids Research
    Excerpt

    The Snf2 family of helicase-related proteins includes the catalytic subunits of ATP-dependent chromatin remodelling complexes found in all eukaryotes. These act to regulate the structure and dynamic properties of chromatin and so influence a broad range of nuclear processes. We have exploited progress in genome sequencing to assemble a comprehensive catalogue of over 1300 Snf2 family members. Multiple sequence alignment of the helicase-related regions enables 24 distinct subfamilies to be identified, a considerable expansion over earlier surveys. Where information is known, there is a good correlation between biological or biochemical function and these assignments, suggesting Snf2 family motor domains are tuned for specific tasks. Scanning of complete genomes reveals all eukaryotes contain members of multiple subfamilies, whereas they are less common and not ubiquitous in eubacteria or archaea. The large sample of Snf2 proteins enables additional distinguishing conserved sequence blocks within the helicase-like motor to be identified. The establishment of a phylogeny for Snf2 proteins provides an opportunity to make informed assignments of function, and the identification of conserved motifs provides a framework for understanding the mechanisms by which these proteins function.

    Title A Preliminary Crystallographic Analysis of the Putative Mevalonate Diphosphate Decarboxylase from Trypanosoma Brucei.
    Date June 2006
    Journal Acta Crystallographica. Section F, Structural Biology and Crystallization Communications
    Excerpt

    Mevalonate diphosphate decarboxylase catalyses the last and least well characterized step in the mevalonate pathway for the biosynthesis of isopentenyl pyrophosphate, an isoprenoid precursor. A gene predicted to encode the enzyme from Trypanosoma brucei has been cloned, a highly efficient expression system established and a purification protocol determined. The enzyme gives monoclinic crystals in space group P2(1), with unit-cell parameters a = 51.5, b = 168.7, c = 54.9 A, beta = 118.8 degrees. A Matthews coefficient VM of 2.5 A3 Da(-1) corresponds to two monomers, each approximately 42 kDa (385 residues), in the asymmetric unit with 50% solvent content. These crystals are well ordered and data to high resolution have been recorded using synchrotron radiation.

    Title Wound-induced Terpene Synthase Gene Expression in Sitka Spruce That Exhibit Resistance or Susceptibility to Attack by the White Pine Weevil.
    Date May 2006
    Journal Plant Physiology
    Excerpt

    We analyzed the expression pattern of various terpene synthase (TPS) genes in response to a wounding injury applied to the apical leader of Sitka spruce (Picea sitchensis Bong. Carr.) genotypes known to be resistant (R) or susceptible (S) to white pine weevil (Pissodes strobi Peck.) attack. The purpose was to test if differences in constitutive or wound-induced TPS expression can be associated with established weevil resistance. All wounding treatments were conducted on 9-year-old R and S trees growing under natural field conditions within the range of variation for weevil R and S genotypes. Representative cDNAs of the monoterpene synthase (mono-TPS), sesquiterpene synthase (sesqui-TPS), and diterpene synthase (di-TPS) classes were isolated from Sitka spruce to assess TPS transcript levels. Based on amino acid sequence similarity, the cDNAs resemble Norway spruce (Picea abies) (-)-linalool synthase (mono-TPS; PsTPS-Linl) and levopimaradiene/abietadiene synthase (di-TPS; PsTPS-LASl), and grand fir (Abies grandis) delta-selinene synthase (sesqui-TPS; PsTPS-Sell). One other mono-TPS was functionally identified as (-)-limonene synthase (PsTPS-Lim). No significant difference in constitutive expression levels for these TPSs was detected between R and S trees. However, over a postwounding period of 16 d, only R trees exhibited significant transcript accumulation for the mono- and sesqui-TPS tested. Both R and S trees exhibited a significant accumulation of PsTPS-LASl transcripts. An assessment of traumatic resin duct formation in wounded leaders showed that both R and S trees responded by forming traumatic resin ducts; however, the magnitude of this response was significantly greater in R trees. Collectively, our data imply that the induced resinosis response is an important aspect of defense in weevil R Sitka spruce trees growing under natural conditions.

    Title Personality Disorders in People with Learning Disabilities: Follow-up of a Community Survey.
    Date February 2006
    Journal Journal of Intellectual Disability Research : Jidr
    Excerpt

    BACKGROUND: A sample of community-based service users with intellectual disability (ID) was re-examined after 5 years to determine the impact of a diagnosis of personality disorder (PD). METHODS: Seventy-five of the original 101 participants were followed up. Of these, 21 people had a PD identified during the original study. RESULTS: Compared with controls, people with a PD were significantly more likely to receive central nervous system (CNS) drugs, have more contact with psychiatric services, show increased offending behaviour, score higher on the Aberrant Behaviour Checklist and score above the threshold on the Psychiatric Assessment Schedule for Adults with Developmental Disability (PAS-ADD). Participants with PD recorded were more likely to have a recorded psychiatric disorder, have contact with specialist teams, and have more hospital admissions. CONCLUSION: People with ID and PD are able to live in the community with specialist support but improved assessment, diagnosis and support services need to be targeted more effectively to them.

    Title Pitx2, Beta-catenin and Lef-1 Interact to Synergistically Regulate the Lef-1 Promoter.
    Date September 2005
    Journal Journal of Cell Science
    Excerpt

    PITX2, beta-catenin and lymphoid enhancer factor (LEF-1) are required for the inductive formation of several epithelial-derived organs, including teeth. Lef-1 is expressed in the dental epithelium after Pitx2, and both factors have overlapping expression patterns in the tooth bud and cap stages. Our analysis of Pitx2-/- mutant mice showed reduced Lef-1 expression in facial tissues by RT-PCR and quantitative RT-PCR. Consistent with these results we show that the human 2.5 kb LEF-1 promoter is activated by PITX2. Furthermore, the LEF-1 promoter is differentially activated by PITX2 isoforms, which are co-expressed in dental epithelium. The 2.5 kb LEF-1 promoter contains two regions that act to inhibit its transcription in concert with PITX2. The proximal region contains a Wnt-responsive element (WRE) that attenuates PITX2 activation. LEF-1 cannot autoregulate LEF-1 expression; however co-transfection of PITX2 and LEF-1 result in a synergistic activation of the 2.5 kb LEF-1 promoter. LEF-1 specifically interacts with the PITX2 C-terminal tail. Deletion of a distal 800 bp segment of the LEF-1 promoter resulted in enhanced PITX2 activation, and increased synergistic activation in the presence of LEF-1. Furthermore, beta-catenin in combination with PITX2 synergistically activates the LEF-1 promoter and this activation is independent of the Wnt-responsive element. beta-catenin directly interacts with PITX2 to synergistically regulate LEF-1 expression. We show a new mechanism where LEF-1 expression is regulated through PITX2, LEF-1 and beta-catenin direct physical interactions. LEF-1 and beta-catenin interactions with PITX2 provide new mechanisms for the regulation of PITX2 transcriptional activity.

    Title Retrotransposon Populations of Vicia Species with Varying Genome Size.
    Date August 2005
    Journal Molecular Genetics and Genomics : Mgg
    Excerpt

    The (non-LTR) LINE and Ty3-gypsy-type LTR retrotransposon populations of three Vicia species that differ in genome size (Vicia faba, Vicia melanops and Vicia sativa) have been characterised. In each species the LINE retrotransposons comprise a complex, very heterogeneous set of sequences, while the Ty3-gypsy elements are much more homogeneous. Copy numbers of all three retrotransposon groups (Ty1-copia, Ty3-gypsy and LINE) in these species have been estimated by random genomic sequencing and Southern hybridisation analysis. The Ty3-gypsy elements are extremely numerous in all species, accounting for 18-35% of their genomes. The Ty1-copia group elements are somewhat less abundant and LINE elements are present in still lower amounts. Collectively, 20-45% of the genomes of these three Vicia species are comprised of retrotransposons. These data show that the three retrotransposon groups have proliferated to different extents in members of the Vicia genus and high proliferation has been associated with homogenisation of the retrotransposon population.

    Title The Genome of the African Trypanosome Trypanosoma Brucei.
    Date July 2005
    Journal Science (new York, N.y.)
    Excerpt

    African trypanosomes cause human sleeping sickness and livestock trypanosomiasis in sub-Saharan Africa. We present the sequence and analysis of the 11 megabase-sized chromosomes of Trypanosoma brucei. The 26-megabase genome contains 9068 predicted genes, including approximately 900 pseudogenes and approximately 1700 T. brucei-specific genes. Large subtelomeric arrays contain an archive of 806 variant surface glycoprotein (VSG) genes used by the parasite to evade the mammalian immune system. Most VSG genes are pseudogenes, which may be used to generate expressed mosaic genes by ectopic recombination. Comparisons of the cytoskeleton and endocytic trafficking systems with those of humans and other eukaryotic organisms reveal major differences. A comparison of metabolic pathways encoded by the genomes of T. brucei, T. cruzi, and Leishmania major reveals the least overall metabolic capability in T. brucei and the greatest in L. major. Horizontal transfer of genes of bacterial origin has contributed to some of the metabolic differences in these parasites, and a number of novel potential drug targets have been identified.

    Title Gotcha: a New Method for Prediction of Protein Function Assessed by the Annotation of Seven Genomes.
    Date July 2005
    Journal Bmc Bioinformatics
    Excerpt

    BACKGROUND: The function of a novel gene product is typically predicted by transitive assignment of annotation from similar sequences. We describe a novel method, GOtcha, for predicting gene product function by annotation with Gene Ontology (GO) terms. GOtcha predicts GO term associations with term-specific probability (P-score) measures of confidence. Term-specific probabilities are a novel feature of GOtcha and allow the identification of conflicts or uncertainty in annotation. RESULTS: The GOtcha method was applied to the recently sequenced genome for Plasmodium falciparum and six other genomes. GOtcha was compared quantitatively for retrieval of assigned GO terms against direct transitive assignment from the highest scoring annotated BLAST search hit (TOPBLAST). GOtcha exploits information deep into the 'twilight zone' of similarity search matches, making use of much information that is otherwise discarded by more simplistic approaches.At a P-score cutoff of 50%, GOtcha provided 60% better recovery of annotation terms and 20% higher selectivity than annotation with TOPBLAST at an E-value cutoff of 10(-4). CONCLUSIONS: The GOtcha method is a useful tool for genome annotators. It has identified both errors and omissions in the original Plasmodium falciparum annotation and is being adopted by many other genome sequencing projects.

    Title Protein Kinase C Phosphorylation Modulates N- and C-terminal Regulatory Activities of the Pitx2 Homeodomain Protein.
    Date June 2005
    Journal Biochemistry
    Excerpt

    PKC phosphorylation regulates PITX2 DNA binding and transcriptional activity. Mutation of individual PKC sites demonstrates the functional regulation of PITX2 through phosphorylation. Immunoprecipitation of PITX2 and a PITX2 PKC mutant protein reveal specific in vivo phosphorylation by PKC in transfected cells. The transcriptional activity of PITX2 is negatively regulated by N-terminal phosphorylation and positively regulated by C-terminal phosphorylation. We demonstrate a mechanism of increased PITX2 transcriptional activation through protein interactions facilitated by phosphorylation of the PITX2 C-terminal tail. Phosphorylation of the PITX2 C terminus enhances the interaction with cellular factors. In corroboration with the PITX2 PKC functional studies, a newly identified C-terminal PITX2 mutation associated with Axenfeld-Rieger syndrome (ARS) demonstrates reduced phosphorylation. This mutation (PITX2 DeltaT1261) creates a frameshift mutation in codon 227 resulting in 11 novel amino acids downstream followed by premature truncation of the protein. Three PKC sites in the C-terminal tail and OAR domain are deleted, which results in decreased transcriptional activation. PITX2 DeltaT1261 is unable to interact with a cellular factor to synergistically activate transcription and demonstrates the first link of ARS with defective PITX2 protein interactions. Gene expression profiling of homozygous Pitx2 mutant mouse tissue reveals decreased Dlx2 expression as a potential molecular basis for developmental defects associated with ARS patients. Overall, phosphorylation imparts another level of regulation to the activity of the PITX2 homeodomain protein during development.

    Title Genetics of Subthalamic Nucleus in Development and Disease.
    Date May 2005
    Journal Experimental Neurology
    Excerpt

    The subthalamic nucleus (STN) is a crucial node in the basal ganglia. Clinical success in targeting the STN for deep brain stimulation in Parkinson's disease patients has prompted increased interest in understanding STN biology. In this report, we discuss recent evidence for transcription factor mediated regulation of STN development. We also review STN developmental neurobiology and known patterns of gene expression in the developing and mature STN.

    Title Skewed X-inactivation in Carriers Establishes Linkage in an X-linked Deafness-mental Retardation Syndrome.
    Date May 2005
    Journal American Journal of Medical Genetics. Part A
    Title Brain Glutamine by Mrs in a Patient with Urea Cycle Disorder and Coma.
    Date April 2005
    Journal Pediatric Neurology
    Excerpt

    In patients who undergo metabolic decompensation from urea cycle disorders, cerebrospinal fluid glutamine level may be a better marker of cerebral dysfunction than blood ammonia or glutamine levels. However, obtaining cerebrospinal fluid by lumbar puncture carries risk in these acutely ill patients with cerebral edema. Using magnetic resonance single voxel spectroscopy as an alternative to cerebrospinal fluid analysis, elevated brain glutamine/glutamate complex levels were detected in a patient with carbamyl phosphate synthetase deficiency, who had been comatose for many days after normalization of blood ammonia and improvement in blood glutamine levels. Brain glutamine by single voxel spectroscopy decreased toward normal with neurologic recovery. We conclude that brain glutamine may be a better marker than serum ammonia for the management of urea cycle disorders, particularly in patients with prolonged mental status changes.

    Title Assessment of a Contrast Medium As an Adjunct to Endodontic Radiography.
    Date January 2005
    Journal International Endodontic Journal
    Excerpt

    AIM: To assess if a contrast medium improved diagnostic yield of endodontic radiographs. METHODOLOGY: Forty-five extracted mandibular premolar teeth were radiographed in bucco-lingual and mesio-distal planes. Access cavities were prepared, pulpal tissue extirpated and Ultravist contrast medium introduced under pressure. Radiographs were retaken and the teeth cleared following perfusion with India ink. Three examiners assessed all the films for: number of roots, number of root canals, curvature of root and/or root canal, presence of lateral canals, presence of a single foramen or apical delta and the presence or absence of canal obstructions. The examiners' interpretations were compared with the anatomy revealed by clearing. RESULTS: Kappa scores were calculated for each of the examiners, for each set of radiographs, to assess the level of intra- and inter-examiner agreement. Only moderate agreement was found throughout (kappa = 0.40-0.61). For multiple root canals a false-positive result was significantly more likely with contrast (P < 0.05). The use of contrast did not significantly improve the sensitivity of diagnosis of lateral canals or a single apical foramen. Contrast significantly increased the risk of falsely perceiving lateral canals (P < 0.002). Overall there was no statistically significant difference in the overall assessment of the anatomy of the root canals using contrast or plain radiographs (P > 0.2). CONCLUSIONS: Plain film radiographs confidently predict the presence of root or canal curvature but apical anatomy was assessed accurately in only 46% of cases. Plain radiographs were insensitive in assessing the number of root canals present, the presence of lateral canals and the occurrence of canal obstructions. The use of Ultravist contrast medium to improve diagnosis of root canal morphology of premolars is not supported.

    Title Sema3e Mutation in a Patient with Charge Syndrome.
    Date December 2004
    Journal Journal of Medical Genetics
    Title Functional Characterization of Nine Norway Spruce Tps Genes and Evolution of Gymnosperm Terpene Synthases of the Tps-d Subfamily.
    Date December 2004
    Journal Plant Physiology
    Excerpt

    Constitutive and induced terpenoids are important defense compounds for many plants against potential herbivores and pathogens. In Norway spruce (Picea abies L. Karst), treatment with methyl jasmonate induces complex chemical and biochemical terpenoid defense responses associated with traumatic resin duct development in stems and volatile terpenoid emissions in needles. The cloning of (+)-3-carene synthase was the first step in characterizing this system at the molecular genetic level. Here we report the isolation and functional characterization of nine additional terpene synthase (TPS) cDNAs from Norway spruce. These cDNAs encode four monoterpene synthases, myrcene synthase, (-)-limonene synthase, (-)-alpha/beta-pinene synthase, and (-)-linalool synthase; three sesquiterpene synthases, longifolene synthase, E,E-alpha-farnesene synthase, and E-alpha-bisabolene synthase; and two diterpene synthases, isopimara-7,15-diene synthase and levopimaradiene/abietadiene synthase, each with a unique product profile. To our knowledge, genes encoding isopimara-7,15-diene synthase and longifolene synthase have not been previously described, and this linalool synthase is the first described from a gymnosperm. These functionally diverse TPS account for much of the structural diversity of constitutive and methyl jasmonate-induced terpenoids in foliage, xylem, bark, and volatile emissions from needles of Norway spruce. Phylogenetic analyses based on the inclusion of these TPS into the TPS-d subfamily revealed that functional specialization of conifer TPS occurred before speciation of Pinaceae. Furthermore, based on TPS enclaves created by distinct branching patterns, the TPS-d subfamily is divided into three groups according to sequence similarities and functional assessment. Similarities of TPS evolution in angiosperms and modeling of TPS protein structures are discussed.

    Title Identification of Vitis Vinifera (-)-alpha-terpineol Synthase by in Silico Screening of Full-length Cdna Ests and Functional Characterization of Recombinant Terpene Synthase.
    Date August 2004
    Journal Phytochemistry
    Excerpt

    The flavour and aroma of certain Vitis vinifera grape varieties is dominated by volatile terpenes and small volatile aldehydes. Monoterpenes contribute to the final grape and wine aroma and flavour in form of free volatiles and as glycoside conjugates of monoterpene alcohols. Typical monoterpenol components of the cultivar Gewürztraminer and other aroma-rich grape varieties are linalool, geraniol, nerol, citronellol, and alpha-terpineol. In a functional genomics effort to identify genes for the formation of monoterpene alcohols in V. vinifera, a database of full-length cDNA sequences was screened in silico and yielded two clones for putative monoterpene synthases. The gene products were functionally characterized by expression in Escherichia coli, in vitro enzyme assay and gas chromatography-mass spectrometry (GC-MS) product identification as multi-product (-)-alpha-terpineol synthases.

    Title Myo15 Function is Distinct from Myo6, Myo7a and Pirouette Genes in Development of Cochlear Stereocilia.
    Date June 2004
    Journal Human Molecular Genetics
    Excerpt

    The unconventional myosin genes Myo15, Myo6 and Myo7a are essential for hearing in both humans and mice. Despite the expression of each gene in multiple organs, mutations result in identifiable phenotypes only in auditory or ocular sensory organs. The pirouette (pi) mouse also exhibits deafness and an inner ear pathology resembling that of Myo15 mutant mice and thus may be functionally related to Myo15. In order to investigate possible interactions between Myo15 and Myo6, Myo7a, and the gene affected in pirouette, we crossed Myo15(sh2/sh2) mice to the three other mutant mouse strains. Hearing in doubly heterozygous mice was similar to age-matched singly heterozygous animals, indicating that partial deficiency for both Myo15 and one of these other deafness genes does not reduce hearing. Viable double mutants were obtained from each cross, indicating that potential overlapping functions between these genes in other organs are not essential for viability. All critical cell types of the cochlear sensory epithelium were present in double mutant mice and cochlear stereocilia exhibited a superimposition of single mutant phenotypes. These data suggest that the function of Myo15 is distinct from that of Myo6, Myo7a or pi in development and/or maintenance of stereocilia.

    Title Pitx2 is Required for Normal Development of Neurons in the Mouse Subthalamic Nucleus and Midbrain.
    Date June 2004
    Journal Developmental Biology
    Excerpt

    Pitx2, a homeodomain transcription factor, is essential for normal development of the pituitary gland, craniofacial region, eyes, heart, abdominal viscera, and limbs. Complete loss of Pitx2 in mice (Pitx2(-/-)) results in embryonic lethality by approximately e15 due to cardiac defects, whereas embryos with partial loss of function (Pitx2(neo/-) or Pitx2(neo/neo)) survive until later in development (e17-e19). Pitx2 is expressed in discrete populations of postmitotic neurons in the mouse brain, but its role in mammalian central nervous system (CNS) development is not known. We undertook an analysis of Pitx2-deficient embryos to determine whether loss of Pitx2 affects CNS development. The CNS is normal in hypomorphic e16.5 Pitx2(neo/-) and e18.5 Pitx2(neo/neo) embryos, with no evidence of midline or other defects. Midgestation (e10.5) Pitx2(-/-) embryos have normally formed neural tube structures and cerebral vesicles, whereas older (e14.5) Pitx2(-/-) embryos exhibit loss of gene expression and axonal projections in the subthalamic nucleus (a group of cells in the ventrolateral thalamus) and in the developing superior colliculus of dorsal midbrain. Our results suggest a role for Pitx2 in regulating regionally specific terminal neuronal differentiation in the developing ventrolateral thalamus and midbrain.

    Title Gene-based Diagnostic and Treatment Methods for Tinnitus.
    Date March 2004
    Journal The International Tinnitus Journal
    Excerpt

    The etiology of tinnitus combines hereditary and environmental factors. To help develop optimal therapies for tinnitus, it is necessary to characterize the genetic contributors to the pathophysiology and to design treatments at the level of the gene. Inner ear gene therapy involves delivery of genes into the vestibular or auditory portions of the inner ear for preventive or reparative therapies at the level of the sensory epithelium or the eighth nerve neurons. BDNF and GDNF are among the neurotrophic factors shown to be overexpressed with gene therapy and to protect the inner ear against trauma. Combined treatment with Ad.GDNF and electrical stimulation provided enhanced preservation of denervated spiral ganglion neurons. The use of viral vectors for gene therapy may involve side effects, including immune response to the viral proteins. Treatment with immunosuppressive medications can reduce the negative consequences of adenovirus-mediated gene therapy.

    Title Learning Disabilities and the Menopause.
    Date February 2004
    Journal The Journal of the British Menopause Society
    Excerpt

    How menopause affects women with learning disabilities is a neglected area of research. Women with learning disabilities experience the same physiological effects of the menopause as others, including hot flushes and night sweats, but difficulties in understanding and communication mean that additional supports are often required. They are less likely to report the psychological difficulties or symptoms associated with menopause than women in the general population. Menopause is usually earlier in women with learning disability and earlier still for those with Down's syndrome. Debate about hormone replacement therapy often ignores the needs of women with learning disabilities who, as a result, are very often excluded from the decision-making process. Physical problems among women with learning disabilities and other aspects of ageing warrant particular focus.

    Title Malignant Duodenal Somatostatinoma Presenting in Association with Von Recklinghausen Disease.
    Date January 2004
    Journal The American Surgeon
    Excerpt

    Somatostatinomas are extremely rare periampullary malignant neuroendocrine tumors that may be associated with von Recklinghausen disease or type-I neurofibromatosis. Duodenal somatostatinomas are distinguished from pancreatic somatostatinomas by their frequent association with type-I neurofibromatosis and typically absence of somatostatinoma syndrome. We report a very rare and atypical case of malignant duodenal somatostatinoma presenting with somatostatinoma syndrome in association with type-I neurofibromatosis.

    Title Insect Attack and Wounding Induce Traumatic Resin Duct Development and Gene Expression of (-)-pinene Synthase in Sitka Spruce.
    Date January 2004
    Journal Plant Physiology
    Excerpt

    Conifers possess inducible terpenoid defense systems. These systems are associated with the formation of traumatic resin ducts (TRD) and are underpinned by enhanced gene expression and activity of terpene synthases (TPS), enzymes responsible for oleoresin formation. We first determined that Sitka spruce (Picea sitchensis [Bong.] Carriere) had the capacity for TRD formation by mechanically wounding representative trees. We then proceeded to investigate whether the white pine weevil (Pissodes strobi Peck.), a stem-boring insect, can influence the expression of genes encoding monoterpene synthases (mono-tps) in Sitka spruce. We went on to compare this response with the effects of a simulated insect attack by drill wounding. A significant increase in mono-tps transcript level was observed in the leaders of lateral branches of weevil-attacked and mechanically wounded trees. In this study, weevils induced a more rapid enhancement of mono-tps gene expression. A full-length Sitka spruce mono-tps cDNA (PsTPS2) was isolated, expressed in Escherichia coli, and functionally identified as (-)-pinene synthase. The recombinant (-)-pinene synthase catalyzes the formation of (-)-alpha-pinene and (-)-beta-pinene, both of which are known constituents of stem oleoresin in Sitka spruce and increase in abundance after weevil attack. These data suggest that increased (-)-pinene synthase gene expression is an important element of the direct defense system deployed in Sitka spruce after insect attack.

    Title [home Care for the Terminal Patient]
    Date December 2003
    Journal Revista De Enfermería (barcelona, Spain)
    Title Nestin-lineage Cells Contribute to the Microvasculature but Not Endocrine Cells of the Islet.
    Date December 2003
    Journal Diabetes
    Excerpt

    To clarify the lineage relationship between cells that express the neural stem cell marker nestin and endocrine cells of the pancreas, we analyzed offspring of a cross between mice carrying a nestin promoter/enhancer-driven cre-recombinase (Nestin-cre) and C57BL/6J-Gtrosa26(tm1Sor) mice that carry a loxP-disrupted beta-galactosidase gene (Rosa26). In nestin-cre(+/tg);R26R(loxP/+) embryos, cre-recombinase was detected in association with nestin-positive cells in the pancreatic mesenchyme with some of the nestin-positive cells lining vascular channels. In postnatal mice, pancreatic beta-galactosidase expression was restricted to vascular endothelial cells of the islet and a subset of cells in the muscularis of arteries in a distribution identical to endogenous nestin expression. Ex vivo explants of mouse pancreatic ducts grew dense cultures that costained for nestin and beta-galactosidase, demonstrating recombination in vitro. The cultures could be differentiated into complex stereotypic structures that contain nestin- and insulin-expressing cells. Nestin-cre(+/tg);R26R(loxP/+)-derived duct cultures showed that insulin-positive cells were negative for beta-galactosidase. These results indicate that both in vivo and in vitro pancreatic endocrine cells arise independently of nestin-positive precursors. The apparent vascular nature of the nestin-positive cell population and the close association with endocrine cells suggest that nestin-positive cells play an important role in the growth and maintenance of the islet.

    Title Induction of Volatile Terpene Biosynthesis and Diurnal Emission by Methyl Jasmonate in Foliage of Norway Spruce.
    Date November 2003
    Journal Plant Physiology
    Excerpt

    Terpenoids are characteristic constitutive and inducible defense chemicals of conifers. The biochemical regulation of terpene formation, accumulation, and release from conifer needles was studied in Norway spruce [Picea abies L. (Karst)] saplings using methyl jasmonate (MeJA) to induce defensive responses without inflicting physical damage to terpene storage structures. MeJA treatment caused a 2-fold increase in monoterpene and sesquiterpene accumulation in needles without changes in terpene composition, much less than the 10- and 40-fold increases in monoterpenes and diterpenes, respectively, observed in wood tissue after MeJA treatment (D. Martin, D. Tholl, J. Gershenzon, J. Bohlmann [2002] Plant Physiol 129: 1003-1018). At the same time, MeJA triggered a 5-fold increase in total terpene emission from foliage, with a shift in composition to a blend dominated by oxygenated monoterpenes (e.g. linalool) and sesquiterpenes [e.g. (E)-beta-farnesene] that also included methyl salicylate. The rate of linalool emission increased more than 100-fold and that of sesquiterpenes increased more than 30-fold. Emission of these compounds followed a pronounced diurnal rhythm with the maximum amount released during the light period. The major MeJA-induced volatile terpenes appear to be synthesized de novo after treatment, rather than being released from stored terpene pools, because they are almost completely absent from needle oleoresin and are the major products of terpene synthase activity measured after MeJA treatment. Based on precedents in other species, the induced emission of terpenes from Norway spruce foliage may have ecological and physiological significance.

    Title Visual Representation of Database Search Results: the Rhims Plot.
    Date September 2003
    Journal Bioinformatics (oxford, England)
    Excerpt

    SUMMARY: An algorithm and software are described that provide a fast method to produce a novel, function-oriented visualization of the results of a sequence database search. Text mining of sequence annotations allows position specific plots of potential functional similarity to be compared in a simple compact representation. AVAILABILITY: The application can be accessed via a web server at http://www.compbio.dundee.ac.uk. The RHIMS software may be obtained by request to the authors.

    Title Elm Server: A New Resource for Investigating Short Functional Sites in Modular Eukaryotic Proteins.
    Date August 2003
    Journal Nucleic Acids Research
    Excerpt

    Multidomain proteins predominate in eukaryotic proteomes. Individual functions assigned to different sequence segments combine to create a complex function for the whole protein. While on-line resources are available for revealing globular domains in sequences, there has hitherto been no comprehensive collection of small functional sites/motifs comparable to the globular domain resources, yet these are as important for the function of multidomain proteins. Short linear peptide motifs are used for cell compartment targeting, protein-protein interaction, regulation by phosphorylation, acetylation, glycosylation and a host of other post-translational modifications. ELM, the Eukaryotic Linear Motif server at http://elm.eu.org/, is a new bioinformatics resource for investigating candidate short non-globular functional motifs in eukaryotic proteins, aiming to fill the void in bioinformatics tools. Sequence comparisons with short motifs are difficult to evaluate because the usual significance assessments are inappropriate. Therefore the server is implemented with several logical filters to eliminate false positives. Current filters are for cell compartment, globular domain clash and taxonomic range. In favourable cases, the filters can reduce the number of retained matches by an order of magnitude or more.

    Title Acute Extrapyramidal Syndrome in Mild Ornithine Transcarbamylase Deficiency: Metabolic Stroke Involving the Caudate and Putamen Without Metabolic Decompensation.
    Date August 2003
    Journal European Journal of Pediatrics
    Excerpt

    A 6-year-old male with partial ornithine transcarbamylase (OTC) deficiency had acute and rapidly progressive symmetrical swelling of the head of the caudate nuclei and putamina. Clinical presentation was ataxia and dysarthria progressing to seizures and coma; these symptoms gradually resolved with supportive management. Although he had been recently treated for mild hyperammonemia, there was no evidence of acute metabolic decompensation prior to presentation, and plasma ammonia and amino acids were consistent with good metabolic control. This case is novel in that the neurological insult affected the neostriatum of the basal ganglia and the episode occurred in the absence of an apparent metabolic abnormality, unique observations in a patient with OTC deficiency. CONCLUSION: This case suggests that the pathophysiology of metabolic stroke is complicated. It also argues for an evaluation for metabolic stroke in patients with known inborn errors of metabolism who present with unusual neurological symptoms in the absence of biochemical abnormalities. Similarly, this case suggests that patients presenting with unexplained neurological insults might benefit from an evaluation for an inborn error of metabolism.

    Title Interrupted Aortic Arch in a Child with Trisomy 5q31.1q35.1 Due to a Maternal (20;5) Balanced Insertion.
    Date April 2003
    Journal American Journal of Medical Genetics. Part A
    Excerpt

    Complex congenital heart defects (CHD) are associated with a variety of single gene abnormalities and chromosomal rearrangements. Of the various forms of CHD, aortic arch interruption, a conotruncal heart defect, is relatively uncommon. Here we report a male neonate with aortic arch interruption type B, secundum atrial septal defect, perimembranous ventricular septal defect, patent ductus arteriosus, aortic and subaortic stenosis, and trisomy 5q31.1q35.1 resulting from a maternal balanced insertion (20;5). Chromosomal deletions, including deletion 22q11, have been reported with interrupted aortic arch (IAA); however, to our knowledge this is the first report of a trisomy of distal chromosome 5q associated with aortic arch interruption. Here we compare this child's features to other cases of trisomy 5q31.1q35.1, and review other causes of IAA. We conclude that gene dosage in this chromosomal region likely influences aortic arch development.

    Title Characterization of a Stapes Ankylosis Family with a Nog Mutation.
    Date April 2003
    Journal Otology & Neurotology : Official Publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology
    Excerpt

    OBJECTIVE: To characterize the otologic phenotype in a family with autosomal dominant stapes ankylosis, hyperopia, and skeletal abnormalities caused by a mutation in the noggin gene (NOG). STUDY DESIGN: Case series. SETTING: Academic tertiary care center. PATIENTS: Eight affected and 3 unaffected family members. MAIN OUTCOME MEASURES: History, physical and radiologic examination, and surgical outcomes. RESULTS: Although affected members were initially presumed to have typical nonsyndromic otosclerosis, the clinical data were most consistent with an autosomal dominant congenital stapes ankylosis syndrome. Eight of eight affected family members had bilateral low-frequency conductive hearing loss. Six of eight underwent fenestration procedures and/or stapedectomies. All members with initial postoperative closure of the air-bone gap returned to their baseline conductive loss within 2 years. Two affected family members had documented maximal conductive hearing loss by age 4, and two members without previous otologic surgery have not experienced sensorineural hearing loss. High-resolution temporal bone computed tomography showed stapes ankylosis and indistinction of the incudomalleal junction bilaterally and bony regrowth over the stapedotomy for those with stapedectomies. Detailed physical and radiologic examination identified multiple other skeletal abnormalities. CONCLUSIONS: Although this phenotype may present as classic otosclerosis to the otolaryngologist, detailed investigation revealed a congenital stapes ankylosis syndrome. Because is essential in regulating normal bone development and maturation, mutations in this gene may be associated with excessive bony overgrowth and refixation of the stapes footplate after initial successful surgery. Patients with hereditary conductive hearing loss should be assessed to rule out subtle features of a skeletal syndrome.

    Title Pitx2 Distinguishes Subtypes of Terminally Differentiated Neurons in the Developing Mouse Neuroepithelium.
    Date January 2003
    Journal Developmental Biology
    Excerpt

    Pitx2, a homeodomain transcription factor, is essential for normal development of pituitary, eyes, heart, and teeth. In the developing mouse brain, Pitx2 (Rieg, Ptx2, Otlx2, Brx1) mRNA is expressed in discrete regions of the diencephalon, mesencephalon, and rhombencephalon. While prior reports have provided an overview of the temporal and regional specificity of Pitx2 mRNA expression in the brain, the precise cell types that express PITX2 are not known. In this study, we analyzed Pitx2 mRNA and PITX2 protein expression in individual cells of the developing e10.5-e14.5 mouse CNS using multiple markers of cellular proliferation and differentiation. We identified Pitx2 expression in nestin-positive neural progenitors and in postmitotic, developing neurons. In the diencephalon, PITX2 is expressed in neurons of the zona limitans intrathalamica and mammillary region and in gamma-aminobutyric acid (GABA)-producing neurons of the zona incerta. In the mesencephalon, PITX2-labeled nuclei also appear in differentiated neurons, some of which are GABAergic and destined to occupy superior colliculus. Our results suggest that PITX2 expression in postmitotic neurons may contribute to development of GABAergic and other differentiated neuronal phenotypes.

    Title Exclusion of Pitx2 Mutations As a Major Cause of Charge Association.
    Date January 2003
    Journal American Journal of Medical Genetics
    Excerpt

    CHARGE is a nonrandom association of ocular coloboma, congenital heart defects, atresia of the choanae, retarded growth and development, genital hypoplasia, and ear anomalies including deafness. The cause of CHARGE remains unknown; however, there is considerable evidence of an underlying genetic basis, as discussed by Tellier et al. [1996: Clin Genet 50:548-550; 1998: Am J Med Genet 76:402-409] and by Martin et al. [2001: Am J Med Genet 99:115-119]. Based on the ocular, cardiac, and craniofacial expression pattern of Pitx2, a homeodomain transcription factor, and the pleiotropic effects of loss of PITX2 function in both mouse and human, we hypothesized that PITX2 mutations may contribute to the multiple phenotypic anomalies present in CHARGE individuals. By direct sequencing of DNA from 29 individuals with CHARGE, we did not identify any mutations in PITX2. We did, however, identify two PITX2 sequence polymorphisms. Large deletions of PITX2 were excluded in most patients by heterozygosity in at least one of several polymorphic markers near the PITX2 locus. Together, these data indicate that PITX2 mutations are unlikely to be a major contributing cause of the multiple anomalies present in individuals with CHARGE.

    Title Genome Sequence of the Human Malaria Parasite Plasmodium Falciparum.
    Date October 2002
    Journal Nature
    Excerpt

    The parasite Plasmodium falciparum is responsible for hundreds of millions of cases of malaria, and kills more than one million African children annually. Here we report an analysis of the genome sequence of P. falciparum clone 3D7. The 23-megabase nuclear genome consists of 14 chromosomes, encodes about 5,300 genes, and is the most (A + T)-rich genome sequenced to date. Genes involved in antigenic variation are concentrated in the subtelomeric regions of the chromosomes. Compared to the genomes of free-living eukaryotic microbes, the genome of this intracellular parasite encodes fewer enzymes and transporters, but a large proportion of genes are devoted to immune evasion and host-parasite interactions. Many nuclear-encoded proteins are targeted to the apicoplast, an organelle involved in fatty-acid and isoprenoid metabolism. The genome sequence provides the foundation for future studies of this organism, and is being exploited in the search for new drugs and vaccines to fight malaria.

    Title Autosomal Dominant Stapes Ankylosis with Broad Thumbs and Toes, Hyperopia, and Skeletal Anomalies is Caused by Heterozygous Nonsense and Frameshift Mutations in Nog, the Gene Encoding Noggin.
    Date October 2002
    Journal American Journal of Human Genetics
    Excerpt

    Although fixation of the stapes is usually progressive and secondary to otosclerosis, it may present congenitally, with other skeletal manifestations, as an autosomal dominant syndrome-such as proximal symphalangism (SYM1) or multiple-synostoses syndrome (SYNS1), both of which are caused by mutations in NOG, the gene encoding noggin. We describe a family that was ascertained to have nonsyndromic otosclerosis but was subsequently found to have a congenital stapes ankylosis syndrome that included hyperopia, a hemicylindrical nose, broad thumbs and great toes, and other minor skeletal anomalies but lacked symphalangism. A heterozygous nonsense NOG mutation-c.328C-->T (Q110X), predicted to truncate the latter half of the protein-was identified, and a heterozygous insertion in NOG-c.252-253insC, in which the frameshift is predicted to result in 96 novel amino acids before premature truncation-was identified in a previously described second family with a similar phenotype. In contrast to most NOG mutations that have been reported in kindreds with SYM1 and SYNS1, the mutations observed in these families with stapes ankylosis without symphalangism are predicted to disrupt the cysteine-rich C-terminal domain. These clinical and molecular findings suggest that (1) a broader range of conductive hearing-loss phenotypes are associated with NOG mutations than had previously been recognized, (2) patients with sporadic or familial nonsyndromic otosclerosis should be evaluated for mild features of this syndrome, and (3) NOG alterations should be considered in conductive hearing loss with subtle clinical and skeletal features, even in the absence of symphalangism.

    Title Still-well Osteopathic Medical Student Wellness Program.
    Date June 2002
    Journal The Journal of the American Osteopathic Association
    Excerpt

    In 1991, the Kirksville College of Osteopathic Medicine in Kirksville, Missouri, initiated a wellness program for its first- and second-year medical students. The program was based on the concept that to practice and promote preventive medicine, students must first understand and integrate wellness practices and theory into their own lives. With nearly 11 years of experience, the Kirksville College of Osteopathic Medicine offers a wellness program to its students that addresses areas of their personal, professional, and physical development of mind, body, and spirit. Voluntary student participation has been exceptional, and research at KCOM was initiated to determine to what extent the program was working to modify the wellness of its medical students.

    Title Health of the Nation Outcome Scales for People with Learning Disabilities (honos-ld).
    Date February 2002
    Journal The British Journal of Psychiatry : the Journal of Mental Science
    Excerpt

    BACKGROUND: The Health of the Nation Outcomes Scales (HoNOS) have been developed to measure outcomes in people with mental health problems. AIMS: Frequent impaired social functioning, problems with communication and associated physical conditions meant that a bespoke instrument was needed for people with learning disabilities. We describe the development of the Health of the Nation Outcomes Scales for People with Learning Disabilities (HoNOS-LD). METHOD: HoNOS-LD was piloted at 26 sites. Two raters, at two points in time, rated 372 subjects. Analysis determined acceptability, ease of use, interrater reliability, sensitivity to change and reliability with the Aberrant Behavior Checklist (ABC). RESULTS: The resulting 18-item instrument demonstrated good reliability and validity characteristics and is generally acceptable to clinicians. CONCLUSIONS: HoNOS-LD is an appropriate instrument for measuring outcome in people with learning disabilities with additional mental health needs.

    Title Health of the Nation Outcome Scales for People with Learning Disabilities (honos-ld): Glossary for Honos-ld Score Sheet.
    Date February 2002
    Journal The British Journal of Psychiatry : the Journal of Mental Science
    Title Ocular Malformations, Postaxial Polydactyly, and Delayed Intramembranous Ossification: a New Autosomal Dominant Condition.
    Date December 2001
    Journal Journal of Medical Genetics
    Title Systemic Lupus Erythematosus in a Man with Noonan Syndrome.
    Date August 2001
    Journal American Journal of Medical Genetics
    Excerpt

    Noonan syndrome is a multiple congenital anomaly condition characterized by craniofacial anomalies, short stature, cardiac malformations, and normal peripheral blood karyotype analysis. Prior reports of individuals with Noonan syndrome have revealed an association with several autoimmune diseases, including vasculitis and anterior uveitis, but no reports of systemic lupus erythematosus (SLE). Here we present the first case report of a 21-year-old man with a clinical diagnosis of Noonan syndrome and a recent history of mitral valve dysfunction and systemic lupus erythematosus. We discuss his findings in the context of known features of Noonan syndrome and propose that individuals with Noonan syndrome be regularly monitored for associated autoimmune phenomena.

    Title Charge Association with Choanal Atresia and Inner Ear Hypoplasia in a Child with a De Novo Chromosome Translocation T(2;7)(p14;q21.11).
    Date June 2001
    Journal American Journal of Medical Genetics
    Excerpt

    A 3-year-old boy was diagnosed with CHARGE association on the basis of bilateral choanal atresia, absence of the semicircular canals, hypoplastic cochleae, genital hypoplasia, growth and developmental delays, cranial nerve dysfunction, and facial anomalies. Ophthalmologic and cardiac evaluations were normal. He was found to have an apparently balanced t(2;7)(p14;q21.11) chromosomal translocation. Parental karyotypes were normal. Although there is evidence suggesting a genetic basis for CHARGE association, individuals with chromosomal abnormalities and CHARGE are rare. In the described patient, the presence of characteristic CHARGE features suggests that the t(2;7)(p14;q21.11) translocation breakpoints may cause a deletion or disruption of genes within the involved regions that are involved in the generation of the CHARGE association phenotype.

    Title Characterisation and Genetic Mapping of a New X Linked Deafness Syndrome.
    Date December 2000
    Journal Journal of Medical Genetics
    Excerpt

    BACKGROUND: Hereditary forms of hearing loss are classified as syndromic, when deafness is associated with other clinical features, or non-syndromic, when deafness occurs without other clinical features. Many types of syndromic deafness have been described, some of which have been mapped to specific chromosomal regions. METHODS: Here we describe a family with progressive sensorineural hearing loss, cognitive impairment, facial dysmorphism, and variable other features, transmitted by apparent X linked recessive inheritance. Haplotype analysis of PCR products spanning the X chromosome and direct sequencing of candidate genes were used to begin characterising the molecular basis of features transmitted in this family. Comparison to known syndromes involving deafness, mental retardation, facial dysmorphism, and other clinical features was performed by review of published reports and personal discussions. RESULTS: Genetic mapping places the candidate locus for this syndrome within a 48 cM region on Xq1-21. Candidate genes including COL4A5, DIAPH, and POU3F4 were excluded by clinical and molecular analyses. CONCLUSIONS: The constellation of clinical findings in this family (deafness, cognitive impairment, facial dysmorphism, variable renal and genitourinary abnormalities, and late onset pancytopenia), along with a shared haplotype on Xq1-21, suggests that this represents a new form of syndromic deafness. We discuss our findings in comparison to several other syndromic and non-syndromic deafness loci that have been mapped to the X chromosome.

    Title The Motor and Tail Regions of Myosin Xv Are Critical for Normal Structure and Function of Auditory and Vestibular Hair Cells.
    Date October 2000
    Journal Human Molecular Genetics
    Excerpt

    Recessive mutations in myosin 15, a class XV unconventional myosin, cause profound congenital deafness in humans and both deafness and vestibular dysfunction in mice homozygous for the shaker 2 and shaker 2(J) alleles. The shaker 2 allele is a previously described missense mutation of a highly conserved residue in the motor domain of myosin XV. The shaker 2(J) lesion, in contrast, is a 14.7 kb deletion that removes the last six exons from the 3"-terminus of the Myo15 transcript. These exons encode a FERM (F, ezrin, radixin and moesin) domain that may interact with integral membrane proteins. Despite the deletion of six exons, Myo15 mRNA transcripts and protein are present in the post-natal day 1 shaker 2(J) inner ear, which suggests that the FERM domain is critical for the development of normal hearing and balance. Myo15 transcripts are first detectable at embryonic day 13.5 in wild-type mice. Myo15 transcripts in the mouse inner ear are restricted to the sensory epithelium of the developing cristae ampularis, macula utriculi and macula sacculi of the vestibular system as well as to the developing organ of Corti. Both the shaker 2 and shaker 2(J) alleles result in abnormally short hair cell stereocilia in the cochlear and vestibular systems. This suggests that Myo15 may be important for both the structure and function of these sensory epithelia.

    Title Alpha-actinin-2 in Rat Striatum: Localization and Interaction with Nmda Glutamate Receptor Subunits.
    Date October 2000
    Journal Brain Research. Molecular Brain Research
    Excerpt

    Alpha-actinin (alpha-actinin-2) is a protein which links the NR1 and NR2B subunits of N-methyl-D-aspartate (NMDA) glutamate receptors to the actin cytoskeleton. Because of the importance of NMDA receptors in modulating the function of the striatum, we have examined the localization of alpha-actinin-2 protein and mRNA in striatal neurons, and its biochemical interaction with NMDA receptor subunits present in the rat striatum. Using an alpha-actinin-2-specific antibody, we found intense immunoreactivity in the striatal neuropil and within striatal neurons that also expressed parvalbumin, calretinin and calbindin. Conversely, alpha-actinin-2 immunoreactivity was not detected in neurons expressing choline acetyltransferase and neuronal nitric oxide synthase. Dual-label in situ hybridization revealed that the highest expression of alpha-actinin-2 mRNA is in substance P-containing striatal projection neurons. The alpha-actinin-2 mRNA is also present in enkephalinergic projection neurons and interneurons expressing parvalbumin, choline acetyl transferase and the 67-kDa isoform of glutamic acid decarboxylase, but was not detected in somatostatin-expressing interneurons. Immunoprecipitation of membrane protein extracts showed that alpha-actinin-2 is present in heteromeric complexes of NMDA subunits, but is not associated with AMPA receptors in the striatum. A subunit-specific anti-NR1 antibody co-precipitated major fractions of NR2A and NR2B subunits, but only a minor fraction of striatal alpha-actinin-2. Conversely, alpha-actinin-2 antibody immunoprecipitated only modest fractions of striatal NR1, NR2A and NR2B subunits. These data demonstrate that alpha-actinin-2 is a very abundant striatal protein, but exhibits cellular specificity in its expression, with very high levels in substance-P-containing projection neurons, and very low levels in somatostatin and neuronal nitric oxide synthase interneurons. Despite the high expression of this protein in the striatum, only a minority of NMDA receptors are linked to alpha-actinin-2. This interaction may identify a subset of receptors with distinct anatomical and functional properties.

    Title The Control of Carrier Frequency in Cricket Calls: a Refutation of the Subalar-tegminal Resonance/auditory Feedback Model.
    Date April 2000
    Journal The Journal of Experimental Biology
    Excerpt

    The subalar-tegminal resonance/auditory feedback hypothesis attempts to explain how crickets control the carrier frequency (f(C)), the loudness and the spectral purity of their calls. This model contrasts with the 'clockwork cricket' or escapement model by proposing that f(C) is not controlled by the resonance of the cricket's radiators (the harps) but is instead controlled neurally. It suggests that crickets are capable of driving their harps to vibrate at any frequency and that they use a tunable Helmholtz-like resonator consisting of the tegmina and the air within the subalar space to amplify and filter the f(C). This model predicts that f(C) is variable, that call loudness is related to tegminal position (and subalar volume) and that low-density gases should cause f(C) to increase. In Anurogryllus arboreus, f(C) is not constant and varied by as much as 0.8 % between pulses. Within each sound pulse, the average f(C) typically decreased from the first to the last third of a sound pulse by 9 %. When crickets called in a mixture of heliox and air, f(C) increased 1.07- to 1.14-fold above the value in air. However, if the subalar space were part of a Helmholtz-like resonator, then its resonant frequency should have increased by 40-50 %. Moreover, similar increases occurred in species that lack a subalar space (oecanthines). Experimental reduction of the subalar volume of singing crickets resulted neither in a change in f(C) nor in a change in loudness. Nor did crickets attempt to restore the subalar volume to its original value. These results disprove the presence of a subalar-tegminal resonator. The free resonance of freshly excised Gryllus rubens tegmina shifted by 1.09-fold when moved between air and a mixture of helium and air. Auditory feedback cannot be the cause of this shift, which is similar to the f(C) shifts in intact individuals of other species. Calculations show that the harp is 3.9-1.8 times more massive than the air that moves en masse with the vibrating harps. Replacing air with heliox-air lowers the mass of the vibrating system sufficiently to account for the f(C) shifts. These results re-affirm the 'clockwork cricket' (escapement) hypothesis. However, as realized by others, the harps should be viewed as narrow-band variable-frequency oscillators whose tuning may be controlled by factors that vary the effective mass.

    Title Frontal Lobe Dysfunction in Progressive Supranuclear Palsy: Evidence for Oxidative Stress and Mitochondrial Impairment.
    Date February 2000
    Journal Journal of Neurochemistry
    Excerpt

    Recent data from our laboratory have shown a regionally specific increase in lipid peroxidation in postmortem progressive supranuclear palsy (PSP) brain. To extend this finding, we measured activities of mitochondrial enzymes as well as tissue malondialdehyde (MDA) levels in postmortem superior frontal cortex (Brodmann's area 9; SFC) from 14 pathologically confirmed cases of PSP and 13 age-matched control brains. Significant decreases (-39%) in alpha-ketoglutarate dehydrogenase complex/glutamate dehydrogenase ratio and significant increases (+36%) in tissue MDA levels were observed in the SFC in PSP; no differences in complex I or complex IV activities were detected. Together, these results suggest that mitochondrial dysfunction and lipid peroxidation may underlie the frontal metabolic and functional deficits observed in PSP.

    Title Distribution of the Mrnas Encoding Torsina and Torsinb in the Normal Adult Human Brain.
    Date November 1999
    Journal Annals of Neurology
    Excerpt

    To gain insight into the neural pathways involved in the pathogenesis of DYT1 dystonia, we have mapped the cellular expression of the mRNA encoding torsinA and the closely related family member, torsinB, in normal adult human brain. Here, we report an intense expression of torsinA mRNA in the substantia nigra pars compacta dopamine neurons, the locus ceruleus, the cerebellar dentate nucleus, Purkinje cells, the basis pontis, numerous thalamic nuclei, the pedunculopontine nucleus, the oculomotor nucleus, the hippocampal formation, and the frontal cortex. Within the caudateputamen, the cellular expression of torsinA mRNA was heterogeneous; a moderate signal was found overlying large cholinergic neurons, and most striatal neurons exhibited only a very weak signal. A moderate signal was detected in numerous midbrain and hindbrain nuclei. A weak cellular signal was detected in neurons of the globus pallidus and subthalamic nucleus. In marked contrast to torsinA, no specific mRNA signal was detected for torsinB. That torsinA mRNA is enriched in several basal ganglia nuclei, including the dopamine neurons in the substantia nigra, is intriguing since it suggests that DYT1 dystonia may be associated with a dysfunction in dopamine transmission.

    Title Evidence for Oxidative Stress in the Subthalamic Nucleus in Progressive Supranuclear Palsy.
    Date August 1999
    Journal Journal of Neurochemistry
    Excerpt

    Increased free radical production and oxidative stress have been proposed as pathogenic mechanisms in several neurodegenerative disorders. Free radicals interact with biological macromolecules, such as lipids, which can lead to lipid peroxidation. A well-established marker of oxidative damage to lipids is malondialdehyde (MDA). We measured tissue MDA levels in the subthalamic nucleus (STN) and cerebellum from 11 progressive supranuclear palsy (PSP) cases and 11 age-matched control cases using sensitive HPLC techniques. In PSP, a significant increase in tissue MDA levels was observed in the STN when compared with the age-matched control group. By contrast, no significant difference between tissue MDA content was observed in cerebellar tissue from the same PSP and age-matched control cases. These results indicate that lipid peroxidation may play a role in the pathogenesis of PSP.

    Title An in Vitro Investigation into the Wear Effects of Glazed, Unglazed and Refinished Dental Porcelain on an Opposing Material.
    Date August 1999
    Journal Journal of Oral Rehabilitation
    Excerpt

    A machine designed to simulate the physical parameters of masticatory function was used to investigate the amount of wear produced on perspex plates opposing discs of porcelain which were glazed, unglazed or finished to varying stages of a polishing sequence recommended with a proprietary finishing kit. The perspex specimens were abraded, under water at 37 degrees C for a total of 800000 contacts using a contact time of 0.2 s, a sliding distance of 15 mm and a constant load of 0.19 N/mm2. Assessments of the wear of the perspex were based upon depth measurements of the wear track recorded on surfometric tracings. Further measurements of the cross-sectional area of the wear track were made using an image analysing computer. The investigation confirmed that the best finish and least abrasive surface was produced by glazing of porcelain. The finish produced by intermediate components of the proprietary finishing kit did not reduce the abrasiveness of the porcelain surface. It was necessary to complete the polishing sequence with diamond paste to achieve a surface which approached the wear characteristics of glazed porcelain. It is recommended that any adjusted porcelain restoration should be re-glazed or subjected to a finishing sequence which is followed through to a final stage of polishing with a diamond paste.

    Title Dna Vaccines Targeting Dendritic Cells for the Immunotherapy of Cancer.
    Date March 1999
    Journal Advances in Experimental Medicine and Biology
    Title Glazing and Finishing Dental Porcelain: a Literature Review.
    Date January 1999
    Journal Journal (canadian Dental Association)
    Excerpt

    BACKGROUND: Dental porcelain has found an increased number of applications in recent years with the development of new methods for the construction of porcelain veneers and intracoronal restorations. In addition, it is used in metal-ceramic and all-porcelain crowns and bridges for the restoration of anterior and posterior teeth. METHODS: This paper presents a review of a number of studies that have examined the visual and microscopic appearance and roughness of glazed, unglazed and polished porcelain surfaces using techniques such as, scanning electron microscopy and surface profilometry. FINDINGS: All have agreed that glazed porcelain provides a smooth and dense surface. Many have shown that polishing can produce an equally smooth surface, which may even be esthetically better. Some studies supported the use of polishing as an alternative to glazing. However, reports have shown that unglazed porcelain is more abrasive than glazed. CLINICAL SIGNIFICANCE: This paper aims to guide general practitioners in the proper polishing of adjusted porcelain in the dental office. The recommendations of various authors are summarized in Table I.

    Title Tissue Factor and Biotechnology.
    Date October 1998
    Journal Thrombosis Research
    Title Autologous Human Dendriphages Pulsed with Synthetic or Natural Tumor Peptides Elicit Tumor-specific Ctls in Vitro.
    Date May 1998
    Journal Journal of Immunotherapy (hagerstown, Md. : 1997)
    Excerpt

    The recent identification of tumor-associated antigens and tumor-associated antigen-derived peptide epitopes recognized by cytolytic T lymphocytes (CTLs) in the context of major histocompatibility complex (MHC) class I molecules has prompted the development of peptide-based vaccines for the treatment of human cancers, particularly melanoma. The design of such clinical protocols requires an understanding of the inherent immunogenicity of the peptide(s) and a choice of a facilitating adjuvant promoting cellular immunity against these peptides. We have evaluated the abilities of a series of defined synthetic peptide epitopes derived from MART-1/Melan-A, gp100, tyrosinase, and MAGE-3 or unfractionated peptides naturally presented by melanoma MHC molecules to elicit HLA-A2-restricted and melanoma-reactive CTLs from the peripheral blood of normal donors or patients with metastatic melanoma. Autologous peripheral blood dendritic cells (DCs), which were easily generated from all donors when cultured in the presence of recombinant human interleukin-4 and recombinant human granulocyte-macrophage colony-stimulating factor were pulsed with melanoma peptides and used to "prime" and/or "boost" CTL cultures in vitro. Our results suggest that antimelanoma CTLs may be reproducibly generated in short-term in vitro cultures in this manner using either a subset of the defined synthetic peptides (MART-1/Melan-A27-35, MART-1/Melan-A32-40, gp100(280-288), tyrosinase368-376, and MAGE-3(271-279)) or unfractionated peptides (containing both idiotypic and shared melanoma epitopes) derived from freshly isolated autologous melanoma lesions. These in vitro data support the use of autologous DCs prepulsed with such peptides as an appropriate antigen adjuvant delivery system in melanoma peptide-based vaccines.

    Title Autologous Human Monocyte-derived Dendritic Cells Genetically Modified to Express Melanoma Antigens Elicit Primary Cytotoxic T Cell Responses in Vitro: Enhancement by Cotransfection of Genes Encoding the Th1-biasing Cytokines Il-12 and Ifn-alpha.
    Date May 1998
    Journal Journal of Immunology (baltimore, Md. : 1950)
    Excerpt

    DNA-based immunization strategies designed to elicit cellular antitumor immunity offer an attractive alternative to protein- or peptide-based approaches. In the present study we have evaluated the feasibility of DNA vaccination for the induction of CTL reactivity to five different melanoma Ags in vitro. Cultured, monocyte-derived dendritic cells (DC) were transiently transfected with plasmid DNA encoding human MART-1/Melan-A, pMel-17/gp100, tyrosinase, MAGE-1, or MAGE-3 by particle bombardment and used to stimulate autologous PBMC responder T cells. CTL reactivity to these previously identified melanoma Ags was reproducibly generated after two or three stimulations with genetically modified DC. Co-ordinate transfection of two melanoma Ag cDNAs into DC promoted CTL responders capable of recognizing epitopes from both gene products. Coinsertion of genes encoding the Th1-biasing cytokines IL-12 or IFN-alpha consistently enhanced the magnitude of the resulting Ag-specific CTL reactivity. Importantly, DC transfected with a single melanoma Ag cDNA were capable of stimulating Ag-specific CTL reactivity restricted by multiple host MHC alleles, some of which had not been previously identified. These results support the inherent strengths of gene-based vaccine approaches that do not require prior knowledge of responder MHC haplotypes or of relevant MHC-restricted peptide epitopes. Given previous observations of in situ tumor HLA allele-loss variants, DC gene vaccine strategies may elicit a greater diversity of host therapeutic immunity, thereby enhancing the clinical utility and success of such approaches.

    Title Health Gain Through Health Checks: Improving Access to Primary Health Care for People with Intellectual Disability.
    Date February 1998
    Journal Journal of Intellectual Disability Research : Jidr
    Excerpt

    People with intellectual disability were identified through the local register and through liaison with general practitioners (GPs). A consultation exercise was conducted with users and carers to ascertain their experiences and perspectives of primary health care (GP services). A comprehensive health check was devised and administered to about 120 people to detect physical disorders, especially cardiovascular risk factors. A standardized checklist was used to determine the population of people with psychological and psychiatric problems. Case notes were reviewed after nearly one year to determine physical and psychological health gain. Significant gains were noted with regard to physical disorders. In contrast, mental health problems were underreported and participants had achieved few gains on follow-up. The reasons and implications for future service planning are discussed.

    Title Stereoselective Bimolecular Phenoxy Radical Coupling by an Auxiliary (dirigent) Protein Without an Active Center.
    Date January 1997
    Journal Science (new York, N.y.)
    Excerpt

    The regio- and stereospecificity of bimolecular phenoxy radical coupling reactions, of especial importance in lignin and lignan biosynthesis, are clearly controlled in some manner in vivo; yet in vitro coupling by oxidases, such as laccases, only produce racemic products. In other words, laccases, peroxidases, and comparable oxidases are unable to control regio- or stereospecificity by themselves and thus some other agent must exist. A 78-kilodalton protein has been isolated that, in the presence of an oxidase or one electron oxidant, effects stereoselective bimolecular phenoxy radical coupling in vitro. Itself lacking a catalytically active (oxidative) center, its mechanism of action is presumed to involve capture of E-coniferyl alcohol-derived free-radical intermediates, with consequent stereoselective coupling to give (+)-pinoresinol.

    Title Tcr Usage in Ctls Recognizing Melanoma/melanocyte Antigens.
    Date March 1996
    Journal Immunology Today
    Title Factor Viia and the Extracellular Domains of Human Tissue Factor Form a Compact Complex: a Study by X-ray and Neutron Solution Scattering.
    Date December 1995
    Journal Febs Letters
    Excerpt

    The four-domain structure of human factor VIIa and the two-domain structure of tissue factor form a tight complex to initiate blood coagulation. By solution scattering, the mean X-ray and neutron radii of gyration RG (which determine macro-molecular elongation) were found to be 3.25 nm, 2.13 nm and 3.14 nm (+/- 0.13 nm) for factor VIIa, the extracellular region of tissue factor and their complex in that order. The mean cross-sectional radii of gyration RXS were 1.33 nm, 0.56 nm and 1.42 nm (+/- 0.13 nm) in that order. The mean lengths were 10.3 nm, 7.7 nm and 10.2 nm in that order. The data show that, in solution, the free proteins have extended domain structures, and the complex is formed by a compact side-by-side alignment of the two proteins along their long axes. The high binding affinity of tissue factor for factor VIIa may thus be accounted for by the occurrence of many intermolecular contacts in the complex.

    Title Host Immune Response in Renal Cell Cancer: Interleukin-4 (il-4) and Il-10 Mrna Are Frequently Detected in Freshly Collected Tumor-infiltrating Lymphocytes.
    Date October 1995
    Journal Cancer Immunology, Immunotherapy : Cii
    Excerpt

    Human renal cell cancer (RCC) is clearly responsive to immunotherapy. Clinical responses may be mediated by "non-specific" (e.g. natural killer, NK, cells) or "specific" MHC-class-I-restricted tumor-specific CD8+ T lymphocytes. Typically RCC progresses, however, despite significant infiltration of various lymphoid cells. We examined freshly isolated RCC tumor-infiltrating lymphocytes (TIL) derived from seven RCC patients for cytokine expression by the polymerase chain reaction (PCR). Established RCC tumor cell lines derived from these RCC patients were negative for interleukin-2 (IL-2), IL-4, IL-10, and interferon gamma and found to be positive for tumor necrosis factor alpha (TNF alpha), IL-6, IL-1 beta, granulocyte/macrophage-colony-stimulating factor (GM-CSF), and transforming growth factor beta 1 (TGF beta 1) message as detected by PCR. An identical pattern of cytokine mRNA expression was identified in other long-term RCC lines and in normal human kidney cells upon culture, but not in two Wilms tumor cell lines tested. Short-term-, and long-term-established RCC lines, but not Wilms tumor lines, secreted substantial levels of GM-CSF, TNF alpha, IL-1 beta, and IL-6 as detected by enzyme-linked immunosorbent assay. Both RCC lines and Wilms tumor lines secreted TGF beta 1. In comparison, normal kidney cells secreted IL-6 and GM-CSF, but not IL-1 beta, or TFG beta 1 under identical in vitro cell culture conditions. We applied PCR-based methods to characterize the cytokine mRNA expression pattern in immune cells infiltrating into renal cell cancer without the need for expansion of such effector cells in vitro. Examining freshly collected RCC TIL by PCR from patients with primary cell cell cancer, we could demonstrate that such cells, but not lympho-mononuclear cells harvested from normal human kidney tissue, typically exhibit IL-4 and IL-10 mRNA expression.

    Title Tissue Factor: Molecular Recognition and Cofactor Function.
    Date August 1995
    Journal The Faseb Journal : Official Publication of the Federation of American Societies for Experimental Biology
    Excerpt

    One aspect of the inflammatory response is the activation of the coagulation protease cascade resulting from the expression of tissue factor (TF) on vascular cells. TF is the cell-surface receptor for the coagulation serine protease factor VIIa, providing cofactor function by "switching on" the catalytic site of the bound enzyme and by contributing to the assembly with macromolecular substrate. The recently determined crystal structure of the TF extracellular domain shows two beta-strand modules of C2 immunoglobulin-like topology that align at a 125 degrees angle with an extensive intermodule interface. Mutagenesis studies have identified residues in both modules that are important for the binding of ligand. The deduced ligand interface extends from the convex side of the molecule into the concave side of the elbow angle. Specific binding residues control the catalytic activity of the bound protease. At the lower end of the carboxyl-terminal module, basic residues form part of a region that is important for both recognition and activation of macromolecular substrate and, potentially, for modulation of proteolytic function. After combining the biochemical data with the crystal structure, a model of TF function can be proposed in which the catalytic activity of the active site of the protease and the extended recognition of macromolecular substrates are separately controlled by distinct structural sites of the cofactor.

    Title An in Vitro Assessment of Tooth Preparation for Porcelain Veneer Restorations.
    Date July 1995
    Journal Journal of Dentistry
    Excerpt

    OBJECTIVES: This in vitro study aimed to examine the depth of preparation and incidence of dentine exposure resulting from the use of a 'freehand' technique to prepare maxillary central incisors for porcelain veneers. METHODS: Twenty-two maxillary central incisors were selected. Prior to preparation an index of the labial surface of each tooth was recorded and the tooth secured in a jig to permit accurate relocation. Two operators each prepared 11 teeth aiming to reduce the labial thickness evenly by 0.5 mm. Low viscosity silicone impression material was then placed on the index and the teeth relocated into the jig. Upon removal, this material was sectioned in the cervical, middle and incisal thirds of the tooth and its thickness measured using a toolmaker's microscope. The teeth were acid etched and also stained with a dentine dye to identify any area of dentine exposed during preparation. RESULTS: Significant differences (P < 0.001) in the depth of preparation at different sites, with least reduction in the mid-incisal region, were found. Greater reduction was found at the cervical and proximal margins with areas of dentine exposed at those sites in the majority of teeth. CONCLUSIONS: In view of the incidence and position of dentine exposure found in this study, the use of a dentine bonding system during the placement of porcelain veneers would appear essential when employing a 'freehand' preparation technique.

    Title Energetic Contributions and Topographical Organization of Ligand Binding Residues of Tissue Factor.
    Date June 1995
    Journal Biochemistry
    Excerpt

    Tissue factor is the cellular receptor and macromolecular enzymatic cofactor for the serine protease coagulation factor VIIa. The ligand binding extracellular domain of tissue factor consists of two structural modules which fold similar to fibronectin type III modules, consistent with the classification of tissue factor as a member of the class 2 cytokine receptor family. On the basis of the three-dimensional structure, we here analyze the importance of tissue factor residues for binding of ligand by scanning alanine mutagenesis. The identified significant binding contacts account for as much as 80% of the calculated total free energy of ligand binding. Most residues with energetic contributions to ligand binding are well exposed to solvent, and the area for ligand interaction extends from the cleft formed by the two structural modules (residues Lys20, Ile22, Lys48, Asp58, Arg135, Phe140) to the convex-shaped edge of the three- and four-stranded sheets characterized by a patch of surface-exposed hydrophobic side chains in the amino-terminal module (residues Gln37, Asp44, Trp45, Phe76, Tyr78). The binding residues are dispersed over an extended surface area, indicating adaptation to the recognition of specific structural modules of the macromolecular ligand factor VIIa. This analysis provides detailed insight into the three-dimensional organization of the ligand docking structure of the initiating cofactor for the coagulation pathways.

    Title Comparison of the Quality of Obturation Following Endosonic Versus Hand Instrumentation.
    Date February 1995
    Journal International Endodontic Journal
    Excerpt

    This study was undertaken to compare the quality of root canal obturation following preparation by endosonic or hand instrumentation. Forty single-canal, extracted lower premolar teeth were selected. One group of 20 teeth was prepared using a standard step-back technique, the other 20 teeth were prepared with an ultrasonic machine. The groups were subdivided, with two operators preparing 10 teeth of each group. The teeth were obturated by a third operator using cold laterally condensed gutta percha. The root apices were then immersed in methylene blue dye for 48 h and the teeth sectioned longitudinally. Image analysis recorded the amount of sealer and void within the obturated canal. The linear distance of dye penetration was measured to provide an indication of apical seal. Examination of the root canal shape resulting from the different preparation techniques used was also undertaken. No significant difference was noted in the percentage of sealer and void present in the root canals obturated after endosonic or hand instrumentation. There was a slightly greater although not significant increase in the degree of linear penetration of dye in canals prepared endosonically. The endosonic technique used in this study appeared to produce a canal preparation of slightly less continuous taper than that obtained with hand preparation.

    Title Influence of Age on the Extent of Voids in Root Canals Sealed Using a Cold Lateral Condensation Technique.
    Date February 1995
    Journal International Endodontic Journal
    Excerpt

    The aim of this study was to examine whether it is more difficult to achieve complete obturation of the root canal in teeth from different age groups, using the measurement of voids within the obturated canal to determine the quality of endodontic therapy. One-hundred and fifty-two single-rooted premolar teeth extracted from patients of known age were collected. Following cleaning and storage the teeth were decoronated and radiographed. Forty selected teeth were allocated to one of four age-groups, (under 20, 20-35, 36-50, over 50 years) each consisting of 10 teeth. The working length was determined radiographically and preparation was carried out using the step-back technique. Each canal was obturated using cold lateral condensation with Tubliseal cement. The roots were then sectioned longitudinally and photographed. Sections and transparencies were subjected to image analysis to determine the total areas of root canal, sealer and voids respectively and statistical analysis of the differences between the various age groups was undertaken. There was a trend towards a reduction in the areas of sealer and sealer plus void with respect to increasing age group, although no significant differences existed. A significant relationship (P < 0.05) was found between the area of voids found in the youngest group when compared with all other groups, the greatest cumulative area of voids being found in the youngest teeth.

    Title Mass Spectrometric Identification of a Naturally Processed Melanoma Peptide Recognized by Cd8+ Cytotoxic T Lymphocytes.
    Date January 1995
    Journal The Journal of Experimental Medicine
    Excerpt

    We and others have previously reported that melanoma-specific, cytotoxic T lymphocytes (CTL) define a minimum of six class I-presented peptide epitopes common to most HLA-A2+ melanomas. Here we show that three of these peptide epitopes are coordinately recognized by a CTL clone obtained by limiting dilution from the peripheral blood of an HLA-A2+ melanoma patient. Tandem mass spectrometry was used to characterize and sequence one of these three naturally processed melanoma peptides. One of the potential forms of the deduced peptide sequence (XXTVXXGVX, X = I or L) matches positions 32-40 of the recently identified melanoma gene MART-1/Melan-A. This peptide (p939; ILTVILGVL) binds to HLA-A2 with an intermediate-to-low affinity and is capable of sensitizing the HLA-A2+ T2 cell line to lysis by CTL lines and clones derived from five different melanoma patients. A relative high frequency of anti-p939-specific effector cells appear to be present in situ in HLA-A2+ melanoma patients, since p939 is also recognized by freshly isolated tumor infiltrating lymphocytes. p939 represents a good candidate for the development of peptide-based immunotherapies for the treatment of patients with melanoma.

    Title Changes in Patient Age and Tooth Distribution for Root Canal Treatment in a Teaching Hospital over a 15-year Period.
    Date January 1995
    Journal International Endodontic Journal
    Excerpt

    This study was undertaken to determine the changing pattern of root canal treatment undertaken by undergraduates in a teaching hospital over a period between 1976 and 1990 in terms of the incidence of root canal treatment, noting particularly changes in the types of tooth treated and in the age distribution of patients receiving treatment. It was found that the pattern of provision of root canal treatment has altered in recent years to involve a greater proportion of multi-rooted posterior teeth. More treatment is also being provided for older patients. The trends are comparable with those that have occurred in general dental practice.

    Title Surface Plasmon Resonance Studies of the Interaction Between Factor Vii and Tissue Factor. Demonstration of Defective Tissue Factor Binding in a Variant Fvii Molecule (fvii-r79q).
    Date December 1994
    Journal Biochemistry
    Excerpt

    The blood coagulation cascade is initiated when vessel injury allows factor VII (FVII) to form a complex with tissue factor (TF). Complete deficiency of FVII causes a lethal bleeding diathesis, but individuals with moderately reduced FVII levels are often asymptomatic. Some of these individuals have circulating partially functional FVII, as a result of point missense mutations in critical parts of the molecule. One such mutation has been reported at position 79 in the first epidermal growth factor-like (EGF) domain of FVII, where an arginine residue has been replaced by glutamine. There is controversy as to whether or not this mutation reduces the affinity of the FVII/TF interaction compared to wild-type FVII. To address this problem, we have expressed recombinant FVII-R79Q and subjected it to detailed biochemical analysis. One-stage FVII:C assays show the variant FVII to have reduced activity with respect to the wild type. Rates of autoactivation and activation by FXa to the two-chain molecule were identical for wild-type and variant FVII. The Vmax for FX activation was lower for the mutant as measured using an amidolytic assay for FX activity. In contrast, the Km for FX was lower for the variant than the wild-type molecule. Peptidyl substrate hydrolysis was virtually identical for both variant and normal FVIIa in the presence and absence of TF. The variant has reduced affinity for TF as measured by surface plasmon resonance. FVII-R79Q has an association rate constant (kassoc) one-fifth of that of normal FVII, but a similar kdiss, resulting in a decrease in the affinity of the enzyme for its cofactor.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Crystal Structure of the Extracellular Region of Human Tissue Factor.
    Date September 1994
    Journal Nature
    Excerpt

    Tissue factor is a cell-surface glycoprotein receptor which initiates the blood coagulation cascade after vessel injury by interacting with blood clotting factor VII/VIIa and which is implicated in various pathological processes. When bound to tissue factor, factor VII is readily converted to the active protease factor VIIa by trace amounts of factors Xa, IXa or VIIa. Human tissue factor consists of 263 residues, the first 219 of which comprise the extracellular region. We have determined the crystal structure of the extracellular region at a resolution of 2.2 A. Tissue factor consists of two immunoglobulin-like domains associated through an extensive, novel, interdomain interface region. The binding site for factor VII lies at the interface region and involves residues from domain 1 and an extended loop (binding 'finger') of domain 2. This is the first reported structure of a representative of the class 2 cytokine receptor family, which also includes interferon-alpha, interferon-gamma (refs 2, 3) and interleukin-10 (ref. 4) receptors.

    Title Delineation of Two Functionally Distinct Domains of Cytosolic Phospholipase A2, a Regulatory Ca(2+)-dependent Lipid-binding Domain and a Ca(2+)-independent Catalytic Domain.
    Date August 1994
    Journal The Journal of Biological Chemistry
    Excerpt

    Cytosolic phospholipase A2 (cPLA2) associates with natural membranes in response to physiological increases in Ca2+, resulting in the selective hydrolysis of arachidonyl phospholipids. The isolation and sequence analysis of cPLA2 cDNA clones from four different species revealed several highly conserved regions. The NH2-terminal conserved region is homologous to several other Ca(2+)-dependent lipid-binding proteins. Here we report that the first 178 residues of cPLA2, containing the homologous Ca(2+)-dependent lipid-binding (CaLB) motif, and another recombinant protein containing the cPLA2(1-178) fragment placed at the COOH terminus of the maltose-binding protein (MBP-CaLB) associate with membranes in a Ca(2+)-dependent manner. cPLA2 and MBP-CaLB also bind to synthetic liposomes at physiological Ca2+ concentrations, demonstrating that accessory proteins are not required. In contrast, delta C2, a truncated cPLA2 lacking the CaLB domain, fails to associate with membranes and fails to hydrolyze liposomal substrates. However, both delta C2 and cPLA2 hydrolyze monomeric 1-palmitoyl-2-lysophosphatidylcholine at identical rates in a Ca(2+)-independent fashion. These results delineate two functionally distinct domains of cPLA2, the Ca(2+)-independent catalytic domain, and the regulatory CaLB domain that presents the catalytic domain to the membrane in response to elevated Ca2+.

    Title Symptoms of Premenstrual Syndrome As a Function of Beta-endorphin: Two Subtypes.
    Date July 1994
    Journal Progress in Neuro-psychopharmacology & Biological Psychiatry
    Excerpt

    1. Forty six women presenting with symptoms of premenstrual syndrome (PMS) were studied. Ages ranged from 21 to 32. All women answered a questionnaire based on DSM-III-R criteria. They then had serum beta-endorphin levels drawn on day 1 and day 20 of their menstrual Cycle. 2. Beta-endorphin levels were compared with symptom presentation. Such symptoms as anxiety, food cravings and physical discomfort were associated with significant decline in beta-endorphin. Other symptoms were found equally distributed in both groups. The existence or absence of beta-endorphin decline in specific PMS subgroup was postulated.

    Title Activation of Factor X by Factor Viia on Monocyte Cell Surfaces.
    Date July 1994
    Journal Blood
    Title Synthesis and Characterization of Wild-type and Variant Gamma-carboxyglutamic Acid-containing Domains of Factor Vii.
    Date January 1994
    Journal Biochemistry
    Excerpt

    Synthetic peptides corresponding to portions of the wild-type and variant sequences of the human factor VII gamma-carboxyglutamic acid (Gla)-containing domain have been prepared by direct peptide synthesis using the Fmoc-based protection strategy. Peptides were purified by ion-exchange and reversed-phase chromatography and characterized as the correct products. A peptide comprising residues 1-49 (GP 1-49) inhibited the activation of factor X (FX) by soluble tissue factor (sTF) and recombinant activated factor VII (rFVIIa). In the absence of phospholipid, no inhibition by this peptide was observed. GP 1-49 did not inhibit the hydrolysis of a peptidyl substrate by rFVIIa in the presence of either sTF or relipidated TF apoprotein in the presence or absence of phospholipid. A similar peptide (residues 1-38, GP 1-38) that did not contain the aromatic stack region was also inhibitory. Two variant peptides, one identical to GP 1-49 but lacking the N-terminal alanine residue (GP 2-49) and one identical to GP 1-38 but with an arginine to alanine substitution at position 9 (GP 1-38 R9A), showed substantially reduced inhibitory activity. Kinetic analysis of the inhibition of Xa generation by GP 1-49 revealed a noncompetitive mode of inhibition, probably via a substrate-depletion mechanism. GP 1-49 does not inhibit by preventing FX binding to phospholipid surfaces. This indicates that the N-terminal residues of the FVII Gla domain are important for the structural integrity of the peptide, and implicates the Gla domain per se in a direct interaction with phospholipid-bound FX.

    Title Effects of Serum and Insulin-like Growth Factors on Human Neuroblastoma Cell Growth.
    Date January 1994
    Journal Regulatory Peptides
    Excerpt

    Insulin-like growth factors (IGF-I and IGF-II) are mitogenic polypeptides expressed in both developing and adult tissues. To examine the effects of IGFs on neuronal growth, we used SH-SY5Y neuroblastoma cells as an in vitro model of nervous system development. In the current study, we found that either IGF-I (0.1 to 10 nM), insulin (0.1 to 5 micrograms/ml) or calf serum (0.1 to 3%) increased SH-SY5Y proliferation over a 3 day period in a dose dependent manner. In each case, treatment with anti-IGF-I receptor antibodies blocked cell proliferation. IGF-II mRNA levels correlated with SH-SY5Y cell density; subconfluent cells expressed high levels of IGF-II mRNA while low levels of IGF-II mRNA were present in confluent cells. Similarly, serum deprivation increased IGF-I receptor mRNA by 4-fold. Collectively, these results support the concept that an IGF/IGF-I receptor system at least partially mediates SH-SY5Y cell proliferation and suggests the importance of IGFs in regulating neuronal growth.

    Title Igf Receptor Function and Regulation in Autocrine Human Neuroblastoma Cell Growth.
    Date January 1994
    Journal Regulatory Peptides
    Excerpt

    Insulin-like growth factor-II (IGF-II) and its receptors (type I and II IGF receptors) are expressed in the nervous system in a tissue and developmentally specific manner. We have previously shown that SH-SY5Y human neuroblastoma cells synthesize and secrete high levels of IGF-II, and respond to it with increased neuritic outgrowth, DNA synthesis, and cell proliferation. SH-SY5Y cells also produce type I IGF and IGF-II/M6P receptors; however, it is not known whether these receptors mediate the observed growth promoting effects of IGF-II. In this study, we assayed the role of type I IGF receptor and IGF-II/M6P receptor expression in mediating autocrine IGF-II induced growth. Using anti-receptor antibodies, we found that IGF-II stimulates cell proliferation via the type I IGF receptor but not via the IGF-II/M6P receptor. By Northern analysis, we detected increased mRNA expression of both receptors, with more dramatic changes in type I IGF receptor expression. Collectively, our results indicate a role for the type I IGF receptor in mediating IGF-II induced autocrine neuroblastoma cell growth.

    Title Crystallization and Preliminary X-ray Analysis of Human Tissue Factor Extracellular Domain.
    Date January 1994
    Journal Journal of Molecular Biology
    Excerpt

    The extracellular domain (residues 1 to 220) of human tissue factor has been cloned and expressed in Escherichia coli and purified to isoelectric homogeneity. Single crystals suitable for X-ray analysis have been obtained by vapour diffusion. They belong to the tetragonal space group P4(1)2(1)2 or P4(3)2(1)2 with a = b = 45.2 A, c = 231.5 A, contain one molecule per asymmetric unit and diffract to 2.6 A resolution. Native and derivative data sets have been collected to 3.6 and 3.9 A, respectively.

    Title Detection of Missense Mutations by Single-strand Conformational Polymorphism (sscp) Analysis in Five Dysfunctional Variants of Coagulation Factor Vii.
    Date December 1993
    Journal Human Molecular Genetics
    Excerpt

    Five unrelated subjects with dysfunctional coagulation factor VII (FVII) were studied in order to identify missense mutations affecting function. Exons 2 to 8 and the intron-exon junctions of their FVII genes were amplified from peripheral white blood cell DNA by PCR and screened by SSCP analysis. DNA fragments showing aberrant mobility were sequenced. The following mutations were identified: in case 1 (FVII:C < 1%, FVII:Ag 18%) a heterozygous A to G transition at nucleotide 8915 in exon 6 results in the amino acid substitution Lys-137 to Glu near the C-terminus of the FVIIa light chain; in case 2 (FVII:C 7%, FVII:Ag 47%) a heterozygous A to G transition at nucleotide 7834 in exon 5 results in the substitution of Gln-100 by Arg in the second EGF-like domain; in case 3 (FVII:C 20%, FVII:Ag 76%) a homozygous G to A transition at nucleotide position 6055 in exon 4 was detected resulting in substitution of Arg-79 by Gln in the first EGF-like domain; in case 5 (FVII:C 10%, FVII:Ag 52%) a heterozygous C to T transition at nucleotide position 6054 in exon 4 also results in the substitution of Arg79, but in this case it is replaced by Trp; case 4 (FVII:C < 1%, FVII:Ag 100%) was homozygous for a previously reported mutation (G to A) at nucleotide position 10715 in exon 8, substituting Gln for Arg at position 304 in the protease domain. Cases 1, 2 and 5 evidently have additional undetected mutations.

    Title Reversibility of Serum Removal Effects on Igf-ii Mrna in Human Neuroblastoma Cells.
    Date November 1993
    Journal Annals of the New York Academy of Sciences
    Title Pkc Activity and Pkc-alpha Mrna Content Are Reduced in Serum-derived Human Neuroblastoma Cells Without Concomitant Induction of Differentiation.
    Date September 1993
    Journal Experimental Cell Research
    Excerpt

    Protein kinase C (PKC) is a serine/threonine kinase which is thought to play an important role in cellular proliferation and differentiation. PKC activity is stimulated physiologically by diacylglycerol and experimentally by phorbol esters. Long-term exposure of human neuroblastoma cells to phorbol esters results in down-regulation of PKC activity and induction of neuronal differentiation. In this study, we explored the hypothesis that reduced PKC expression is necessary for differentiation of the human neuroblastoma cell line SK-N-SH. PKC activity and PKC-alpha mRNA levels were assayed in cultured SK-N-SH cells over a period of several days in the presence or absence of serum. These determinants of PKC expression were compared with several known markers of neuroblastoma differentiation, including neurite outgrowth and steady-state levels of c-myc and GAP43 mRNA. We observed steady losses of PKC activity and PKC-alpha mRNA content after transfer of cells to serum-free or chemically defined media. However, morphological and biochemical differentiation of SK-N-SH cells occurred only in chemically defined medium, perhaps due to the presence of insulin. We conclude that while loss of PKC may be associated with neuroblastoma differentiation, diminished PKC alone is not sufficient to induce or support the differentiation process.

    Title Structural Requirements for the Interaction Between Tissue Factor and Factor Vii: Characterization of Chymotrypsin-derived Tissue Factor Polypeptides.
    Date June 1993
    Journal The Biochemical Journal
    Excerpt

    Tissue Factor (TF) is the cellular receptor for coagulation Factor VII/VIIa (FVII/VIIa). TF binds to FVIIa and promotes the rapid activation of the zymogen substrates Factors IX and X (FIX and FX) to the respective serine proteinases. In order to probe structure-function relationships in TF, we have subjected the truncated membrane-bound variant, TF 1-243, to proteolytic digestion in SDS-containing gels. Three major polypeptide fragments were generated by proteolysis of TF 1-243 with chymotrypsin, producing cleavages C-terminal to residues 34, 76 and 103. All three polypeptides, TF 35-243, 77-243 and 104-243, bound biotinylated human FVII in a highly specific ligand blot assay. High-performance electrophoretic chromatography was used to isolated chymotrypsin-derived fragments of TF. These purified fragments bound FVII in ligand blots, and two of the three polypeptides exhibited much reduced, but significant, procoagulant activity in a chromogenic assay for the generation of Factor Xa in the presence of FVIIa and Ca2+. The smallest chymotrypsin-derived TF polypeptide, TF 104-243, showed reduced binding of FVII in ligand blot analyses, inhibited the activity of the full-length molecule, but had no procoagulant activity. These data suggest that a part of the binding site for FVII is contained within the TF sequence 104-243. The sequence TF 1-34 either contains a part of the FVII-binding domain or its removal leads to dysfunctional folding, disrupting binding sites elsewhere in the molecule.

    Title Regulation of Insulin-like Growth Factor-il Expression and Its Role in Autocrine Growth of Human Neuroblastoma Cells.
    Date May 1993
    Journal Journal of Cellular Physiology
    Excerpt

    Insulin-like growth factor-II (IGF-II) is highly expressed in fetal tissues and may act as an autocrine growth factor during early embryogenesis. The SH-SY5Y human neuroblastoma cell line also expresses IGF-II and its receptors and responds to exogenous IGF-II with increased DNA synthesis, cell division, and neuritic outgrowth. For this study, we tested the hypothesis that IGF-II mediates autocrine growth of SH-SY5Y cells in serum-free media. SH-SY5Y cells plated at high densities proliferated in serum-free media, whereas sparsely plated cells did not. IGF-II mRNA levels increased within 24 hours of serum deprivation and were associated with increased immunoreactive IGF-II protein. Exogenous addition of IGF-II increased 3H-TdR incorporation and cell number in a dose- and time-dependent fashion. By nuclear labelling experiments using 5-Bromo-2' deoxyuridine (BrdU), we detected a twofold higher percentage of S phase nuclei after a 24-hour incubation in IGF-II. Treatment of SH-SY5Y cells with anti-IGF-II antibodies in serum-free media inhibited cell proliferation, and this inhibition was partially overcome by the addition of increasing concentrations of IGF-II. Collectively, our results indicate that IGF-II mediates an autocrine growth mechanism in SH-SY5Y cells that is associated with increased IGF-II expression.

    Title Interferon-gamma Inhibits Dna Synthesis and Insulin-like Growth Factor-ii Expression in Human Neuroblastoma Cells.
    Date May 1993
    Journal Journal of Neuroscience Research
    Excerpt

    Interferon-gamma (IFN-gamma) is known to be an antiproliferative, differentiating agent in many cell types, including neuroblastoma. In this study, we determined the effects of IFN-gamma on cellular growth and expression of insulin-like growth factor II (IGF-II) and IGF receptors in the human neuroblastoma cell line SH-SY5Y. Incubation of SH-SY5Y cells in IFN-gamma (20-100 U/ml) induced the formation of long neuritic processes. IFN-gamma treatment also induced decreases in [3H]TdR incorporation, as well as serum-dependent changes in cell number. Treatment with IFN-gamma reduced cell number 33% in the presence of serum but had no effect on cell number in the absence of serum. IGF-II mRNA content was 60% inhibited by IFN-gamma, and was not serum dependent. The concentration of immunoreactive IGF-II in SH-SY5Y conditioned medium was also reduced in the presence of IFN-gamma, to less than half of control levels. In contrast, type I IGF receptor mRNA content was increased more than three-fold after treatment with IFN-gamma and serum. Co-incubation in IFN-gamma (20-100 U/ml) and IGF-II (3-10 nM) prevented the inhibitory effects of IFN-gamma on [3H]TdR incorporation in serum-free media. Our results suggest that IFN-gamma may inhibit DNA synthesis and cell growth by interfering with an IGF-II/type I IGF receptor autocrine growth or survival mechanism.

    Title Gene Expression of the Insulin-like Growth Factors and Their Receptors in Human Neuroblastoma Cell Lines.
    Date December 1992
    Journal Brain Research. Molecular Brain Research
    Excerpt

    Insulin-like growth factors (IGF) I and II are polypeptides with both growth-promoting and insulin-like metabolic effects. The developmentally specific expression of IGF I and II in the nervous system implies a role for these growth factors in neuronal growth and differentiation. In the present study, we analyzed IGF and IGF receptor mRNA transcripts from two related human neuroblastoma cell lines, SH-SY5Y and SK-N-SH. These cell lines provide a good in vitro model of neuronal development. Northern analysis of total RNA from each cell line revealed three IGF II mRNA transcripts (6.0, 4.8, and 1.8 kb), and one mRNA transcript each for the type I (11.0 kb) and type II (9.4 kb) IGF receptors. The size distribution of these multiple transcripts is similar to that found during normal human fetal development. These results establish both cell lines as good in vitro models for investigating the mechanisms which underly IGF gene expression during nervous system development.

    Title Gene Expression of the Insulin-like Growth Factors and Their Receptors in Cultured Human Retinal Pigment Epithelial Cells.
    Date April 1992
    Journal Brain Research. Molecular Brain Research
    Excerpt

    Insulin-like growth factors I and II (IGF I and II) are polypeptides with both growth-promoting and insulin-like metabolic effects. Immunoreactive IGF I is present in the retina and both IGF I and II are present in vitreal fluid. The type I and type II IGF receptors are also localized within the neural retina. The presence of IGFs and IGF receptors within the eye suggests a possible growth-promoting effect of IGFs on ocular tissues. IGF may enter the eye from the blood or, alternatively, arise from an ocular cell type which synthesizes and secretes IGF. IGF I and II mRNA synthesis in scleral cells and IGF I synthesis in rat retina suggests endogenous IGF production in the eye. We hypothesized that IGFs and IGF receptors are synthesized by one ocular cell type, the retinal pigment-epithelium (RPE). As a first step in studying IGF production by the RPE, we analyzed expression of the IGF and IGF receptor genes by cultured human RPE cells. Using Northern analysis, RNase protection and reverse-transcriptase polymerase chain reaction (RT-PCR), we found that cultured RPE cells synthesize mRNA for IGF I and the type I and type II IGF receptors.

    Title Nuclear Magnetic Resonance Studies of the Snake Toxin Echistatin. 1h Resonance Assignments and Secondary Structure.
    Date February 1992
    Journal European Journal of Biochemistry / Febs
    Excerpt

    The 1H-NMR spectrum of the snake toxin echistatin has been assigned using homonuclear two-dimensional methods. Consideration of the NOE patterns, coupling constants and putative hydrogen bonds enabled two regular features of secondary structure to be deduced: a beta-sheet/turn between residues 8 and 13 and a small anti-parallel beta-sheet and bulge linking residues 16-20 with residues 30-33. The recognition region of the protein containing the residues RGD lies in a loop joining the two strands of the beta-sheet. The beta-bulge and the loop containing the RGD sequence undergo pH-dependent conformational interconversion, modulated by the side chain of Asp29.

    Title Specialization in Endodontics.
    Date November 1991
    Journal International Endodontic Journal
    Excerpt

    The dental profession within the UK is currently reviewing the desirability of recognition of practice-based specialties and the establishment of specialist registers in various disciplines, including endodontics. In order to merit consideration for specialty status, in any discipline there must be an increase in the level of theoretical knowledge, and in the range and complexity of clinical procedures beyond the basic level of training. There must be an identified public need extending beyond the provisions of the general dental services for the particular skills of the practice-based specialist, who would also complement the consultant services, which have a limited capacity to provide the level of treatment demanded. Acceptance of the principle of specialist practice implies a belief that this will enhance the development of the profession, improve academic and clinical standards and provide a higher-quality and more widely available service to the public. The case for the specialist endodontist is argued, as is the importance of establishing appropriate academic and clinical training programmes to equip individuals with the requisite knowledge and skills. Academic institutions must develop imaginative and innovative courses to provide such education within the profession.

    Title Predictability of Radiographic Diagnosis of Variations in Root Canal Anatomy in Mandibular Incisor and Premolar Teeth.
    Date October 1991
    Journal International Endodontic Journal
    Excerpt

    Four hundred and fifty-five extracted mandibular incisor and 340 extracted mandibular premolar teeth were radiographed to assess the incidence of twin canals as visualized on radiographs taken in the mesio-distal direction. The ability to detect the presence of these twin canals by viewing radiographs taken in the standard bucco-lingual direction was then assessed. Using the guideline that 'disappearance or narrowing infers division' when viewing these radiographs resulted in a failure to diagnose one-third of the twin canals.

    Title Fluorescence and Kinetic Properties of Ru(iii) (nh3)5 Modified Transferrin.
    Date April 1991
    Journal Biochimica Et Biophysica Acta
    Excerpt

    Diferric transferrin was modified using aquopentaammine ruthenium(II), a reagent for surface-accessible uncoordinated histidines. Introduction of the cationic Ru(III) (NH3)3 + 5 group on the imidazole of only 5.5 of the 17 uncoordinated histidines enhances the rates of pyrophosphate-assisted iron removal from the N-terminal and C-terminal binding sites by 16- and 2-fold, respectively. This differential effect on the kinetics of the two sites may partially explain why in the native protein the N-terminal site is more labile than the C-terminal site in acidic solutions where histidine residues become positively charged through protonation. The distance between the metal site and nearby uncoordinated histidines was estimated from fluorescence energy transfer measurements using Tb (III) as the donor and pentaammine ruthenium(III)-labeled imidazole of histidine as the acceptor chromophore. A Tsou Chen-Lu statistical analysis of the fluorescence quenching data suggest that two residues in each lobe of the protein are involved in quenching the fluorescence. By using estimates for the index of refraction and the quantum yield and assuming the energy transfer follows parallel first-order kinetics, an upper limit for the donor-acceptor distance of about 1.4 nm was obtained, assuming two uncoordinated histidine residues equidistant from the metal. His-207 and His-242 in the N-terminal lobe of transferrin and His-535 and His-577 in the C-terminal lobe are within this distance, based on information from the lactoferrin crystal structure. It is postulated that His-207 in the N-terminal lobe and His-535 in the C-terminal lobe are the uncoordinated residues that, when protonated or modified with Ru(III) (NH3)3 + 5, lead to accelerated loss of iron from the two binding sites of the protein.

    Title Beta-endorphin Decline in Late Luteal Phase Dysphoric Disorder.
    Date February 1991
    Journal International Journal of Psychiatry in Medicine
    Excerpt

    The beta-endorphin hypothesis of late luteal phase dysphoric disorder (premenstrual syndrome or L2D2) was tested. Twenty-two PMS patients were compared to twenty-two controls. Levels of beta-endorphin, ACTH, FSH, LH, cortisol, prolactin and TRH were measured on the first and twentieth days after menses. PMS subjects exhibited a significantly greater drop in the opiate, beta-endorphin, (p less than .001) than controls. No relationship or significant e was seen with the other hormones/transmitters tested. The symptoms of PMS may be due to noradrenergic rebound following beta-endorphin decline. Symptomatic and pharmacological morphine withdrawal and manic phase of bipolar disorder are discussed as possible models for L2D2.

    Title In Vitro Marginal Microleakage Associated with Five Dentine Bonding Systems and Associated Composite Restorations.
    Date November 1990
    Journal Journal of Dentistry
    Excerpt

    Fifty sound premolar teeth, extracted for orthodontic purposes and stored at room temperature in physiological saline since extraction, were prepared with a standardized minimal two-surface Class II cavity. The teeth were then ascribed randomly to five groups, each of ten teeth. Each of four groups was restored using a different dentine bonding system and the associated posterior composite resin according to the manufacturer's instructions. The fifth group was restored with Superbond C & B dentine bonding system and Occlusin composite. After immersion in de-ionized water for at least 7 days, the teeth were sealed with nail varnish to within 1 mm of the margin of the restoration. The teeth were then immersed in 5 per cent buffered Eosin for 48 h. Following mesiodistal sectioning the sections were photographed and subjected to image analysis to establish the length of dye penetration at the tooth/restoration interface and the amount of dye penetration into the crown dentine. Tripton/Occlusin and XR Bond/Herculite XR groups showed a significantly (P less than 0.05) smaller amount of leakage than Gluma/Lumifor or Scotchbond 2/P50 combinations when assessed as a percentage of the tooth/restoration interface exhibiting leakage. When the percentage of crown dentine showing dye penetration was considered, the Tripton/Occlusin group showed less leakage than the other material combinations. It is concluded that Tripton, when used with the recommended composite, will allow significantly less microleakage than Gluma/Lumifor, Scotchbond 2/P50 or Superbond C & B/Occlusin combinations and a similar amount to XR Bond/Herculite XR in vitro.

    Title Immunologic Monitoring with Orthoclone Okt3 Therapy.
    Date November 1989
    Journal The Journal of Heart Transplantation
    Excerpt

    Muromonab-CD3 monoclonal antibody (Orthoclone OKT3) was used 146 times in 123 transplant recipients to treat or prevent rejection. Reversal and prevention of rejection were evaluated 1 week and 1 year after OKT3 therapy. Eighty-one percent (73 of 90) of the rejection episodes in kidney transplant patients were reversed with 67% of these grafts functioning at 1 year. Eighteen of 20 (90%) rejection episodes in liver transplant recipients were reversed, as were 11 of 13 (85%) heart transplant rejection episodes. Only one of five pancreas transplant episodes were reversed. OKT3 was used prophylactically in 18 transplant recipients (13 kidney, four heart, one liver). Immunologic monitoring (lymphocyte subsets, serum OKT3 levels, and antimurine antibodies) was performed during and after OKT3 therapy. Antimurine antibody formation rate was 28% (26 of 94 patients monitored). OKT3 therapy resulted in a rapid depletion of CD3+ cells from the peripheral circulation (less than 20/mm3) and trough serum OKT3 levels of greater than 800 ng/ml by the third day of therapy in all transplant types. Twenty-three patients (14 kidney, five liver, three heart, and one pancreas) were retreated with OKT3; reversal of rejection occurred in 87% of patients (13 of 15) with no antimurine antibodies and in 83% of patients (five of six) with a low antibody titer but did not occur in the two patients with a high antibody titer. Retreatment of patients with no anti-OKT3 antibody resulted in a depletion of CD3+ cells from the peripheral blood, but it took longer than in patients treated with OKT3 for the first time. Similarly, serum OKT3 levels increased slower in retreated patients compared with first treatment. In retreatment patients with a low titer antimurine antibody, often it was necessary to increase the dose of OKT3 to achieve adequate serum OKT3 levels and to deplete CD3+ cells. Antimurine antibody developed de novo in four of the 15 antibody negative patients (27%) who were retreated. Overall, OKT3 was an effective agent in reversing and preventing rejection in solid organ transplantation with few severe side effects and a low mortality. Retreatment with OKT3 should not be considered unless the antibody status of the patient is known. Development of low titer antibodies does not preclude successful retreatment with OKT3. Alternate antirejection therapy, however, should be used in patients with high titer antimurine responses.

    Title The Effect of Thyroxine, 3, 5-dimethyl-3'isopropyl-l-thyronine and Iodized Oil on Fetal Brain Development in the Iodine-deficient Sheep.
    Date August 1989
    Journal Acta Endocrinologica
    Excerpt

    Studies have been carried out to investigate the role of maternal and fetal thyroid function in the effects of iodine deficiency on fetal brain development in sheep. Iodine deficiency was established with an especially prepared low-iodine diet of maize and pea pollard. The iodine-deficient sheep were mated and the end of the second trimester of pregnancy (100 days gestation) were divided into groups which received either a sc injection of T4 or 3,5-dimethyl-3-isopropyl-L-thyromine or an injection of iodized oil. AT 140 days gestation (10 days prior to parturition) comparison of the fetuses delivered by hysterotomy revealed that the retarded fetal brain development observed in iodine deficiency was greatly improved by T4 and by iodized oil. However, T4 and iodized oil failed to correct the reduction in the number and the increase in the length of synaptic appositions which were observed in the fetal cerebral cortex after iodine deficiency. In addition, the histological appearance of the fetal thyroid gland and the levels of plasma thyroid hormones were restored to normal. The administration of 3,5-dimethyl-3'-isopropyl-L-thyronine had no effect on the retarded fetal brain and body development of the iodine-deficient fetuses. The lack of response may be due to the ability of 3,5-dimethyl-3'-isopropyl-L-thyronine to cross the ovine placenta as no reduction in the abnormally elevated fetal plasma TSH observed in spite of a fall in maternal plasma TSH and apparent restoration of maternal thyroid function.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Heavy Cocaine Use by Adolescents.
    Date April 1989
    Journal Pediatrics
    Excerpt

    Adolescents are susceptible to becoming cocaine users. Twenty-eight teenagers in a drug rehabilitation program were identified as heavy cocaine users and questioned about their experiences. They reported family conflict leading to running away (86%), school drop-out (24%) and delinquent behaviors such as stealing (96%) and vandalism (57%). Cocaine use started at 14 years for 21%, with progression from onset to at least weekly use within eight weeks (54%). Side effects included sleep disturbance (18%) and tolerance to cocaine (25%). Withdrawal was characterized by cocaine craving up to one month later (93%). The majority (96%) were polydrug abusers. Possible causes of teen substance abuse are discussed, and the importance of prevention is emphasized.

    Title Impaired Reception of Nonverbal Cues in Women with Premenstrual Tension Syndrome.
    Date April 1989
    Journal The Journal of Psychology
    Excerpt

    The ability to perceive nonverbal facial cues was tested in 30 White, middle-class females. Pre- and post-menses responses of 15 subjects diagnosed as having Premenstrual Tension Syndrome (PMS) were compared to the responses of age-matched controls. Each subject was asked to interpret videotaped facial cues of individuals engaged in a gambling task. Interpretive ability fluctuated during the menstrual cycle and was significantly impaired during the premenstrual phase.

    Title Vanadium.
    Date July 1988
    Journal Methods in Enzymology
    Title Interpretation of Drug Abuse Testing: Strengths and Limitations of Current Methodology.
    Date March 1988
    Journal Psychiatric Medicine
    Title Carboxyhemoglobin Concentration As an Index of Bilirubin Production in Neonates with Birth Weights Less Than 1,500 Grams: a Randomized Double-blind Comparison of Supplemental Oral Vitamin E and Placebo.
    Date January 1988
    Journal Journal of Pediatric Gastroenterology and Nutrition
    Excerpt

    A randomized double-blind study of the efficacy of oral vitamin E supplementation as a prophylactic treatment for hyperbilirubinemia was undertaken in preterm infants weighing less than 1,500 g. Hemoglobin (Hb) levels, blood carboxyhemoglobin saturation (HbCOc), end-tidal carbon monoxide concentration (ETCO), and serum total bilirubin levels were determined in each subject on the first and third days of the study. We found no differences between the vitamin E-treated and placebo-treated groups with respect to Hb, HbCOc, ETCO, or serum bilirubin levels on day 1 or 3. In addition, we reanalyzed our data to compare those infants who had low vitamin E levels at birth with those who had vitamin E levels greater than 0.4 mg/dl on day 1. We still observed no differences in Hb, HbCOc, ETCO, or serum bilirubin levels on day 1 or 3. The results of our study suggest that supplemental oral vitamin E therapy has no major effect on bilirubin production during the first 3 days of life in premature infants weighing less than 1,500 g at birth.

    Title The Effects of Breast Cancer Chemotherapy on Wound Healing in the Rat.
    Date July 1987
    Journal The Journal of Surgical Research
    Title Restoration of Brain Growth in Fetal Sheep After Iodized Oil Administration to Pregnant Iodine-deficient Ewes.
    Date February 1985
    Journal Journal of the Neurological Sciences
    Excerpt

    Iodized oil was administered as a single intramuscular injection to pregnant iodine-deficient ewes at 100 days gestation and the subsequent growth of their fetuses compared with that of fetuses of severely iodine-deficient ewes and of iodine-replete ewes, all of which were fed the same low-iodine diet. The administered iodine produced a remarkable improvement in thyroid function and physical appearance of the fetuses, accompanied by an increase in brain growth and to a lesser extent in body growth, which at 140 days was only slightly (but significantly) less than that of the controls. There was restoration of the number of cells (DNA) and myelination (cholesterol/DNA) in the cerebellum and cerebral hemispheres which suggests a catch-up of neuroblast development during pregnancy. Histological examination, however, revealed that counts of synapses (density) in the cerebral cortex after iodized oil were still less than those of the control fetal brains. The relevance of these findings to the effects of iodine deficiency on human brain development is discussed.

    Title The Use of Endodontically Treated Teeth in Restorative Dentistry.
    Date January 1985
    Journal Restorative Dentistry
    Title The Relationship of Endodontic Procedures to the Coronal Restoration.
    Date October 1984
    Journal Restorative Dentistry
    Title Value of Serum Immunoglobulins in the Diagnosis of Liver Disease.
    Date September 1984
    Journal Liver
    Excerpt

    Serum immunoglobulins were determined in 145 consecutive patients with biopsy-proven steatosis, alcoholic hepatitis, alcoholic hepatitis with fibrosis, alcoholic hepatitis with cirrhosis, inactive cirrhosis, chronic active alcoholic hepatitis, chronic active hepatitis, primary biliary cirrhosis and nonspecific hepatitis. IgM was both a sensitive (90.5%) and specific (86.2%) marker for primary biliary cirrhosis, and mean IgM levels were higher in primary biliary cirrhosis than in other diagnostic categories (p less than 0.05). IgA levels were most commonly elevated in alcoholic liver disease (p less than 0.005). IgA detected 95% of alcoholic disease, but was poorly specific (41.1%). A trend of rising IgA with increasing severity of alcoholic injury was observed, but the differences were not significant. IgG was most commonly elevated in chronic active hepatitis and alcoholic hepatitis with cirrhosis, but the IgG values did not differ significantly from those found in other diagnostic categories. Our results substantiate assertions of a diagnostic sensitivity for elevated IgA in alcoholic liver disease and IgM in primary biliary cirrhosis. With the exception of IgM in primary biliary cirrhosis, however, serum immunoglobulins are not specific markers of liver histology.

    Title Comparative Effects of Criticare Hn and Vivonex Hn in the Treatment of Malnutrition Due to Pancreatic Insufficiency.
    Date March 1984
    Journal The American Journal of Clinical Nutrition
    Excerpt

    The effect of high nitrogen Criticare and Vivonex on nutritional repletion was evaluated in 12 patients with malnutrition secondary to pancreatic insufficiency. The patients were randomized to receive either Criticare HN or Vivonex HN for a total period of 9 days. Each patient received 3000 kcal/day of either preparation, in addition to 1000 kcal of solid food. A significant weight gain was encountered in the group of patients receiving Criticare HN. Increased blood urea nitrogen was encountered in both groups of patients. All patients tolerated both diets well without evidence of relapse of their pancreatitis. No significant complications were encountered. Our results indicate that Criticare HN is of superior nutritional value, but both preparations resulted in increased blood urea nitrogen retention.

    Title Nortriptyline Plasma Levels and Clinical Response in Patients with Familial Pure Unipolar Depression and Blunted Trh Tests.
    Date February 1984
    Journal International Journal of Psychiatry in Medicine
    Excerpt

    We studied the efficacy of nortriptyline (NT) when given in doses which produce tricyclic antidepressant (TCA) levels within the proposed therapeutic "window" in a select patient group to assess the "window" hypothesis in a group of patients that was biologically homogeneous with respect to the TRH test and clinically homogeneous with respect to RDC, DSM III, and Winokur criteria. Pharmacokinetic and dose differences were controlled for by administering a NT dose-prediction test, giving the indicated dose, allowing levels to reach steady state and changing the dose, if necessary, to maintain NT levels within the range of 90-130 ng/ml. Using this protocol nine of ten patients responded to NT. This rate of response for a severely depressed patient group is comparable to response data for ECT and recent European data using regular NT levels to change doses of NT and assess appropriate NT trial duration.

    Title The Management of Root Resorption in Replanted and Transplanted Teeth.
    Date February 1984
    Journal International Endodontic Journal
    Title Serum Isoamylase As a Test for Pancreatic Insufficiency.
    Date July 1983
    Journal Gut
    Excerpt

    Total and pancreatic serum isoamylases were performed on 38 control subjects (21 non-smokers and 17 smokers) and 21 consecutive patients with pancreatic insufficiency before and after meal stimulation. There was no difference in the fasting or stimulated levels of total amylase (T), pancreatic isoamylase (P), or % P/T between smokers and non-smokers. The P/T ratio was significantly reduced in patients with pancreatic insufficiency when compared with each of the control groups (p less than 0.0005). Eleven of 21 patients with pancreatic insufficiency had raised total serum amylase, but none had a rise in the pancreatic fraction or P/T ratio. Our findings indicate that the T, P, and P/T ratio of serum amylase are not influenced by smoking or meal stimulation. A reduced P/T ratio in a patient with steatorrhoea suggests pancreatic insufficiency as the cause. Hyperamylasaemia in patients with pancreatic insufficiency does not necessarily imply a relapse.

    Title Small Intestinal Capsule Biopsy Under Endoscopic Guidance.
    Date April 1983
    Journal Gastrointestinal Endoscopy
    Title The Trh Test in the Diagnosis of Major and Minor Depression.
    Date March 1982
    Journal Psychoneuroendocrinology
    Title The Effect of Prostaglandin E2 on Ethionine-induced Pancreatitis in the Rat.
    Date October 1981
    Journal Gastroenterology
    Excerpt

    Prostaglandins have been reported to exert a protective effect against short-term experimental pancreatic injury. We evaluated the protective effect of PGE2 using a model designed to maintain pancreatitis over a period of 5-10 days. Acute pancreatitis was induced by daily intraperitoneal injections of DL-ethionine in rats maintained on a protein-free diet. Test periods of 10 and 5 days (parts I and II, respectively) were employed. In parts I and II, PGE2 0.1 microgram/g body wt was given subcutaneously 30 min before ethionine. In part II, a second daily dose of PGE2 0.1 microgram/g body wt was given 7 h after ethionine. PGE2 did not protect against the weight loss, decrease in food consumption, alteration in serum amylase, pancreatic necrosis, or mortality induced by ethionine. This study indicates that the protective effect of PGE2 observed in short-term experimental pancreatitis is not reproducible in a model in which pancreatitis is maintained for 5 and 10 day periods.

    Title Gold-induced Eosinophilic Enterocolitis: Response to Oral Cromolyn Sodium.
    Date July 1981
    Journal Gastroenterology
    Title The Thyroid-stimulating Hormone Response to Thyrotropin-releasing Hormone in Mania and Bipolar Depression.
    Date November 1980
    Journal Psychiatry Research
    Excerpt

    The release of thyroid-stimulating hormone (TSH) from the pituitary after infusion of 500 microgram of thyrotropin-releasing hormone (TRH) was decreased (p < 0.01) in manic patients and increased (p < 0.01) in bipolar depressed patients compared to a control group of patients with personality disorders. These results suggest that the TRH test may be useful in the diagnosis of psychiatric disorders and in the prediction of response to pharmacotherapy. We discuss the role of central monoaminergic systems in changes in the TSH response to TRH.

    Title Differentiating Mania from Schizophrenia by the Trh Test.
    Date November 1980
    Journal The American Journal of Psychiatry
    Title Trh-induced Tsh Response in Unipolar, Bipolar, and Secondary Depressions: Possible Utility in Clinical Assessment and Differential Diagnosis.
    Date September 1980
    Journal Psychoneuroendocrinology
    Title Thyroid Stimulating Hormone and Growth Hormone Responses to Thyrotropin Releasing Hormone in Anorexia Nervosa.
    Date August 1980
    Journal International Journal of Psychiatry in Medicine
    Excerpt

    Ten female patients who satisfied objective criteria for the diagnosis of anorexia nervosa were given 500 microgram of thyrotropin releasing hormone. Thyroid stimulating hormone and growth hormone responses were measured in duplicate by radioimmunoassay. These patients had a low normal delta thyroid stimulating hormone but a delayed peak response. In addition, these patients had pathological growth hormone release in response to thytotropin releasing hormone infusion. Both delayed peak thyroid stimulating hormone and growth hormone response to thyrotropin releasing hormone have been reported for patients with hypothalamic disorders.

    Title Deficient Prolactin Response to Morphine in Depressed Patients.
    Date August 1980
    Journal The American Journal of Psychiatry
    Title Irrigation and Medication of the Root Canal.
    Date July 1980
    Journal Journal of the British Endodontic Society
    Title Further Evidence of Hypothalamic-pituitary Dysfunction in Anorexia Nervosa.
    Date March 1980
    Journal The American Journal of Psychiatry
    Title Distinguishing Unipolar and Bipolar Depression by Thyrotropin Release Test.
    Date October 1979
    Journal Lancet
    Title A Direct Method for Determining Dopamine Synthesis and Output of Dopamine Metabolites from Brain in Awake Animals.
    Date June 1979
    Journal Journal of Neurochemistry
    Title A Method for the Study of Internal Spaces in Hard Tissue Matrices by Sem, with Special Reference to Dentine.
    Date June 1978
    Journal Journal of Microscopy
    Excerpt

    Infiltration of a porous hard tissue with methyl methacrylate, followed by dissolution of the tissue provides a three-dimensional methacrylate cast of spaces within the tissue. Examination of such a cast by scanning electron microscopy provides information on the nature and extent of the pore system to a degree that cannot readily be visualized by the direct examination of fractured surfaces. The findings described concern human dentine but the technique may have a wider application in studies on the internal structure of other hard tissues.

    Title G4 Dna Replication. I. Origin of Synthesis of the Viral and Complementary Dna Strands.
    Date April 1978
    Journal Journal of Molecular Biology
    Title Calcium Hydroxide in Root Canal Therapy. A Review.
    Date June 1977
    Journal British Dental Journal
    Title Critique of "rhythmic Correlates of Shift Work".
    Date December 1976
    Journal Communicating Nursing Research
    Title Critique of "effect on Postoperative Recovery Rate and Comfort of Four Approaches to Nursing Care of Dogs: a Pilot Study".
    Date December 1976
    Journal Communicating Nursing Research
    Title Glucose Modulation of Amino Acid-induced Glucagon and Insulin Release in the Isolated Perfused Rat Pancreas.
    Date February 1975
    Journal The Journal of Clinical Investigation
    Excerpt

    Interactions between glucose and arginine and a mixture of 20 amino acids found in normal rat serum were studied in the isolated perfused rat pancreas of normal rats, with release of immunoreactive glucagon and insulin as parameters. Secretion of both pancreatic hormones was low during the steady state, whether glucose (5 mM) was included in the perfusion medium or not. This glucose concentration significantly stimulated insulin release twofold and resulted in an 80% inhibition of basal glucagon release. Arginine and the amino acid mixture were potent stimulants of both hormones. Secretion of both hormones followed identical biphasic response patterns after addition of arginine or the amino acid mixture. However, stimulation of insulin release occurred only when glucose was included, whereas both phases of glucagon release were elicited in the absence of glucose and markedly reduced in its presence. The dose-dependency curves of hormone release due to arginine on one hand and the amino acid mixture on the other differed substantially: with arginine, release of insulin and glucagon was linear between a concentration of 0.3 and 20 mM. In contrast, the amino acid mixture resulted in half-maximal release for both hormones between a concentration of 3 and 4.5 mM, and maximal release between 6 and 8 mM. The dose-dependencies of glucose modulation of alpha- and beta-cell activity were also different: when the amino acid mixture was maintained at 15 mM and glucose varied (0-6.25 nM), no insulin release occurred until glucose was above 2.5 mM, whereas incremental inhibition of glucagon occurred through the complete dose range. It was also observed that glucose inhibition of amino acid-stimulated glucagon release was dissociated from glucose-dependent increase of insulin release.THESE STUDIES INDICATE THAT: (a) the alpha-cell, like the beta-cell, secretes at a low basal rate; (b) hypoglycemia per se is a weak stimulus for glucagon secretion compared to the high efficacy of a physiologic amino acid mixture; (c) glucose plays opposite roles in the mechanisms leading to amino acid-induced hormone release from the alpha- and beta-cells, functioning as an inhibitor in the first case and a permissive agent in the second, and (d) the data are compatible with the postulated existence of glucose and amino acid receptors in both the alpha- and beta-cells.

    Title Some Digenetic Trematodes from Synaphobranchid Eels.
    Date April 1974
    Journal The Journal of Parasitology
    Title Newborn Methemoglobinemia Following Propitocaine Intrapartum Epidural Block. First Case Report.
    Date February 1970
    Journal Obstetrics and Gynecology
    Title The Restoration of Vital Anterior Teeth.
    Date October 1969
    Journal Edinburgh Dental Hospital Gazette
    Title Hyperkinetic Behavior Disorders in Children: Clinical Results with Methylphenidate Hydrochloride (ritalin).
    Date October 1967
    Journal Western Medicine; the Medical Journal of the West
    Title Doping in Sports and Its Spread to At-risk Populations: an International Review.
    Date
    Journal World Psychiatry : Official Journal of the World Psychiatric Association (wpa)
    Excerpt

    Doping is now a global problem that follows international sporting events worldwide. International sports federations, led by the International Olympic Committee, have for the past half century attempted to stop the spread of this problem, with little effect. It was expected that, with educational programs, testing, and supportive medical treatment, this substance-abusing behavior would decrease. Unfortunately, this has not been the case. In fact, new, more powerful and undetectable doping techniques and substances are now abused by professional athletes, while sophisticated networks of distribution have developed. Professional athletes are often the role models of adolescent and young adult populations, who often mimic their behaviors, including the abuse of drugs. This review of doping within international sports is to inform the international psychiatric community and addiction treatment professionals of the historical basis of doping in sport and its spread to vulnerable athletic and non-athletic populations.

    Title Clinical Characterization of Individuals with Deletions of Genes in Holoprosencephaly Pathways by Acgh Refines the Phenotypic Spectrum of Hpe.
    Date
    Journal Human Genetics
    Excerpt

    Holoprosencephaly (HPE) is the most common developmental forebrain anomaly in humans. Both environmental and genetic factors have been identified to play a role in the HPE phenotype. Previous studies of the genetic bases of HPE have taken a phenotype-first approach by examining groups of patients with HPE for specific mutations or deletions in known or candidate HPE genes. In this study, we characterized the presence or absence of HPE or a microform in 136 individuals in which microarray-based comparative genomic hybridization (aCGH) identified a deletion of one of 35 HPE loci. Frank holoprosencephaly was present in 11 individuals with deletions of one of the common HPE genes SHH, ZIC2, SIX3, and TGIF1, in one individual with a deletion of the HPE8 locus at 14q13, and in one individual with a deletion of FGF8, whereas deletions of other HPE loci and candidate genes (FOXA2 and LRP2) expressed microforms of HPE. Although individuals with deletions of other HPE candidates (DISP1, LSS, HHIP, SMO, BMP4, CDON, CDC42, ACVR2A, OTX2, and WIF1) had clinically significant features, none had frank HPE or a microform. A search for significant aCGH findings in individuals referred for testing for HPE revealed a novel association of a duplication involving GSK3B at 3q13.33 with HPE or a microform, seen in two unrelated individuals.

    Title Avoiding Skin Burns with Transcranial Direct Current Stimulation: Preliminary Considerations.
    Date
    Journal The International Journal of Neuropsychopharmacology / Official Scientific Journal of the Collegium Internationale Neuropsychopharmacologicum (cinp)
    Title Functional Annotation, Genome Organization and Phylogeny of the Grapevine (vitis Vinifera) Terpene Synthase Gene Family Based on Genome Assembly, Flcdna Cloning, and Enzyme Assays.
    Date
    Journal Bmc Plant Biology
    Excerpt

    Terpenoids are among the most important constituents of grape flavour and wine bouquet, and serve as useful metabolite markers in viticulture and enology. Based on the initial 8-fold sequencing of a nearly homozygous Pinot noir inbred line, 89 putative terpenoid synthase genes (VvTPS) were predicted by in silico analysis of the grapevine (Vitis vinifera) genome assembly 1. The finding of this very large VvTPS family, combined with the importance of terpenoid metabolism for the organoleptic properties of grapevine berries and finished wines, prompted a detailed examination of this gene family at the genomic level as well as an investigation into VvTPS biochemical functions.

    Title Drug-eluting Stents for Coronary Artery Disease: A Review.
    Date
    Journal Medical Engineering & Physics
    Excerpt

    Over the past decade the introduction of drug-eluting stents (DESs) has revolutionised the treatment of coronary artery disease. However, in recent years concern has arisen over the long-term safety and efficacy of DESs due to the occurrence of late adverse clinical events such as stent thrombosis. With this concern in mind, research and development is currently centred on increasing the long-term safety and efficacy of DESs. The aim of this paper is to provide a thorough review of currently approved and promising investigational DESs. With dozens of companies involved in the development of new and innovative anti-restenotic agents, polymeric coatings and stent platforms, it is intended that this review paper will provide a clear indication of how DESs are currently evolving and prove a valuable reference tool for future research in this area.

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