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Sample records for human craniofacial disorders

  1. Regenerative Strategies for Craniofacial Disorders

    PubMed Central

    Garland, Catharine B.; Pomerantz, Jason H.

    2012-01-01

    Craniofacial disorders present markedly complicated problems in reconstruction because of the complex interactions of the multiple, simultaneously affected tissues. Regenerative medicine holds promise for new strategies to improve treatment of these disorders. This review addresses current areas of unmet need in craniofacial reconstruction and emphasizes how craniofacial tissues differ from their analogs elsewhere in the body. We present a problem-based approach to illustrate current treatment strategies for various craniofacial disorders, to highlight areas of need, and to suggest regenerative strategies for craniofacial bone, fat, muscle, nerve, and skin. For some tissues, current approaches offer excellent reconstructive solutions using autologous tissue or prosthetic materials. Thus, new “regenerative” approaches would need to offer major advantages in order to be adopted. In other tissues, the unmet need is great, and we suggest the greatest regenerative need is for muscle, skin, and nerve. The advent of composite facial tissue transplantation and the development of regenerative medicine are each likely to add important new paradigms to our treatment of craniofacial disorders. PMID:23248598

  2. Mouse Models of Rare Craniofacial Disorders.

    PubMed

    Achilleos, Annita; Trainor, Paul A

    2015-01-01

    A rare disease is defined as a condition that affects less than 1 in 2000 individuals. Currently more than 7000 rare diseases have been documented, and most are thought to be of genetic origin. Rare diseases primarily affect children, and congenital craniofacial syndromes and disorders constitute a significant proportion of rare diseases, with over 700 having been described to date. Modeling craniofacial disorders in animal models has been instrumental in uncovering the etiology and pathogenesis of numerous conditions and in some cases has even led to potential therapeutic avenues for their prevention. In this chapter, we focus primarily on two general classes of rare disorders, ribosomopathies and ciliopathies, and the surprising finding that the disruption of fundamental, global processes can result in tissue-specific craniofacial defects. In addition, we discuss recent advances in understanding the pathogenesis of an extremely rare and specific craniofacial condition known as syngnathia, based on the first mouse models for this condition. Approximately 1% of all babies are born with a minor or major developmental anomaly, and individuals suffering from rare diseases deserve the same quality of treatment and care and attention to their disease as other patients. PMID:26589934

  3. Heritability of the Human Craniofacial Complex.

    PubMed

    Šešelj, Maja; Duren, Dana L; Sherwood, Richard J

    2015-09-01

    Quantifying normal variation and the genetic underpinnings of anatomical structures is one of the main goals of modern morphological studies. However, the extent of genetic contributions to normal variation in craniofacial morphology in humans is still unclear. The current study addresses this gap by investigating the genetic underpinnings of normal craniofacial morphology. The sample under investigation consists of 75 linear and angular measurements spanning the entire craniofacial complex, recorded from lateral cephalographs of 1,379 participants in the Fels Longitudinal Study. Heritabilities for each trait were estimated using SOLAR, a maximum-likelihood variance components approach utilizing all pedigree information for parameter estimation. Trait means and mean effects of the covariates age, sex, age(2) , sex × age, and sex × age(2) were simultaneously estimated in the analytic models. All traits of the craniofacial complex were significantly heritable. Heritability estimates ranged from 0.10 to 0.60, with the majority being moderate. It is important to note that we found similar ranges of heritability occurring across the different functional/developmental components of the craniofacial complex, the splanchnocranium, the basicranium, and the neurocranium. This suggests that traits from different regions of the craniofacial complex are of comparable utility for the purposes of population history and phylogeny reconstruction. At the same time, this genetic influence on craniofacial morphology signals a caution to researchers of nongenetic studies to consider the implications of this finding when selecting samples for study given their project design and goals. PMID:26097051

  4. A review of craniofacial disorders caused by spliceosomal defects.

    PubMed

    Lehalle, D; Wieczorek, D; Zechi-Ceide, R M; Passos-Bueno, M R; Lyonnet, S; Amiel, J; Gordon, C T

    2015-11-01

    The spliceosome is a large ribonucleoprotein complex that removes introns from pre-mRNA transcripts. Mutations in EFTUD2, encoding a component of the major spliceosome, have recently been identified as the cause of mandibulofacial dysostosis, Guion-Almeida type (MFDGA), characterized by mandibulofacial dysostosis, microcephaly, external ear malformations and intellectual disability. Mutations in several other genes involved in spliceosomal function or linked aspects of mRNA processing have also recently been identified in human disorders with specific craniofacial malformations: SF3B4 in Nager syndrome, an acrofacial dysostosis (AFD); SNRPB in cerebrocostomandibular syndrome, characterized by Robin sequence and rib defects; EIF4A3 in the AFD Richieri-Costa-Pereira syndrome, characterized by Robin sequence, median mandibular cleft and limb defects; and TXNL4A in Burn-McKeown syndrome, involving specific craniofacial dysmorphisms. Here, we review phenotypic and molecular aspects of these syndromes. Given the apparent sensitivity of craniofacial development to defects in mRNA processing, it is possible that mutations in other proteins involved in spliceosomal function will emerge in the future as causative for related human disorders. PMID:25865758

  5. Vertical Craniofacial Morphology and its Relation to Temporomandibular Disorders

    PubMed Central

    Bavia, Paula Furlan

    2016-01-01

    ABSTRACT Objectives This study investigated the association between craniofacial morphology and temporomandibular disorders in adults. The influence of different craniofacial morphologies on painful temporomandibular disorders was also evaluated. Material and Methods A total of 200 subjects were selected, including 100 with temporomandibular disorders (TMD) and 100 without TMD (control), diagnosed by research diagnostic criteria for temporomandibular disorders. All subjects were submitted to lateral cephalometric radiographs, and classified as brachyfacial, mesofacial, or dolichofacial by Ricketts’ analysis. Data were analysed by Tukey-Kramer and Chi-square tests. Results No association between craniofacial morphology and TMD was found (P = 0.6622). However, brachyfacial morphology influences the presence of painful TMD (P = 0.0077). Conclusions Craniofacial morphology is not related to temporomandibular disorders in general. PMID:27489610

  6. Altered FGF signalling in congenital craniofacial and skeletal disorders.

    PubMed

    Moosa, Shahida; Wollnik, Bernd

    2016-05-01

    The fibroblast growth factor (FGF) signalling pathway has been the focus of intense genetic and functional research for several decades. The emerging data implicate FGF signalling in diverse regulatory processes, both in the developing embryo as well as in the adult organism. Alterations in this tightly regulated pathway can lead to a number of pathological conditions, ranging from well-recognized congenital disorders to cancer. In order to mediate their cellular processes, FGFs signal through a subfamily of tyrosine kinase receptors, called FGF receptors (FGFRs). In humans, four FGFRs are described, and, to date, mutations in FGFR1, FGFR2, and FGFR3 have been shown to underlie human developmental disorders. FGFs/FGFRs are known to be key players in both endochondral and intramembranous bone development. In this review, we focus on the major developmental craniofacial and skeletal disorders which result from altered FGF signalling. PMID:26686047

  7. Single gene disorders with craniofacial and oral manifestations.

    PubMed

    Patil, Shankargouda; Rao, Roopa S; Majumdar, Barnali

    2014-01-01

    Gene and environmental factors are instrumental in genesis of complex and wide range of disorders and syndromes. The newer gene sequencing and other advanced technologies have made our previous knowledge of genetic etiopathogenesis of various disorders more transparent. Single gene disorders refer to the disorders caused due to mutations in a single gene and a fair number of these manifest as craniofacial defects and anomalies. This review is an attempt to give a detailed insight into the varied single gene disorders and syndromes with an emphasis on dental implications. PMID:25707843

  8. Oral and Craniofacial Clinical Signs Associated to Genetic Conditions in Human Identification Part I: A Review

    PubMed Central

    Ayoub, Fouad; Aoun, Nicole; el Husseini, Hassan; Jassar, Houssam; Sayah, Fida; Salameh, Ziad

    2015-01-01

    Background: Forensic dentistry is one of the most reliable methods used in human identification when other technique as fingerprint, DNA, visual identification cannot be used. Genetic disorders have several manifestations that can target the intra-oral cavity, the cranio-facial area or any location in the human body. Materials and Methods: A literature search of the scientific database (Medline and Science Direct) for the years 1990 to 2014 was carried out to find out all the available papers that indicate oral, cranio-facial signs, genetic and human identification. Results: A table with 10 genetic conditions was described with oral and cranio-facial signs that can help forensic specialist in human identification. Conclusion: This review showed a correlation between genetics, facial and intra-oral signs that would help forensic ondontologist in the identification procedures. PMID:26028912

  9. Craniofacial syndromes and sleep-related breathing disorders.

    PubMed

    Tan, Hui-Leng; Kheirandish-Gozal, Leila; Abel, François; Gozal, David

    2016-06-01

    Children with craniofacial syndromes are at risk of sleep disordered breathing, the most common being obstructive sleep apnea. Midface hypoplasia in children with craniosynostosis and glossoptosis in children with Pierre Robin syndrome are well recognized risk factors, but the etiology is often multifactorial and many children have multilevel airway obstruction. We examine the published evidence and explore the current management strategies in these complex patients. Some treatment modalities are similar to those used in otherwise healthy children such as adenotonsillectomy, positive pressure ventilation and in the refractory cases, tracheostomy. However, there are some distinct approaches such as nasopharyngeal airways, tongue lip adhesion, mandibular distraction osteogenesis in children with Pierre Robin sequence, and midface advancement in children with craniosynostoses. Clinicians should have a low threshold for referral for evaluation of sleep-disordered-breathing in these patients. PMID:26454241

  10. The old and new face of craniofacial research: How animal models inform human craniofacial genetic and clinical data.

    PubMed

    Van Otterloo, Eric; Williams, Trevor; Artinger, Kristin Bruk

    2016-07-15

    The craniofacial skeletal structures that comprise the human head develop from multiple tissues that converge to form the bones and cartilage of the face. Because of their complex development and morphogenesis, many human birth defects arise due to disruptions in these cellular populations. Thus, determining how these structures normally develop is vital if we are to gain a deeper understanding of craniofacial birth defects and devise treatment and prevention options. In this review, we will focus on how animal model systems have been used historically and in an ongoing context to enhance our understanding of human craniofacial development. We do this by first highlighting "animal to man" approaches; that is, how animal models are being utilized to understand fundamental mechanisms of craniofacial development. We discuss emerging technologies, including high throughput sequencing and genome editing, and new animal repository resources, and how their application can revolutionize the future of animal models in craniofacial research. Secondly, we highlight "man to animal" approaches, including the current use of animal models to test the function of candidate human disease variants. Specifically, we outline a common workflow deployed after discovery of a potentially disease causing variant based on a select set of recent examples in which human mutations are investigated in vivo using animal models. Collectively, these topics will provide a pipeline for the use of animal models in understanding human craniofacial development and disease for clinical geneticist and basic researchers alike. PMID:26808208

  11. Disorders of Sex Development: Lessons to be Learned from Studies of Spina Bifida and Craniofacial Conditions.

    PubMed

    Holmbeck, G N; Aspinall, C L

    2015-05-01

    The purpose of this review is to discuss research methods and clinical management strategies employed with other conditions (i. e., spina bifida and craniofacial conditions) and how these methods and strategies could be applied to youth with disorders of sex development (DSD). The review focuses specifically on the potential overlap between DSD and these other conditions across the following 3 areas: (1) developmentally-oriented theories that underlie the research base for chronic physical conditions; (2) research designs and methodological features that have proved fruitful in these areas; and (3) the potential applicability to DSD of clinical management practices for youth with craniofacial conditions. PMID:25719736

  12. A multinational deployment of 3D laser scanning to study craniofacial dysmorphology in fetal alcohol spectrum disorders

    NASA Astrophysics Data System (ADS)

    Rogers, Jeff; Wernert, Eric; Moore, Elizabeth; Ward, Richard; Wetherill, Leah F.; Foroud, Tatiana

    2007-01-01

    Craniofacial anthropometry (the measurement and analysis of head and face dimensions) has been used to assess and describe abnormal craniofacial variation (dysmorphology) and the facial phenotype in many medical syndromes. Traditionally, anthropometry measurements have been collected by the direct application of calipers and tape measures to the subject's head and face, and can suffer from inaccuracies due to restless subjects, erroneous landmark identification, clinician variability, and other forms of human error. Three-dimensional imaging technologies promise a more effective alternative that separates the acquisition and measurement phases to reduce these variabilities while also enabling novel measurements and longitudinal analysis of subjects. Indiana University (IU) is part of an international consortium of researchers studying fetal alcohol spectrum disorders (FASD). Fetal alcohol exposure results in predictable craniofacial dysmorphologies, and anthropometry has been proven to be an effective diagnosis tool for the condition. IU is leading a project to study the use of 3D surface scanning to acquire anthropometry data in order to more accurately diagnose FASD, especially in its milder forms. This paper describes our experiences in selecting, verifying, supporting, and coordinating a set of 3D scanning systems for use in collecting facial scans and anthropometric data from around the world.

  13. The role of physical therapy in craniofacial pain disorders: an adjunct to dental pain management.

    PubMed

    Heinrich, S

    1991-01-01

    Treatment of craniofacial pain disorders is often complicated by diverse factors such as acute or chronic trauma and persistent postural changes. In addition, emotional issues and life stress often cloud the recovery process. Physical therapists, with their diverse knowledge base and highly competent treatment skills, can be quite effective in assisting dentists and physicians with management of the many difficult upper quarter and craniofacial pain syndromes. This article reviews the role of myofascial and craniosacral dysfunction, as well as the function of posture, tension, and stress in the development of these syndromes. Additionally, it provides a comprehensive overview of the many evaluative techniques and treatment options that can be provided by today's physical therapists. PMID:1843484

  14. Utilizing the chicken as an animal model for human craniofacial ciliopathies.

    PubMed

    Schock, Elizabeth N; Chang, Ching-Fang; Youngworth, Ingrid A; Davey, Megan G; Delany, Mary E; Brugmann, Samantha A

    2016-07-15

    The chicken has been a particularly useful model for the study of craniofacial development and disease for over a century due to their relatively large size, accessibility, and amenability for classical bead implantation and transplant experiments. Several naturally occurring mutant lines with craniofacial anomalies also exist and have been heavily utilized by developmental biologist for several decades. Two of the most well known lines, talpid(2) (ta(2)) and talpid(3) (ta(3)), represent the first spontaneous mutants to have the causative genes identified. Despite having distinct genetic causes, both mutants have recently been identified as ciliopathic. Excitingly, both of these mutants have been classified as models for human craniofacial ciliopathies: Oral-facial-digital syndrome (ta(2)) and Joubert syndrome (ta(3)). Herein, we review and compare these two models of craniofacial disease and highlight what they have revealed about the molecular and cellular etiology of ciliopathies. Furthermore, we outline how applying classical avian experiments and new technological advances (transgenics and genome editing) with naturally occurring avian mutants can add a tremendous amount to what we currently know about craniofacial ciliopathies. PMID:26597494

  15. Phenotypic evolution of human craniofacial morphology after admixture: a geometric morphometrics approach.

    PubMed

    Martínez-Abadías, Neus; González-José, Rolando; González-Martín, Antonio; Van der Molen, Silvina; Talavera, Arturo; Hernández, Patricia; Hernández, Miquel

    2006-03-01

    An evolutionary, diachronic approach to the phenotypic craniofacial pattern arisen in a human population after high levels of admixture and gene flow was achieved by means of geometric morphometrics. Admixture has long been studied after molecular data. Nevertheless, few efforts have been made to explain the morphological outcome in human craniofacial samples. The Spanish-Amerindian contact can be considered a good scenario for such an analysis. Here we present a comparative analysis of craniofacial shape changes observed between two putative ancestor groups, Spanish and precontact Aztecs, and two diachronic admixed groups, corresponding to early and late colonial periods from the Mexico's Central Valley. Quantitative shape comparisons of Amerindian, Spanish, and admixed groups were used to test the expectations of quantitative genetics for admixture events. In its simplest form, this prediction states that an admixed group will present phenotypic values falling between those of both parental groups. Results show that, in general terms, although the human skull is a complex, integrated structure, the craniofacial morphology observed fits the theoretical expectations of quantitative genetics. Thus, it is predictive of population structure and history. In fact, results obtained after the craniofacial analysis are in accordance with previous molecular and historical interpretations, providing evidence that admixture is a main microevolutionary agent influencing modern Mexican gene pool. However, expectations are not straightforward when moderate shape changes are considered. Deviations detected at localized structures, such as the upper and lower face, highlight the evolution of a craniofacial pattern exclusively inherent to the admixed groups, indicating that quantitative characters might respond to admixture in a complicated, nondirectional way. PMID:16323202

  16. Localization of the homolog of a mouse craniofacial mutant to human chromosome 18q11 and evaluation of linkage to human CLP and CPO

    SciTech Connect

    Griffith, A.J.; Burgess, D.L.; Kohrman, D.C.; Yu, J.

    1996-06-15

    The transgene-induced mutation 9257 and the spontaneous mutation twirler cause craniofacial and inner ear malformations and are located on mouse chromosome 18 near the ataxia locus ax. To map the human homolog of 9257, a probe from the transgene insertion site was used to screen a human genomic library. Analysis of a cross-hybridizing human clone identified a 3-kb conserved sequence block that does not appear to contain protein coding sequence. Analysis of somatic cell hybrid panels assigned the human locus to 18q11. The polymorphic microsatellite markers D18S1001 and D18S1002 were isolated from the human locus and mapped by linkage analysis using the CEPH pedigrees. The 9257 locus maps close to the centromeres of human chromosome 18q and mouse chromosome 18 at the proximal end of a conserved linkage group. To evaluate the role of this locus in human craniofacial disorders, linkage to D18S1002 was tested in 11 families with autosomal dominant nonsyndromic cleft lip and palate and 3 families with autosomal dominant cleft palate only. Obligatory recombinants were observed in 8 of the families, and negative lod scores from the other families indicated that these disorders are not linked to the chromosome 18 loci. 23 refs., 4 figs., 2 tabs.

  17. A genome-wide linkage scan for quantitative trait loci influencing the craniofacial complex in humans(Homo sapiens sapiens)

    PubMed Central

    Sherwood, Richard J.; Duren, Dana L.; Mahaney, Michael C.; Blangero, John; Dyer, Thomas D.; Cole, Shelley A.; Czerwinski, Stefan A.; Chumlea, Wm. Cameron; Siervogel, Roger M.; Choh, Audrey C.; Nahhas, Ramzi W.; Lee, Miryoung; Towne, Bradford

    2011-01-01

    The genetic architecture of the craniofacial complex has been the subject of intense scrutiny because of the high frequency of congenital malformations. Numerous animal models have been used to document the early development of the craniofacial complex, but few studies have focused directly on the genetic underpinnings of normal variation in the human craniofacial complex. The current study examines 80 quantitative traits derived from lateral cephalographs of 981 participants in the Fels Longitudinal Study, Wright State University, Dayton, Ohio. Quantitative genetic analyses were conducted using the SOLAR analytic platform, a maximum-likelihood variance components method that incorporates all familial information for parameter estimation. Heritability estimates were significant and of moderate to high magnitude for all craniofacial traits. Additionally, significant quantitative trait loci (QTL) were identified for 10 traits from the three developmental components (basicranium, splanchnocranium, and neurocranium) of the craniofacial complex. These QTL were found on chromosomes 3, 6, 11, 12, and 14. This study of the genetic architecture of the craniofacial complex elucidates fundamental information of the genetic architecture of the craniofacial complex in humans. PMID:21328561

  18. Facing up to the Challenges of Advancing Craniofacial Research

    PubMed Central

    Trainor, Paul A.; Richtsmeier, Joan T.

    2015-01-01

    Craniofacial anomalies are among the most common human birth defects and have considerable functional, aesthetic, and social consequences. The early developmental origin as well as the anatomical complexity of the head and face render these tissues prone to genetic and environmental insult. The establishment of craniofacial clinics offering comprehensive care for craniofacial patients at a single site together with international research networks focused on the origins and treatment of craniofacial disorders has led to tremendous advances in our understanding of the etiology and pathogenesis of congenital craniofacial anomalies. However, the genetic, environmental, and developmental sources of many craniofacial disorders remain unknown. To overcome this problem and further advance craniofacial research, we must recognize current challenges in the field and establish priority areas for study. We still need (i) a deeper understanding of variation during normal development and within the context of any disorder, (ii) improved genotyping and phenotyping and understanding of the impact of epigenetics, (iii) continued development of animal models and functional analyses of genes and variants, and (iv) integration of patient derived cells and tissues together with 3D printing and quantitative assessment of surgical outcomes for improved practice. Only with fundamental advances in each of these areas will we be able to meet the challenge of translating potential therapeutic and preventative approaches into clinical solutions and reduce the financial and emotional burden of craniofacial anomalies. PMID:25820983

  19. Sensitivity analysis of a validated subject-specific finite element model of the human craniofacial skeleton.

    PubMed

    Szwedowski, T D; Fialkov, J; Whyne, C M

    2011-01-01

    Developing a more complete understanding of the mechanical response of the craniofacial skeleton (CFS) to physiological loads is fundamental to improving treatment for traumatic injuries, reconstruction due to neoplasia, and deformities. Characterization of the biomechanics of the CFS is challenging due to its highly complex structure and heterogeneity, motivating the utilization of experimentally validated computational models. As such, the objective of this study was to develop, experimentally validate, and parametrically analyse a patient-specific finite element (FE) model of the CFS to elucidate a better understanding of the factors that are of intrinsic importance to the skeletal structural behaviour of the human CFS. An FE model of a cadaveric craniofacial skeleton was created from subject-specific computed tomography data. The model was validated based on bone strain measurements taken under simulated physiological-like loading through the masseter and temporalis muscles (which are responsible for the majority of craniofacial physiologic loading due to mastication). The baseline subject-specific model using locally defined cortical bone thicknesses produced the strongest correlation to the experimental data (r2 = 0.73). Large effects on strain patterns arising from small parametric changes in cortical thickness suggest that the very thin bony structures present in the CFS are crucial to characterizing the local load distribution in the CFS accurately. PMID:21381488

  20. Discovery and characterization of spontaneous mouse models of craniofacial dysmorphology.

    PubMed

    Palmer, Kristina; Fairfield, Heather; Borgeia, Suhaib; Curtain, Michelle; Hassan, Mohamed G; Dionne, Louise; Yong Karst, Son; Coombs, Harold; Bronson, Roderick T; Reinholdt, Laura G; Bergstrom, David E; Donahue, Leah Rae; Cox, Timothy C; Murray, Stephen A

    2016-07-15

    Craniofacial abnormalities are among the most common features of human genetic syndromes and disorders. The etiology of these conditions is often complex, influenced by both genetic context and the environment. Frequently, craniofacial abnormalities present as part of a syndrome with clear comorbid phenotypes, providing additional insight into mechanisms of the causative gene or pathway. The mouse has been a key tool in our understanding of the genetic mechanisms of craniofacial development and disease, and can provide excellent models for human craniofacial abnormalities. While powerful genetic engineering tools in the mouse have contributed significantly our understanding of craniofacial development and dysmorphology, forward genetic approaches provide an unbiased means to identify new genes and pathways. Moreover, spontaneous mutations can occur on any number of genetic backgrounds, potentially revealing critical genes that require a specific genetic context. Here we report discovery and phenotyping of 43 craniofacial mouse models, derived primarily from a screen for spontaneous mutations in production colonies at the Jackson Laboratory. We identify the causative gene for 33 lines, including novel genes in pathways not previously connected to craniofacial development, and novel alleles of known genes that present with unique phenotypes. Together with our detailed characterization, this work provides a valuable gene discovery resource for the craniofacial community, and a rich source of mouse models for further investigation. PMID:26234751

  1. Craniofacial changes and symptoms of sleep-disordered breathing in healthy children

    PubMed Central

    Pacheco, Maria Christina Thomé; Fiorott, Bruna Santos; Finck, Nathalia Silveira; de Araújo, Maria Teresa Martins

    2015-01-01

    INTRODUCTION: The main cause of mouth breathing and sleep-disordered breathing (SDB) in childhood is associated with upper airway narrowing to varying degrees. OBJECTIVE: The aim of this study was to assess the prevalence of morphological and functional craniofacial changes and the main clinical symptoms of SDB in healthy children. METHODS: A cross-sectional observational study was conducted. A sample comprising 687 healthy schoolchildren, aged 7-12 years old and attending public schools, was assessed by medical history, clinical medical and dental examination, and respiratory tests. The self-perceived quality of life of mouth breathing children was obtained by a validated questionnaire. RESULTS: Out of the total sample, 520 children were nose breathers (NB) while 167 (24.3%) were mouth breathers (MB); 32.5% had severe hypertrophy of the palatine tonsils, 18% had a Mallampati score of III or IV, 26.1% had excessive overjet and 17.7% had anterior open bite malocclusion. Among the MB, 53.9% had atresic palate, 35.9% had lip incompetence, 33.5% reported sleepiness during the day, 32.2% often sneezed, 32.2% had a stuffy nose, 19.6% snored, and 9.4% reported having the feeling to stop breathing while asleep. However, the self-perception of their quality of life was considered good. CONCLUSION: High prevalence of facial changes as well as signs and symptoms of mouth breathing were found among health children, requiring early diagnosis and treatment to reduce the risk of SDB. PMID:26154460

  2. Shape covariation between the craniofacial complex and first molars in humans

    PubMed Central

    Polychronis, Georgios; Halazonetis, Demetrios J

    2014-01-01

    The occurrence of mutual genetic loci in morphogenesis of the face and teeth implies shape covariation between these structures. However, teeth finalize their shape at an early age, whereas the face grows and is subjected to environmental influences for a prolonged period; it is therefore conceivable that covariation might modulate with age. Here we investigate the extent of this covariation in humans by measuring the 3D shape of the occlusal surface of the permanent first molars and the shape of the craniofacial complex from lateral radiographs, at two maturations stages. A sample of Greek subjects was divided into two groups (110 adult, 110 prepubertal) with equally distributed gender. The occlusal surfaces of the right first molars were 3D scanned from dental casts; 265 and 274 landmarks (including surface and curve semilandmarks) were digitized on the maxillary and mandibular molars, respectively. The corresponding lateral cephalometric radiographs were digitized with 71 landmarks. Geometric morphometric methods were used to assess shape variation and covariation. The vertical dimension of the craniofacial complex was the main parameter of shape variation, followed by anteroposterior deviations. The male craniofacial complex was larger (4.0–5.7%) and was characterized by a prominent chin and clockwise rotation of the cranial base (adult group only). Allometry was weak and statistically significant only when examined for the sample as a whole (percent variance explained: 2.1%, P = 0.0002). Covariation was statistically significant only between the lower first molar and the craniofacial complex (RV = 14.05%, P = 0.0099, and RV = 12.31%, P = 0.0162, for the prepubertal and adult groups, respectively). Subtle age-related covariation differences were noted, indicating that environmental factors may influence the pattern and strength of covariation. However, the main pattern was similar in both groups: a class III skeletal pattern (relative maxillary retrusion and

  3. [Craniofacial neuralgias].

    PubMed

    Mikula, Ivan

    2008-05-01

    Craniofacial neuralgias are characterized by sudden paroxysmal pain along the distribution of one or more of the cranial or upper cervical spinal nerves. The most significant neuralgia of the craniofacial region is trigeminal neuralgia, while geniculate neuralgia, glossopharyngeal neuralgia and occipital neuralgia are less common. Trigeminal neuralgia may be primary or secondary. Idiopathic trigeminal neuralgia or tic douloureux has been recognized for centuries as an extremely painful disorder most commonly involving the maxillary nerve. Recurrent lancinating, shocklike unilateral pain lasting for seconds to minutes is provoked by non noxious stimulation of the skin at specific sites around the face and less frequently by movement of the tongue. The trigger zones are usually within the same dermatome as the painful sensation. After each episode, there is usually a refractive period during which stimulation of the trigger zone will not induce pain. Idiopathic trigeminal neuralgia occurs somewhat more frequently in women and usually begins in individuals 50 to 70 years of age. There is no pain between attacks, and the frequency of painful episodes can range from several per day to only a few per year. With time, the features may become more atypical, with greater areas of more enduring and dull pain and occasionally bilateral pain, rarely on both sides simultaneously. No sensory or reflex deficit is detectable by routine neurologic testing. Diagnostic local anesthetic blocks will identify the specific nerves involved and the trigger point distribution. Neurologic and neuroradiologic examination is advised in all cases to rule out diseases such as intracranical tumors, vascular malformations or multiple sclerosis. PMID:18710080

  4. Effect of bite force and diet composition on craniofacial diversification of Southern South American human populations.

    PubMed

    Menéndez, Lumila; Bernal, Valeria; Novellino, Paula; Perez, S Ivan

    2014-09-01

    Ecological factors can be important to shape the patterns of morphological variation among human populations. Particularly, diet plays a fundamental role in craniofacial variation due to both the effect of the nutritional status-mostly dependent on the type and amount of nutrients consumed-on skeletal growth and the localized effects of masticatory forces. We examine these two dimensions of diet and evaluate their influence on morphological diversification of human populations from southern South America during the late Holocene. Cranial morphology was measured as 3D coordinates defining the face, base and vault. Size, form, and shape variables were obtained for 474 adult individuals coming from 12 samples. Diet composition was inferred from carious lesions and δ(13) C data, whereas bite forces were estimated using traits of main jaw muscles. The spatial structure of the morphological and ecological variables was measured using correlograms. The influence of diet composition and bite force on morphometric variation was estimated by a spatial regression model. Cranial variation and diet composition display a geographical structure, while no geographical pattern was observed in bite forces. Cranial variation in size and form is significantly associated with diet composition, suggesting a strong effect of systemic factors on cranial growth. Conversely, bite forces do not contribute significantly to the pattern of morphological variation among the samples analyzed. Overall, these results show that an association between diet composition and hardness cannot be assumed, and highlight the complex relationship between morphological diversification and diet in human populations. PMID:24985052

  5. Selective brain cooling seems to be a mechanism leading to human craniofacial diversity observed in different geographical regions.

    PubMed

    Irmak, M K; Korkmaz, A; Erogul, O

    2004-01-01

    Selective brain cooling (SBC) can occur in hyperthermic humans despite the fact that humans have no carotid rete, a vascular structure that facilitates countercurrent heat exchange located at the base of the skull in some mammals. Emissary and angular veins, upper respiratory tract, tympanic cavity and cerebrospinal fluid are major components of SBC system in humans. The efficiency of SBC is increased by evaporation of sweat on the head and by ventilation through the nose, but it is surprising to find out that mammals do not display SBC during exercise hyperthermia. What is the explanation then for the SBC at high body temperatures? Our hypothesis is that selective brain cooling protects the brain from thermal damage in a long-standing manner by allowing adaptive mechanisms to change the craniofacial morphology appropriate for different environmental conditions. Since the brain can only be as big that can cool, it is not surprising to find a lower (below 1300 cm(3)) cranial volume in Australian Aborigines with respect to the one (over 1450 cm(3)) in Eskimos. In addition to lower brain volume, other craniofacial features such as thick everted lips, broader nasal cavity and bigger paranasal sinuses that provide more evaporating surfaces seem to be anatomical variations developed in time for an effective SBC in hot climates. It was reported previously that these biological adaptations result from the tissues of neural crest origin. Among the crest derivatives, leptomeninges (pia and arachnoid mater), skeletal and connective tissues of the face and much of the skull seem to be structures upon which environment operates to produce more convenient craniofacial morphology for an effective SBC. In conclusion, selective brain cooling seems to be a mechanism leading to adaptive craniofacial diversity observed in different geographical regions. Thus, SBC is necessary for long-term biological adaptation, not for protecting the brain from acute thermal damage. PMID:15504564

  6. Craniofacial Abnormalities

    MedlinePlus

    ... of the skull and face. Craniofacial abnormalities are birth defects of the face or head. Some, like cleft ... palate, are among the most common of all birth defects. Others are very rare. Most of them affect ...

  7. Disorders of Human Hemoglobin

    NASA Astrophysics Data System (ADS)

    Bank, Arthur; Mears, J. Gregory; Ramirez, Francesco

    1980-02-01

    Studies of the human hemoglobin system have provided new insights into the regulation of expression of a group of linked human genes, the γ -δ -β globin gene complex in man. In particular, the thalassemia syndromes and related disorders of man are inherited anemias that provide mutations for the study of the regulation of globin gene expression. New methods, including restriction enzyme analysis and cloning of cellular DNA, have made it feasible to define more precisely the structure and organization of the globin genes in cellular DNA. Deletions of specific globin gene fragments have already been found in certain of these disorders and have been applied in prenatal diagnosis.

  8. 75 FR 2150 - National Institute of Dental & Craniofacial Research; Notice of Closed Meetings

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  1. 75 FR 4833 - National Institute of Dental & Craniofacial Research; Notice of Closed Meeting

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  2. 76 FR 80953 - National Institute of Dental & Craniofacial Research; Notice of Meeting

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  1. 77 FR 68136 - National Institute of Dental & Craniofacial Research; Notice of Closed Meeting

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  8. Geometric morphometric analysis of craniofacial variation, ontogeny and modularity in a cross-sectional sample of modern humans

    PubMed Central

    Wellens, H L L; Kuijpers-Jagtman, A M; Halazonetis, D J

    2013-01-01

    This investigation aimed to quantify craniofacial variation in a sample of modern humans. In all, 187 consecutive orthodontic patients were collected, of which 79 were male (mean age 13.3, SD 3.7, range 7.5–40.8) and 99 were female (mean age 12.3, SD 1.9, range 8.7–19.1). The male and female subgroups were tested for differences in mean shapes and ontogenetic trajectories, and shape variability was characterized using principal component analysis. The hypothesis of modularity was tested for six different modularity scenarios. The results showed that there were subtle but significant differences in the male and female Procrustes mean shapes. Males were significantly larger. Mild sexual ontogenetic allometric divergence was noted. Principal component analysis indicated that, of the four retained biologically interpretable components, the two most important sources of variability were (i) vertical shape variation (i.e. dolichofacial vs. brachyfacial growth patterns) and (ii) sagittal relationships (maxillary prognatism vs. mandibular retrognathism, and vice versa). The mandible and maxilla were found to constitute one module, independent of the skull base. Additionally, we were able to confirm the presence of an anterior and posterior craniofacial columnar module, separated by the pterygomaxillary plane, as proposed by Enlow. These modules can be further subdivided into four sub-modules, involving the posterior skull base, the ethmomaxillary complex, a pharyngeal module, and the anterior part of the jaws. PMID:23425043

  9. Hcfc1b, a zebrafish ortholog of HCFC1, regulates craniofacial development by modulating mmachc expression

    PubMed Central

    Quintana, Anita M.; Geiger, Elizabeth A.; Achilly, Nate; Rosenblatt, David S.; Maclean, Kenneth N.; Stabler, Sally P.; Artinger, Kristin B.; Appel, Bruce; Shaikh, Tamim H.

    2014-01-01

    Mutations in HCFC1 (MIM300019), have been recently associated with cblX (MIM309541), an X-linked, recessive disorder characterized by multiple congenital anomalies including craniofacial abnormalities. HCFC1 is a transcriptional co-regulator that modulates the expression of numerous downstream target genes including MMACHC, but it is not clear how these HCFC1 targets play a role in the clinical manifestations of cblX. To begin to elucidate the mechanism by which HCFC1 modulates disease phenotypes, we have carried out loss of function analyses in the developing zebrafish. Of the two HCFC1 orthologs in zebrafish, hcfc1a and hcfc1b, the loss of hcfc1b specifically results in defects in craniofacial development. Subsequent analysis revealed that hcfc1b regulates cranial neural crest cell differentiation and proliferation within the posterior pharyngeal arches. Further, the hcfc1b-mediated craniofacial abnormalities were rescued by expression of human MMACHC, a downstream target of HCFC1 that is aberrantly expressed in cblX. Furthermore, we tested distinct human HCFC1 mutations for their role in craniofacial development and demonstrated variable effects on MMACHC expression in humans and craniofacial development in zebrafish. Notably, several individuals with mutations in either HCFC1 or MMACHC have been reported to have mild to moderate facial dysmorphia. Thus, our data demonstrates that HCFC1 plays a role in craniofacial development, which is in part mediated through the regulation of MMACHC expression. PMID:25281006

  10. Unmasking the ciliopathies: craniofacial defects and the primary cilium.

    PubMed

    Cortés, Claudio R; Metzis, Vicki; Wicking, Carol

    2015-01-01

    Over the past decade, the primary cilium has emerged as a pivotal sensory organelle that acts as a major signaling hub for a number of developmental signaling pathways. In that time, a vast number of proteins involved in trafficking and signaling have been linked to ciliary assembly and/or function, demonstrating the importance of this organelle during embryonic development. Given the central role of the primary cilium in regulating developmental signaling, it is not surprising that its dysfunction results in widespread defects in the embryo, leading to an expanding class of human congenital disorders known as ciliopathies. These disorders are individually rare and phenotypically variable, but together they affect virtually every vertebrate organ system. Features of ciliopathies that are often overlooked, but which are being reported with increasing frequency, are craniofacial abnormalities, ranging from subtle midline defects to full-blown orofacial clefting. The challenge moving forward is to understand the primary mechanism of disease given the link between the primary cilium and a number of developmental signaling pathways (such as hedgehog, platelet-derived growth factor, and WNT signaling) that are essential for craniofacial development. Here, we provide an overview of the diversity of craniofacial abnormalities present in the ciliopathy spectrum, and reveal those defects in common across multiple disorders. Further, we discuss the molecular defects and potential signaling perturbations underlying these anomalies. This provides insight into the mechanisms leading to ciliopathy phenotypes more generally and highlights the prevalence of widespread dysmorphologies resulting from cilia dysfunction. PMID:26173831

  11. Disorder in Complex Human System

    NASA Astrophysics Data System (ADS)

    Akdeniz, K. Gediz

    2011-11-01

    Since the world of human and whose life becomes more and more complex every day because of the digital technology and under the storm of knowledge (media, internet, governmental and non-governmental organizations, etc...) the simulation is rapidly growing in the social systems and in human behaviors. The formation of the body and mutual interactions are left to digital technological, communication mechanisms and coding the techno genetics of the body. Deconstruction begins everywhere. The linear simulation mechanism with modern realities are replaced by the disorder simulation of human behaviors with awareness realities. In this paper I would like to introduce simulation theory of "Disorder Sensitive Human Behaviors". I recently proposed this theory to critique the role of disorder human behaviors in social systems. In this theory the principle of realty is the chaotic awareness of the complexity of human systems inside of principle of modern thinking in Baudrillard's simulation theory. Proper examples will be also considered to investigate the theory.

  12. Human peroxisomal disorders.

    PubMed

    Depreter, Marianne; Espeel, Marc; Roels, Frank

    2003-06-01

    Peroxisomes are single membrane-bound cell organelles performing numerous metabolic functions. The present article aims to give an overview of our current knowledge about inherited peroxisomal disorders in which these organelles are lacking or one or more of their functions are impaired. They are multiorgan disorders and the nervous system is implicated in most. After a summary of the historical names and categories, each having distinct symptoms and prognosis, microscopic pathology is reviewed in detail. Data from the literature are added to experience in the authors' laboratory with 167 liver biopsy and autopsy samples from peroxisomal patients, and with a smaller number of chorion samples for prenatal diagnosis, adrenal-, kidney-, and brain samples. Various light and electron microscopic methods are used including enzyme- and immunocytochemistry, polarizing microscopy, and morphometry. Together with other laboratory investigations and clinical data, this approach continues to contribute to the diagnosis and further characterization of peroxisomal disorders, and the discovery of novel variants. When liver specimens are examined, three main groups including 9 novel variants (33 patients) are distinguished: (1) absence or (2) presence of peroxisomes, and (3) mosaic distribution of cells with and without peroxisomes (10 patients). Renal microcysts, polarizing trilamellar inclusions, and insoluble lipid in macrophages in liver, adrenal cortex, brain, and in interstitial cells of kidney are also valuable for classification. On a genetic basis, complementation of fibroblasts has classified peroxisome biogenesis disorders into 12 complementation groups. Peroxisome biogenesis genes (PEX), knock-out-mice, and induction of redundant genes are briefly reviewed, including some recent results with 4-phenylbutyrate. Finally, regulation of peroxisome expression during development and in cell cultures, and by physiological factors is discussed. PMID:12740827

  13. The Ribosome Biogenesis Factor Nol11 Is Required for Optimal rDNA Transcription and Craniofacial Development in Xenopus

    PubMed Central

    Griffin, John N.; Sondalle, Samuel B.; del Viso, Florencia; Baserga, Susan J.; Khokha, Mustafa K.

    2015-01-01

    The production of ribosomes is ubiquitous and fundamental to life. As such, it is surprising that defects in ribosome biogenesis underlie a growing number of symptomatically distinct inherited disorders, collectively called ribosomopathies. We previously determined that the nucleolar protein, NOL11, is essential for optimal pre-rRNA transcription and processing in human tissue culture cells. However, the role of NOL11 in the development of a multicellular organism remains unknown. Here, we reveal a critical function for NOL11 in vertebrate ribosome biogenesis and craniofacial development. Nol11 is strongly expressed in the developing cranial neural crest (CNC) of both amphibians and mammals, and knockdown of Xenopus nol11 results in impaired pre-rRNA transcription and processing, increased apoptosis, and abnormal development of the craniofacial cartilages. Inhibition of p53 rescues this skeletal phenotype, but not the underlying ribosome biogenesis defect, demonstrating an evolutionarily conserved control mechanism through which ribosome-impaired craniofacial cells are removed. Excessive activation of this mechanism impairs craniofacial development. Together, our findings reveal a novel requirement for Nol11 in craniofacial development, present the first frog model of a ribosomopathy, and provide further insight into the clinically important relationship between specific ribosome biogenesis proteins and craniofacial cell survival. PMID:25756904

  14. The ribosome biogenesis factor Nol11 is required for optimal rDNA transcription and craniofacial development in Xenopus.

    PubMed

    Griffin, John N; Sondalle, Samuel B; Del Viso, Florencia; Baserga, Susan J; Khokha, Mustafa K

    2015-03-01

    The production of ribosomes is ubiquitous and fundamental to life. As such, it is surprising that defects in ribosome biogenesis underlie a growing number of symptomatically distinct inherited disorders, collectively called ribosomopathies. We previously determined that the nucleolar protein, NOL11, is essential for optimal pre-rRNA transcription and processing in human tissue culture cells. However, the role of NOL11 in the development of a multicellular organism remains unknown. Here, we reveal a critical function for NOL11 in vertebrate ribosome biogenesis and craniofacial development. Nol11 is strongly expressed in the developing cranial neural crest (CNC) of both amphibians and mammals, and knockdown of Xenopus nol11 results in impaired pre-rRNA transcription and processing, increased apoptosis, and abnormal development of the craniofacial cartilages. Inhibition of p53 rescues this skeletal phenotype, but not the underlying ribosome biogenesis defect, demonstrating an evolutionarily conserved control mechanism through which ribosome-impaired craniofacial cells are removed. Excessive activation of this mechanism impairs craniofacial development. Together, our findings reveal a novel requirement for Nol11 in craniofacial development, present the first frog model of a ribosomopathy, and provide further insight into the clinically important relationship between specific ribosome biogenesis proteins and craniofacial cell survival. PMID:25756904

  15. A systematic review of the oral and craniofacial manifestations of cri du chat syndrome.

    PubMed

    Corcuera-Flores, José-Ramón; Casttellanos-Cosano, Lizett; Torres-Lagares, Daniel; Serrera-Figallo, María Ángeles; Rodríguez-Caballero, Ángela; Machuca-Portillo, Guillermo

    2016-07-01

    Cri du chat syndrome is an autosomal disorder. Because it affects few people in the population it is considered a rare disease, yet it is one of the most common autosomal chromosomal syndromes in humans. It entails pathognomonic alterations that affect the craniofacial and oral anatomy of patients. The aim of this study is to review these craniofacial and oral abnormalities in patients with Cri du chat syndrome. The PubMed Medline database was searched using two different strategies. First, we used "Dentistry" and "Cri du chat" as keywords; second, we used "Cri du chat" and "craniofacial." Seven articles in which the main orofacial and cranio-skeletal characteristics of patients with Cri du chat syndrome were described were selected according to the inclusion and exclusion criteria. Cri du Chat syndrome entails pathognomonic characteristics in the craniofacial area (epicanthus, short philtrum, and wide nasal bridge), the oral area (mandibular retrognathism and anterior open bite) and the cranial region (alterations at the cranial base angle and a small upper airway). However, more studies on larger samples are needed to specify the orofacial and craniofacial characteristics of patients with Cri du chat syndrome more accurately. Clin. Anat. 29:555-560, 2016. © 2015 Wiley Periodicals, Inc. PMID:26457586

  16. 75 FR 28031 - National Institute of Dental & Craniofacial Research; Notice of Closed Meetings

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    2010-05-19

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  17. 78 FR 3009 - National Institute of Dental & Craniofacial Research; Notice of Closed Meeting

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    2013-01-15

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Dental & Craniofacial Research... personal privacy. Name of Committee: National Institute of Dental and Craniofacial Research...

  18. 76 FR 57061 - National Institute of Dental & Craniofacial Research; Notice of Closed Meeting

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    2011-09-15

    ... HUMAN SERVICES National Institutes of Health National Institute of Dental & Craniofacial Research... personal privacy. Name of Committee: National Institute of Dental and Craniofacial Research Special... Kelly, Scientific Review Officer, Scientific Review Branch, National Inst of Dental &...

  19. 76 FR 5183 - National Institute of Dental & Craniofacial Research; Notice of Closed Meeting

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    2011-01-28

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Dental & Craniofacial Research..., Scientific Review Officer, Scientific Review Branch, National Inst. of Dental & Craniofacial...

  20. 77 FR 64815 - National Institute of Dental & Craniofacial Research; Notice of Closed Meeting

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    2012-10-23

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Dental & Craniofacial Research... personal privacy. Name of Committee: National Institute of Dental and Craniofacial Research...

  1. 77 FR 10540 - National Institute of Dental & Craniofacial Research; Notice of Closed Meeting

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    2012-02-22

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Dental & Craniofacial Research... personal privacy. Name of Committee: National Institute of Dental and Craniofacial Research...

  2. 77 FR 76297 - National Institute of Dental & Craniofacial Research; Notice of Closed Meetings

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    2012-12-27

    ... HUMAN SERVICES National Institutes of Health National Institute of Dental & Craniofacial Research...-594-0652, rwagenaa@mail.nih.gov . Name of Committee: National Institute of Dental and Craniofacial...., MS, Scientific Review Officer, Scientific ] Review Branch, National Institute of...

  3. 78 FR 24761 - National Institute of Dental & Craniofacial Research; Notice of Closed Meetings

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    2013-04-26

    ... HUMAN SERVICES National Institutes of Health National Institute of Dental & Craniofacial Research... personal privacy. Name of Committee: National Institute of Dental and Craniofacial Research Special Emphasis Panel; Design and Development of Novel Dental Composite Restorative Systems Review Panel....

  4. 75 FR 8976 - National Institute of Dental & Craniofacial Research; Notice of Closed Meeting

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    2010-02-26

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Dental & Craniofacial Research... personal privacy. Name of Committee: National Institute of Dental and Craniofacial Research...

  5. 77 FR 57098 - National Institute of Dental & Craniofacial Research; Notice of Closed Meeting

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    2012-09-17

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Dental & Craniofacial Research... personal privacy. Name of Committee: National Institute of Dental and Craniofacial Research...

  6. 75 FR 7486 - National Institute of Dental & Craniofacial Research; Notice of Closed Meetings

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-02-19

    ... HUMAN SERVICES National Institutes of Health National Institute of Dental & Craniofacial Research... personal privacy. Name of Committee: National Institute of Dental and Craniofacial Research Special..., PhD, Scientific Review Officer, Scientific Review Branch, National Institute of Dental...

  7. De Novo Duplication of 7p21.1p22.2 in a Child with Autism Spectrum Disorder and Craniofacial Dysmorphism

    PubMed Central

    Udayakumar, Achandira M.; Al-Mamari, Watfa; Al-Sayegh, Abeer; Al-Kindy, Adila

    2015-01-01

    The duplication of the short arm of chromosome 7 as de novo is extremely rare. The phenotype spectrum varies depending on the region of duplication. We report a case of de novo duplication of chromosomal region 7p21.1p22.2 in a three-year-old male child with autism who presented to the Sultan Qaboos University Hospital in Muscat, Oman, in January 2012. The patient was diagnosed with craniofacial dysmorphism, global developmental delay, hypotonia and bilateral cryptorchidism. The duplication was detected by conventional G-banded karyotype analysis/fluorescence in situ hybridisation and confirmed by array comparative genomic hybridisation. To the best of the authors’ knowledge, this is the first report of chromosomal region 7p21.1 involvement in an autistic patient showing features of a 7p duplication phenotype. Identifying genes in the duplicated region using molecular techniques is recommended to promote characterisation of the phenotype and associated condition. It may also reveal the possible role of these genes in autism spectrum disorder. PMID:26357560

  8. Craniofacial and Dental Development in Costello Syndrome

    PubMed Central

    Goodwin, Alice F.; Oberoi, Snehlata; Landan, Maya; Charles, Cyril; Massie, Jessica C.; Fairley, Cecilia; Rauen, Katherine A.; Klein, Ophir D.

    2014-01-01

    Costello syndrome (CS) is a RASopathy characterized by a wide range of cardiac, musculoskeletal, dermatological, and developmental abnormalities. The RASopathies are defined as a group of syndromes caused by activated Ras/mitogen-activated protein kinase (MAPK) signaling. Specifically, CS is caused by activating mutations in HRAS. Although receptor tyrosine kinase (RTK) signaling, which is upstream of Ras/MAPK, is known to play a critical role in craniofacial and dental development, the craniofacial and dental features of CS have not been systematically defined in a large group of individuals. In order to address this gap in our understanding and fully characterize the CS phenotype, we evaluated the craniofacial and dental phenotype in a large cohort (n=41) of CS individuals. We confirmed that the craniofacial features common in CS include macrocephaly, bitemporal narrowing, convex facial profile, full cheeks, and large mouth. Additionally, CS patients have a characteristic dental phenotype that includes malocclusion with anterior open bite and posterior crossbite, enamel hypo-mineralization, delayed tooth development and eruption, gingival hyperplasia, thickening of the alveolar ridge, and high palate. Comparison of the craniofacial and dental phenotype in CS with other RASopathies, such as cardio-facio-cutaneous syndrome (CFC), provides insight into the complexities of Ras/MAPK signaling in human craniofacial and dental development. PMID:24668879

  9. Craniofacial Surgery Fellowship Websites.

    PubMed

    Silvestre, Jason; Agarwal, Divyansh; Taylor, Jesse A

    2016-06-01

    Applicants for craniofacial surgery fellowships utilize Internet-based resources like the San Francisco (SF) Match to manage applications. The purpose of this study was to evaluate the accessibility and content of craniofacial surgery fellowship websites (CSFWs). A list of available craniofacial surgery fellowships was compiled from directories of the American Society of Craniofacial Surgery (ACSFS) and SF Match. Accessibility of CSFWs was assessed via links from these directories and a Google search. Craniofacial surgery fellowship websites were evaluated on education and recruitment content and compared via program characteristics. Twenty-four of the 28 US-based craniofacial surgery fellowship programs had a CSFW (86%). The ACSFS and SF Match databases had limited CSFW accessibility, but a Google search revealed most CSFWs had the top search result (76%). In total, CSFWs provided an average of 39% of education and recruitment variables. While most programs provided fellowship program descriptions (96%), application links (96%), and faculty listings (83%), relatively few provided rotation schedules (13%), fellow selection process information (13%), or interview dates (8%). CSFW content did not vary by program location, faculty size, accreditation status, or institutional affiliations (P > 0.05). Craniofacial surgery fellowships often lack readily accessible websites from national program lists and have limited information for interested applicants. The consistent lack of online information across programs suggests future opportunities exist to improve these educational resources. PMID:27285892

  10. 76 FR 38193 - National Institute of Dental & Craniofacial Research; Notice of Closed Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-06-29

    ... HUMAN SERVICES National Institutes of Health National Institute of Dental & Craniofacial Research... Institute of Dental and Craniofacial Research Special Emphasis Panel, Review of PAR-11-144 NIDCR U01... of Dental & Craniofacial Research, National Institutes of Health, 6701 Democracy Blvd., Rm...

  11. 77 FR 23488 - National Institute of Dental & Craniofacial Research; Notice of Meeting

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    2012-04-19

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  12. 78 FR 7794 - National Institute of Dental & Craniofacial Research; Notice of Closed Meetings

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    2013-02-04

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  13. 76 FR 30373 - National Institute of Dental & Craniofacial Research; Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-05-25

    ... HUMAN SERVICES National Institutes of Health National Institute of Dental & Craniofacial Research... unwarranted invasion of personal privacy. Name of Committee: National Institute of Dental and Craniofacial...: Marilyn Moore-Hoon, PhD, Scientific Review Officer, Scientific Review Branch, National Institute of...

  14. Brain, Craniofacial, and Dental Lesions of a Free-ranging Gray Wolf (Canis lupus) Implicated in a Human Attack in Minnesota, USA.

    PubMed

    Schwabenlander, Marc; Stepaniuk, Kevin; Carstensen, Michelle; Armién, Aníbal G

    2016-01-01

    We describe significant brain, craniofacial, and dental lesions in a free-ranging wolf (Canis lupus) involved in a human attack. On postmortem examination, the wolf presented asymmetric atrophy and bone remodeling affecting the mandible, incisive, maxilla, lacrimal, palatine, frontal, and ethmoid bones. There was an asymmetrical skeletal malocclusion and dental abnormalities including rotated, malpositioned, partially erupted teeth, and an odontogenic cyst associated with an unerupted canine tooth. Brain changes were bilateral loss and atrophy of extensive cortex regions including olfactory bulb, peduncles, and tract, and the frontal lobe. We highlight the relevance of a thorough postmortem examination of wildlife to elucidate disease-based abnormal behavior as the reason for human-animal conflict. PMID:26540333

  15. Influence of congenital facial nerve palsy on craniofacial growth in craniofacial microsomia.

    PubMed

    Choi, Jaehoon; Park, Sang Woo; Kwon, Geun-Yong; Kim, Sang-Hyun; Hur, Ji An; Baek, Seung-Hak; Kim, Jae Chan; Choi, Tae Hyun; Kim, Sukwha

    2014-11-01

    Facial muscles are of major importance in human craniofacial growth and development. The purpose of our study was to investigate whether congenital facial nerve palsy influences craniofacial growth in craniofacial microsomia. Fifty-one patients with unilateral craniofacial microsomia and no history of craniofacial skeletal surgery whose radiographs were taken after craniofacial growth was complete were included in this study. These patients were divided into groups in which the facial nerve was involved or uninvolved. The authors evaluated a total of seven measurement items to analyze the midface and mandibular asymmetry. Twenty patients had facial nerve involvement, and 31 had no involvement. None of the measurement items revealed any significant differences between the facial nerve-involved group and the uninvolved group within the same modified Pruzansky grade. There was no correlation between the type of facial nerve involvement and the measurement items. In relationships among the measurement items within each group, maxillary asymmetry was indirectly correlated with mandibular asymmetry or midline deviation through the occlusal plane angle in the uninvolved groups. However, in the facial nerve-involved group, the relationships disappeared. When the correlations in the facial nerve-involved group were compared with those of the uninvolved group, the relationships in the uninvolved group appeared more significant than in the facial nerve-involved group. The loss of relationships between the upper and lower jaw in the facial nerve-involved group might have been caused by subtle changes, which occur in midfacial bones and in the mandible due to facial nerve palsy. The main limitation of our study is that aside from facial nerve palsy, craniofacial microsomia has many factors that can influence craniofacial growth, such as hypoplasia of the mandibular condyle and soft tissue deficiencies. PMID:25210001

  16. The Ubiquitin E3 Ligase NOSIP Modulates Protein Phosphatase 2A Activity in Craniofacial Development

    PubMed Central

    Hoffmeister, Meike; Prelle, Carola; Küchler, Philipp; Kovacevic, Igor; Moser, Markus; Müller-Esterl, Werner; Oess, Stefanie

    2014-01-01

    Holoprosencephaly is a common developmental disorder in humans characterised by incomplete brain hemisphere separation and midface anomalies. The etiology of holoprosencephaly is heterogeneous with environmental and genetic causes, but for a majority of holoprosencephaly cases the genes associated with the pathogenesis could not be identified so far. Here we report the generation of knockout mice for the ubiquitin E3 ligase NOSIP. The loss of NOSIP in mice causes holoprosencephaly and facial anomalies including cleft lip/palate, cyclopia and facial midline clefting. By a mass spectrometry based protein interaction screen we identified NOSIP as a novel interaction partner of protein phosphatase PP2A. NOSIP mediates the monoubiquitination of the PP2A catalytic subunit and the loss of NOSIP results in an increase in PP2A activity in craniofacial tissue in NOSIP knockout mice. We conclude, that NOSIP is a critical modulator of brain and craniofacial development in mice and a candidate gene for holoprosencephaly in humans. PMID:25546391

  17. Craniofacial characteristics of Croatian and Syrian populations.

    PubMed

    Grbesa, Durdica; Pezerović-Panijan, Ruzica; Kalaya, Mohamed Nadim; Gorsić, Irma; Cavcić, Anamarija; Zura, Nikolino; Berberović, Behija

    2007-12-01

    Craniofacial area is apart of the human body which undergoes the greatest changes during development and is characterized by uneven growth. External and internal factors affect the growth and development of craniofacial structures. They are responsible for the occurrence of specific craniofacial characteristics in different races or populations within the same race. The present study investigates the possible differences of the basic head and face shapes between the Croatian and Syrian populations. The sample included 400 subjects of both sexes aged 18-24 years and was divided into a Croatian and a Syrian group with 200 subjects each. Six variables defined according to Martin and Saller were measured by standard anthropometric instruments. The results of the study demonstrated statistically significant differences between our subjects in all variables except face width. The dolichocephalic head type and the mesoprosopic face type were predominant in the Croatian population, while the brachycephalic head type and the euryprosopic face type dominated in the Syrian population. PMID:18217470

  18. A noncoding expansion in EIF4A3 causes Richieri-Costa-Pereira syndrome, a craniofacial disorder associated with limb defects.

    PubMed

    Favaro, Francine P; Alvizi, Lucas; Zechi-Ceide, Roseli M; Bertola, Debora; Felix, Temis M; de Souza, Josiane; Raskin, Salmo; Twigg, Stephen R F; Weiner, Andrea M J; Armas, Pablo; Margarit, Ezequiel; Calcaterra, Nora B; Andersen, Gregers R; McGowan, Simon J; Wilkie, Andrew O M; Richieri-Costa, Antonio; de Almeida, Maria L G; Passos-Bueno, Maria Rita

    2014-01-01

    Richieri-Costa-Pereira syndrome is an autosomal-recessive acrofacial dysostosis characterized by mandibular median cleft associated with other craniofacial anomalies and severe limb defects. Learning and language disabilities are also prevalent. We mapped the mutated gene to a 122 kb region at 17q25.3 through identity-by-descent analysis in 17 genealogies. Sequencing strategies identified an expansion of a region with several repeats of 18- or 20-nucleotide motifs in the 5' untranslated region (5' UTR) of EIF4A3, which contained from 14 to 16 repeats in the affected individuals and from 3 to 12 repeats in 520 healthy individuals. A missense substitution of a highly conserved residue likely to affect the interaction of eIF4AIII with the UPF3B subunit of the exon junction complex in trans with an expanded allele was found in an unrelated individual with an atypical presentation, thus expanding mutational mechanisms and phenotypic diversity of RCPS. EIF4A3 transcript abundance was reduced in both white blood cells and mesenchymal cells of RCPS-affected individuals as compared to controls. Notably, targeting the orthologous eif4a3 in zebrafish led to underdevelopment of several craniofacial cartilage and bone structures, in agreement with the craniofacial alterations seen in RCPS. Our data thus suggest that RCPS is caused by mutations in EIF4A3 and show that EIF4A3, a gene involved in RNA metabolism, plays a role in mandible, laryngeal, and limb morphogenesis. PMID:24360810

  19. Human Genetic Disorders of Axon Guidance

    PubMed Central

    Engle, Elizabeth C.

    2010-01-01

    This article reviews symptoms and signs of aberrant axon connectivity in humans, and summarizes major human genetic disorders that result, or have been proposed to result, from defective axon guidance. These include corpus callosum agenesis, L1 syndrome, Joubert syndrome and related disorders, horizontal gaze palsy with progressive scoliosis, Kallmann syndrome, albinism, congenital fibrosis of the extraocular muscles type 1, Duane retraction syndrome, and pontine tegmental cap dysplasia. Genes mutated in these disorders can encode axon growth cone ligands and receptors, downstream signaling molecules, and axon transport motors, as well as proteins without currently recognized roles in axon guidance. Advances in neuroimaging and genetic techniques have the potential to rapidly expand this field, and it is feasible that axon guidance disorders will soon be recognized as a new and significant category of human neurodevelopmental disorders. PMID:20300212

  20. A Noncoding Expansion in EIF4A3 Causes Richieri-Costa-Pereira Syndrome, a Craniofacial Disorder Associated with Limb Defects

    PubMed Central

    Favaro, Francine P.; Alvizi, Lucas; Zechi-Ceide, Roseli M.; Bertola, Debora; Felix, Temis M.; de Souza, Josiane; Raskin, Salmo; Twigg, Stephen R.F.; Weiner, Andrea M.J.; Armas, Pablo; Margarit, Ezequiel; Calcaterra, Nora B.; Andersen, Gregers R.; McGowan, Simon J.; Wilkie, Andrew O.M.; Richieri-Costa, Antonio; de Almeida, Maria L.G.; Passos-Bueno, Maria Rita

    2014-01-01

    Richieri-Costa-Pereira syndrome is an autosomal-recessive acrofacial dysostosis characterized by mandibular median cleft associated with other craniofacial anomalies and severe limb defects. Learning and language disabilities are also prevalent. We mapped the mutated gene to a 122 kb region at 17q25.3 through identity-by-descent analysis in 17 genealogies. Sequencing strategies identified an expansion of a region with several repeats of 18- or 20-nucleotide motifs in the 5′ untranslated region (5′ UTR) of EIF4A3, which contained from 14 to 16 repeats in the affected individuals and from 3 to 12 repeats in 520 healthy individuals. A missense substitution of a highly conserved residue likely to affect the interaction of eIF4AIII with the UPF3B subunit of the exon junction complex in trans with an expanded allele was found in an unrelated individual with an atypical presentation, thus expanding mutational mechanisms and phenotypic diversity of RCPS. EIF4A3 transcript abundance was reduced in both white blood cells and mesenchymal cells of RCPS-affected individuals as compared to controls. Notably, targeting the orthologous eif4a3 in zebrafish led to underdevelopment of several craniofacial cartilage and bone structures, in agreement with the craniofacial alterations seen in RCPS. Our data thus suggest that RCPS is caused by mutations in EIF4A3 and show that EIF4A3, a gene involved in RNA metabolism, plays a role in mandible, laryngeal, and limb morphogenesis. PMID:24360810

  1. Bone Repair Cells for Craniofacial Regeneration

    PubMed Central

    Pagni, G; Kaigler, D; Rasperini, G; Avila-Ortiz, G; Bartel, R; Giannobile, WV

    2012-01-01

    Reconstruction of complex craniofacial deformities is a clinical challenge in situations of injury, congenital defects or disease. The use of cell-based therapies represents one of the most advanced methods for enhancing the regenerative response for craniofacial wound healing. Both Somatic and Stem Cells have been adopted in the treatment of complex osseous defects and advances have been made in finding the most adequate scaffold for the delivery of cell therapies in human regenerative medicine. As an example of such approaches for clinical application for craniofacial regeneration, Ixmyelocel-T or bone repair cells are a source of bone marrow derived stem and progenitor cells. They are produced through the use of single pass perfusion bioreactors for CD90+ mesenchymal stem cells and CD14+ monocyte/macrophage progenitor cells. The application of ixmyelocel-T has shown potential in the regeneration of muscular, vascular, nervous and osseous tissue. The purpose of this manuscript is to highlight cell therapies used to repair bony and soft tissue defects in the oral and craniofacial complex. The field at this point remains at an early stage, however this review will provide insights into the progress being made using cell therapies for eventual development into clinical practice. PMID:22433781

  2. Cichlid fishes as a model to understand normal and clinical craniofacial variation.

    PubMed

    Powder, Kara E; Albertson, R Craig

    2016-07-15

    We have made great strides towards understanding the etiology of craniofacial disorders, especially for 'simple' Mendelian traits. However, the facial skeleton is a complex trait, and the full spectrum of genetic, developmental, and environmental factors that contribute to its final geometry remain unresolved. Forward genetic screens are constrained with respect to complex traits due to the types of genes and alleles commonly identified, developmental pleiotropy, and limited information about the impact of environmental interactions. Here, we discuss how studies in an evolutionary model - African cichlid fishes - can complement traditional approaches to understand the genetic and developmental origins of complex shape. Cichlids exhibit an unparalleled range of natural craniofacial morphologies that model normal human variation, and in certain instances mimic human facial dysmorphologies. Moreover, the evolutionary history and genomic architecture of cichlids make them an ideal system to identify the genetic basis of these phenotypes via quantitative trait loci (QTL) mapping and population genomics. Given the molecular conservation of developmental genes and pathways, insights from cichlids are applicable to human facial variation and disease. We review recent work in this system, which has identified lbh as a novel regulator of neural crest cell migration, determined the Wnt and Hedgehog pathways mediate species-specific bone morphologies, and examined how plastic responses to diet modulate adult facial shapes. These studies have not only revealed new roles for existing pathways in craniofacial development, but have identified new genes and mechanisms involved in shaping the craniofacial skeleton. In all, we suggest that combining work in traditional laboratory and evolutionary models offers significant potential to provide a more complete and comprehensive picture of the myriad factors that are involved in the development of complex traits. PMID:26719128

  3. Craniofacial fibrous dysplasia

    PubMed Central

    Jhamb, Aakarsh; Mohanty, Sujata; Jhamb, Parul A

    2012-01-01

    Fibrous dysplasia can present clinically in varied forms which may appear as collision of different pathologic processes. We report a rare case of craniofacial fibrous dysplasia with coexisting epithelial lined cyst and superimposed osteomyelitis with sequestrum formation. Its clinical features and management with possible hypotheses are described along with the post operative course. Pertinent literature has been reviewed with emphasis on pathogenesis of this unique occurrence. PMID:23248490

  4. Pdgfra protects against ethanol-induced craniofacial defects in a zebrafish model of FASD.

    PubMed

    McCarthy, Neil; Wetherill, Leah; Lovely, C Ben; Swartz, Mary E; Foroud, Tatiana M; Eberhart, Johann K

    2013-08-01

    Human birth defects are highly variable and this phenotypic variability can be influenced by both the environment and genetics. However, the synergistic interactions between these two variables are not well understood. Fetal alcohol spectrum disorders (FASD) is the umbrella term used to describe the wide range of deleterious outcomes following prenatal alcohol exposure. Although FASD are caused by prenatal ethanol exposure, FASD are thought to be genetically modulated, although the genes regulating sensitivity to ethanol teratogenesis are largely unknown. To identify potential ethanol-sensitive genes, we tested five known craniofacial mutants for ethanol sensitivity: cyp26b1, gata3, pdgfra, smad5 and smoothened. We found that only platelet-derived growth factor receptor alpha (pdgfra) interacted with ethanol during zebrafish craniofacial development. Analysis of the PDGF family in a human FASD genome-wide dataset links PDGFRA to craniofacial phenotypes in FASD, prompting a mechanistic understanding of this interaction. In zebrafish, untreated pdgfra mutants have cleft palate due to defective neural crest cell migration, whereas pdgfra heterozygotes develop normally. Ethanol-exposed pdgfra mutants have profound craniofacial defects that include the loss of the palatal skeleton and hypoplasia of the pharyngeal skeleton. Furthermore, ethanol treatment revealed latent haploinsufficiency, causing palatal defects in ∼62% of pdgfra heterozygotes. Neural crest apoptosis partially underlies these ethanol-induced defects in pdgfra mutants, demonstrating a protective role for Pdgfra. This protective role is mediated by the PI3K/mTOR pathway. Collectively, our results suggest a model where combined genetic and environmental inhibition of PI3K/mTOR signaling leads to variability within FASD. PMID:23861062

  5. Pdgfra protects against ethanol-induced craniofacial defects in a zebrafish model of FASD

    PubMed Central

    McCarthy, Neil; Wetherill, Leah; Lovely, C. Ben; Swartz, Mary E.; Foroud, Tatiana M.; Eberhart, Johann K.

    2013-01-01

    Human birth defects are highly variable and this phenotypic variability can be influenced by both the environment and genetics. However, the synergistic interactions between these two variables are not well understood. Fetal alcohol spectrum disorders (FASD) is the umbrella term used to describe the wide range of deleterious outcomes following prenatal alcohol exposure. Although FASD are caused by prenatal ethanol exposure, FASD are thought to be genetically modulated, although the genes regulating sensitivity to ethanol teratogenesis are largely unknown. To identify potential ethanol-sensitive genes, we tested five known craniofacial mutants for ethanol sensitivity: cyp26b1, gata3, pdgfra, smad5 and smoothened. We found that only platelet-derived growth factor receptor alpha (pdgfra) interacted with ethanol during zebrafish craniofacial development. Analysis of the PDGF family in a human FASD genome-wide dataset links PDGFRA to craniofacial phenotypes in FASD, prompting a mechanistic understanding of this interaction. In zebrafish, untreated pdgfra mutants have cleft palate due to defective neural crest cell migration, whereas pdgfra heterozygotes develop normally. Ethanol-exposed pdgfra mutants have profound craniofacial defects that include the loss of the palatal skeleton and hypoplasia of the pharyngeal skeleton. Furthermore, ethanol treatment revealed latent haploinsufficiency, causing palatal defects in ∼62% of pdgfra heterozygotes. Neural crest apoptosis partially underlies these ethanol-induced defects in pdgfra mutants, demonstrating a protective role for Pdgfra. This protective role is mediated by the PI3K/mTOR pathway. Collectively, our results suggest a model where combined genetic and environmental inhibition of PI3K/mTOR signaling leads to variability within FASD. PMID:23861062

  6. Human disorders of peroxisome metabolism and biogenesis.

    PubMed

    Waterham, Hans R; Ferdinandusse, Sacha; Wanders, Ronald J A

    2016-05-01

    Peroxisomes are dynamic organelles that play an essential role in a variety of cellular catabolic and anabolic metabolic pathways, including fatty acid alpha- and beta-oxidation, and plasmalogen and bile acid synthesis. Defects in genes encoding peroxisomal proteins can result in a large variety of peroxisomal disorders either affecting specific metabolic pathways, i.e., the single peroxisomal enzyme deficiencies, or causing a generalized defect in function and assembly of peroxisomes, i.e., peroxisome biogenesis disorders. In this review, we discuss the clinical, biochemical, and genetic aspects of all human peroxisomal disorders currently known. PMID:26611709

  7. Craniofacial fibrous dysplasia.

    PubMed

    Ricalde, Pat; Magliocca, Kelly R; Lee, Janice S

    2012-08-01

    Despite recent advances in the understanding of the natural history and molecular abnormalities, many questions remain surrounding the progression and management of fibrous dysplasia (FD). In the absence of comorbidities, the expected behavior of craniofacial FD (CFD) is to be slow growing and without functional consequence. Understanding of the pathophysiologic mechanisms contributing to the various phenotypes of this condition, as well as the predictors of the different behaviors of FD lesions, must be improved. Long-term follow-up of patients with CFD is vital because spontaneous recovery is unlikely, and the course of disease can be unpredictable. PMID:22771278

  8. Fibronectin and craniofacial surgery.

    PubMed

    Al-Qattan, Mohammad M; AlShomer, Feras; Alqahtani, Abdullah; Alhadlg, Ahmad

    2014-12-01

    Fibronectin is an essential component of the extracellular matrix. The role of fibronectin in craniofacial surgery has not been previously reviewed. Fibronectin mediates bone differentiation and development of the skull. Studies have shown that normal development of the skull requires a specific pattern of expression around the epithelial-mesenchymal interface of the neurocranium. Fibronectin is also essential in mediating the migration of neural crest cells to form the facial skeleton. The calvaria of patients with Apert and Crouzon syndromes have an abnormally elevated collagen level. However, fibronectin levels are elevated in the former syndrome and decreased in the latter syndrome. The significance of this requires further research. Fibronectin gene expression is increased in port wine-derived fibroblasts in patients with Sturge-Weber syndrome. Normal palatogenesis also requires a specific pattern of expression of fibronectin around the maxillary process as well as the roof of the stomodeum, and several studies have linked the development of cleft lip/palate to an imbalance of fibronectin content of the extracellular matrix. Fibronectin mediates cell-to-cell attachment during repair of calvarial defects; hence, fibronectin has been used as a carrier for bone morphogenetic proteins to treat calvarial defects. Finally, fibronectin is now an essential component in stem cell technology related to craniofacial surgery. PMID:24322634

  9. NEUROLOGICAL ASPECTS OF HUMAN GLYCOSYLATION DISORDERS

    PubMed Central

    Freeze, Hudson H.; Eklund, Erik A.; Ng, Bobby G.; Patterson, Marc C.

    2016-01-01

    This review will present principles of glycosylation, describe the relevant glycosylation pathways and their related disorders, and highlight some of the neurological aspects and issues that continue to challenge researchers. Over 100 rare human genetic disorders that result from deficiencies in the different glycosylation pathways are known today. Most of these disorders impact the central and/or peripheral nervous systems. Patients typically have developmental delay/intellectual disability, hypotonia, seizures, neuropathy, and metabolic abnormalities in multiple organ systems. Between these disorders there is great clinical diversity because all cell types differentially glycosylate proteins and lipids. The patients have hundreds of mis-glycosylated products afflicting a myriad of processes including cell signaling, cell-cell interaction and cell migration. This vast complexity in glycan composition and function, along with limited analytic tools has impeded the identification of key glycosylated molecules that cause pathologies, and to date few critical target proteins have been pinpointed. PMID:25840006

  10. 76 FR 4123 - National Institute of Dental & Craniofacial Research; Notice of Closed Meetings

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-24

    ... HUMAN SERVICES National Institutes of Health National Institute of Dental & Craniofacial Research... personal privacy. Name of Committee: National Institute of Dental and Craniofacial Research Special Emphasis Panel, ZDE1 VH (13) NIDCR Review of Small Research Grants for Data Analysis and...

  11. 75 FR 82033 - National Institute of Dental and Craniofacial Research; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-12-29

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  12. 75 FR 13561 - National Institute of Dental & Craniofacial Research; Notice of Meeting

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    ... HUMAN SERVICES National Institutes of Health National Institute of Dental & Craniofacial Research.... App.), notice is hereby given of a meeting of the National Advisory Dental and Craniofacial Research... constitute a clearly unwarranted invasion of personal privacy. Name of Committee: National Advisory...

  13. 75 FR 4833 - National Institute of Dental & Craniofacial Research; Notice of Closed Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-01-29

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Dental & Craniofacial Research.... of Dental & Craniofacial Research, National Institutes of Health, 45 Center Dr., Rm 4AN 32J,...

  14. 75 FR 55592 - National Institute of Dental & Craniofacial Research; Amended Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-13

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Dental & Craniofacial Research... Dental and Craniofacial Research Council, September 27, 2010, 8:30 a.m. to September 27, 2010, 3...

  15. 78 FR 65343 - National Institute of Dental & Craniofacial Research; Amended Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-10-31

    ... published in the Federal Register on September 16, 2013, 78 FR 56902. Meeting date has changed from October... HUMAN SERVICES National Institutes of Health National Institute of Dental & Craniofacial Research... Dental and Craniofacial Research Special Emphasis Panel, October 7, 2013, 10:00 a.m. to October 7,...

  16. 77 FR 49820 - National Institute of Dental & Craniofacial Research; Notice of Meeting

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  17. 75 FR 62546 - National Institute of Dental & Craniofacial Research; Notice of Closed Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-10-12

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Dental & Craniofacial Research..., National Inst of Dental & Craniofacial Research, National Institutes of Health, 45 Center Dr. Rm 4AN...

  18. 78 FR 50066 - National Institute of Dental and Craniofacial Research; Notice of Meeting

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  19. 78 FR 24761 - National Institute of Dental & Craniofacial Research; Notice of Meeting

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  20. 76 FR 23612 - National Institute of Dental & Craniofacial Research; Notice of Meeting

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  1. 76 FR 51995 - National Institute of Dental & Craniofacial Research; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-19

    ... HUMAN SERVICES National Institutes of Health National Institute of Dental & Craniofacial Research.... App.), notice is hereby given of a meeting of the National Advisory Dental and Craniofacial Research... constitute a clearly unwarranted invasion of personal privacy. Name of Committee: National Advisory...

  2. 76 FR 48874 - National Institute Of Dental & Craniofacial Research; Notice of Closed Meeting

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    2011-08-09

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  3. 78 FR 65348 - National Institute of Dental & Craniofacial Research; Amended Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-10-31

    ..., MD 20892 which was published in the Federal Register on September 27, 2013, 78 FR 59708. Meeting date... HUMAN SERVICES National Institutes of Health National Institute of Dental & Craniofacial Research... Dental and Craniofacial Research Special Emphasis Panel, October 21, 2013, 9:00 a.m. to October 21,...

  4. 77 FR 74674 - National Institute of Dental & Craniofacial Research; Notice of Meeting

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  5. 75 FR 51275 - National Institute of Dental and Craniofacial Research; Notice of Meeting

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    2010-08-19

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  6. Parathyroid Hormone Applications in the Craniofacial Skeleton

    PubMed Central

    Chan, H.L.; McCauley, L.K.

    2013-01-01

    Parathyroid hormone (PTH) is known for its ability to ‘build’ bone, with research in this area centered on its use as an osteoporosis therapeutic. Recent interest has developed regarding its potential for regenerative applications such as fracture healing and osseous defects of the oral cavity. Many years of investigation using murine gene-targeted models substantiate a role for signaling at the PTH/PTH-related protein (PTHrP) receptor (PPR) in intramembranous bone formation in the craniofacial region as well as in tooth development. Pre-clinical studies clearly support a positive role of intermittent PTH administration in craniofacial bones and in fracture healing and implant integration. A few human clinical studies have shown favorable responses with teriparatide (the biologically active fragment of PTH) administration. Favorable outcomes have emerged with teriparatide administration in patients with osteonecrosis of the jaw (ONJ). New delivery strategies are in development to optimize targeted application of PTH and to help maximize local approaches. The promising host-modulating potential of PTH requires more information to further its effectiveness for craniofacial regeneration and osseous wound-healing, including a better delineation of cellular targets, temporal effects of PTH action, and improved approaches for local/targeted delivery of PTH. PMID:23071071

  7. 75 FR 65495 - National Institute of Dental and Craniofacial Research; Interagency Pain Research Coordinating...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-10-25

    ... HUMAN SERVICES National Institutes of Health National Institute of Dental and Craniofacial Research; Interagency Pain Research Coordinating Committee; Call for Nominations The Department of Health and Human Services has created the Interagency Pain Research Coordinating Committee and is seeking nominations...

  8. Craniofacial shape variation in Twist1+/- mutant mice.

    PubMed

    Parsons, Trish E; Weinberg, Seth M; Khaksarfard, Kameron; Howie, R Nicole; Elsalanty, Mohammed; Yu, Jack C; Cray, James J

    2014-05-01

    Craniosynostosis (CS) is a relatively common birth defect resulting from the premature fusion of one or more cranial sutures. Human genetic studies have identified several genes in association with CS. One such gene that has been implicated in both syndromic (Saethre-Chotzen syndrome) and nonsyndromic forms of CS in humans is TWIST1. In this study, a heterozygous Twist1 knock out (Twist1(+/-) ) mouse model was used to study the craniofacial shape changes associated with the partial loss of function. A geometric morphometric approach was used to analyze landmark data derived from microcomputed tomography scans to compare craniofacial shape between 17 Twist1(+/-) mice and 26 of their Twist1(+/+) (wild type) littermate controls at 15 days of age. The results show that despite the purported wide variation in synostotic severity, Twist1(+/-) mice have a consistent pattern of craniofacial dysmorphology affecting all major regions of the skull. Similar to Saethre-Chotzen, the calvarium is acrocephalic and wide with an overall brachycephalic shape. Mutant mice also exhibited a shortened cranial base and a wider and shorted face, consistent with coronal CS associated phenotypes. The results suggest that these differences are at least partially the direct result of the Twist1 haploinsufficiency on the developing craniofacial skeleton. This study provides a quantitative phenotype complement to the developmental and molecular genetic research previously done on Twist1. These results can be used to generate further hypotheses about the effect of Twist1 and premature suture fusion on the entire craniofacial skeleton. PMID:24585549

  9. Mouse Genetic Models of Human Brain Disorders.

    PubMed

    Leung, Celeste; Jia, Zhengping

    2016-01-01

    Over the past three decades, genetic manipulations in mice have been used in neuroscience as a major approach to investigate the in vivo function of genes and their alterations. In particular, gene targeting techniques using embryonic stem cells have revolutionized the field of mammalian genetics and have been at the forefront in the generation of numerous mouse models of human brain disorders. In this review, we will first examine childhood developmental disorders such as autism, intellectual disability, Fragile X syndrome, and Williams-Beuren syndrome. We will then explore psychiatric disorders such as schizophrenia and lastly, neurodegenerative disorders including Alzheimer's disease and Parkinson's disease. We will outline the creation of these mouse models that range from single gene deletions, subtle point mutations to multi-gene manipulations, and discuss the key behavioral phenotypes of these mice. Ultimately, the analysis of the models outlined in this review will enhance our understanding of the in vivo role and underlying mechanisms of disease-related genes in both normal brain function and brain disorders, and provide potential therapeutic targets and strategies to prevent and treat these diseases. PMID:27047540

  10. Mouse Genetic Models of Human Brain Disorders

    PubMed Central

    Leung, Celeste; Jia, Zhengping

    2016-01-01

    Over the past three decades, genetic manipulations in mice have been used in neuroscience as a major approach to investigate the in vivo function of genes and their alterations. In particular, gene targeting techniques using embryonic stem cells have revolutionized the field of mammalian genetics and have been at the forefront in the generation of numerous mouse models of human brain disorders. In this review, we will first examine childhood developmental disorders such as autism, intellectual disability, Fragile X syndrome, and Williams-Beuren syndrome. We will then explore psychiatric disorders such as schizophrenia and lastly, neurodegenerative disorders including Alzheimer’s disease and Parkinson’s disease. We will outline the creation of these mouse models that range from single gene deletions, subtle point mutations to multi-gene manipulations, and discuss the key behavioral phenotypes of these mice. Ultimately, the analysis of the models outlined in this review will enhance our understanding of the in vivo role and underlying mechanisms of disease-related genes in both normal brain function and brain disorders, and provide potential therapeutic targets and strategies to prevent and treat these diseases. PMID:27047540

  11. Advances in gene technology: Human genetic disorders

    SciTech Connect

    Scott, W.A.; Ahmad, F.; Black, S.; Schultz, J.; Whelan, W.J.

    1984-01-01

    This book discusses the papers presented at the conference on the subject of ''advances in Gene technology: Human genetic disorders''. Molecular biology of various carcinomas and inheritance of metabolic diseases is discussed and technology advancement in diagnosis of hereditary diseases is described. Some of the titles discussed are-Immunoglobulin genes translocation and diagnosis; hemophilia; oncogenes; oncogenic transformations; experimental data on mice, hamsters, birds carcinomas and sarcomas.

  12. Craniofacial plasticity in ancient Peru.

    PubMed

    Stone, Jessica H; Chew, Kristen; Ross, Ann H; Verano, John W

    2015-01-01

    Numerous studies have utilized craniometric data to explore the roles of genetic diversity and environment in human cranial shape variation. Peru is a particularly interesting region to examine cranial variation due to the wide variety of high and low altitude ecological zones, which in combination with rugged terrain have created isolated populations with vastly different physiological adaptations. This study examines seven samples from throughout Peru in an effort to understand the contributions of environmental adaptation and genetic relatedness to craniofacial variation at a regional scale. Morphological variation was investigated using a canonical discriminant analysis and Mahalanobis D(2) analysis. Results indicate that all groups are significantly different from one another with the closest relationship between Yauyos and Jahuay, two sites that are located geographically close in central Peru but in very different ecozones. The relationship between latitude/longitude and face shape was also examined with a spatial autocorrelation analysis (Moran's I) using ArcMap and show that there is significant spatial patterning for facial measures and geographic location suggesting that there is an association between biological variation and geographic location. PMID:25807293

  13. Craniofacial surgery: present and future.

    PubMed Central

    Whitaker, L A; Schut, L; Randall, P

    1976-01-01

    The possibilities for radical craniofacial restructuring have increased dramatically in the past 6 years with the development of craniofacial surgery. The field developed from a background of patients with major craniofacial birth defects allowing orderly planning and expansion to correction of a multitude of other craniofacial structural problems. The procedures concentrate upon changing the skeletal structures using extensive subperiostial dissection of soft tissue, and adding bone to fill in areas of deficiency. There are three grades of complexity in craniofacial procedures. After extensive soft tissue sub-periostial stripping about the orbits and upper face, the simplest form consists of onlay bone grafts. The next most complicated involves osteotomies to shift the face into a more normal position. In its most complicated form, abnormal proportions of bone are removed and the orbits or cranium are shifted into a new or normal position. We have had experience with 69 patients since September, 1972. Thirty-six have had intracranial procedures. Infection has been the most serious problem, and there have been no instances of death or blindness. A number of lesser problems occur. Future applications of craniofacial surgery are appearing with great frequency as more experience is gained with its uses. It has particular application in acute and late reconstruction of patients with traumatic defects about the face. Preventive osteotomies are an area with great potential, by releasing stenotic areas of bone and allowing the developing brain to mold the upper face and orbits. There is also applicability in surgery of tumors about the craniofacial structure and in cosmetic surgery. Images Fig. 1a. Fig. 1b. Fig. 1c. Fig. 1d. Fig. 1e. Fig. 2a. Fig. 2b. Fig. 2c. PMID:984925

  14. Understanding Cleft and Craniofacial Team Care

    MedlinePlus

    ... Donor Spotlight Fundraising Ideas Vehicle Donation Volunteer Efforts Cleft Lip/Palate & Craniofacial Specialists in Your Area skip to submenu Parents & Individuals Cleft Lip/Palate & Craniofacial Specialists in Your Area Team Disclaimer ...

  15. Prevention of Treacher Collins syndrome craniofacial anomalies in mouse models via maternal antioxidant supplementation

    PubMed Central

    Sakai, Daisuke; Dixon, Jill; Achilleos, Annita; Dixon, Michael; Trainor, Paul A.

    2016-01-01

    Craniofacial anomalies account for approximately one-third of all birth defects and are a significant cause of infant mortality. Since the majority of the bones, cartilage and connective tissues that comprise the head and face are derived from a multipotent migratory progenitor cell population called the neural crest, craniofacial disorders are typically attributed to defects in neural crest cell development. Treacher Collins syndrome (TCS) is a disorder of craniofacial development and although TCS arises primarily through autosomal dominant mutations in TCOF1, no clear genotype–phenotype correlation has been documented. Here we show that Tcof1 haploinsufficiency results in oxidative stress-induced DNA damage and neuroepithelial cell death. Consistent with this discovery, maternal treatment with antioxidants minimizes cell death in the neuroepithelium and substantially ameliorates or prevents the pathogenesis of craniofacial anomalies in Tcof1+/− mice. Thus maternal antioxidant dietary supplementation may provide an avenue for protection against the pathogenesis of TCS and similar neurocristopathies. PMID:26792133

  16. Prevention of Treacher Collins syndrome craniofacial anomalies in mouse models via maternal antioxidant supplementation.

    PubMed

    Sakai, Daisuke; Dixon, Jill; Achilleos, Annita; Dixon, Michael; Trainor, Paul A

    2016-01-01

    Craniofacial anomalies account for approximately one-third of all birth defects and are a significant cause of infant mortality. Since the majority of the bones, cartilage and connective tissues that comprise the head and face are derived from a multipotent migratory progenitor cell population called the neural crest, craniofacial disorders are typically attributed to defects in neural crest cell development. Treacher Collins syndrome (TCS) is a disorder of craniofacial development and although TCS arises primarily through autosomal dominant mutations in TCOF1, no clear genotype-phenotype correlation has been documented. Here we show that Tcof1 haploinsufficiency results in oxidative stress-induced DNA damage and neuroepithelial cell death. Consistent with this discovery, maternal treatment with antioxidants minimizes cell death in the neuroepithelium and substantially ameliorates or prevents the pathogenesis of craniofacial anomalies in Tcof1(+/-) mice. Thus maternal antioxidant dietary supplementation may provide an avenue for protection against the pathogenesis of TCS and similar neurocristopathies. PMID:26792133

  17. Human genetic disorders of sphingolipid biosynthesis.

    PubMed

    Astudillo, Leonardo; Sabourdy, Frédérique; Therville, Nicole; Bode, Heiko; Ségui, Bruno; Andrieu-Abadie, Nathalie; Hornemann, Thorsten; Levade, Thierry

    2015-01-01

    Monogenic defects of sphingolipid biosynthesis have been recently identified in human patients. These enzyme deficiencies affect the synthesis of sphingolipid precursors, ceramides or complex glycosphingolipids. They are transmitted as autosomal recessive or dominant traits, and their resulting phenotypes often replicate the abnormalities seen in murine models deficient for the corresponding enzymes. In quite good agreement with the known critical roles of sphingolipids in cells from the nervous system and the epidermis, these genetic defects clinically manifest as neurological disorders, including paraplegia, epilepsy or peripheral neuropathies, or present with ichthyosis. The present review summarizes the genetic alterations, biochemical changes and clinical symptoms of this new group of inherited metabolic disorders. Hypotheses regarding the molecular pathophysiology and potential treatments of these diseases are also discussed. PMID:25141825

  18. [Hedgehog signaling pathway and human disorders].

    PubMed

    Fujii, Katsunori; Miyashita, Toshiyuki

    2009-07-01

    The hedgehog signaling pathway plays pivotal roles in embryonic development and cancer formation. This pathway in mammals consists of multiple molecules such as Sonic Hedgehog, PTCH, SMO, and GLI. Mutations of these components result in various human malformations or tumors, i.e., holoprosencephaly, Gorlin syndrome, Greig encephalopolysyndactyly, Pallister-Hall syndrome, Rubinstein-Taybi syndrome, basal cell carcinomas, and medulloblastomas. Recently, small molecules that inhibit this signaling pathway were developed, and clinically applied to cancer therapy. Thus, understanding of these molecular relationships may facilitate the development of new therapies and treatments for diseases caused by hedgehog signaling disorders. PMID:19618878

  19. Genetic Basis of Human Circadian Rhythm Disorders

    PubMed Central

    Jones, Christopher R.; Huang, Angela L.; Ptáček, Louis J.; Fu, Ying-Hui

    2012-01-01

    Circadian rhythm disorders constitute a group of phenotypes that usually present as altered sleep-wake schedules. Until a human genetics approach was applied to investigate these traits, the genetic components regulating human circadian rhythm and sleep behaviors remained mysterious. Steady advances in the last decade have dramatically improved our understanding of the genes involved in circadian rhythmicity and sleep regulation. Finding these genes presents new opportunities to use a wide range of approaches, including in vitro molecular studies and in vivo animal modeling, to elevate our understanding of how sleep and circadian rhythms are regulated and maintained. Ultimately, this knowledge will reveal how circadian and sleep disruption contribute to various ailments and shed light on how best to maintain and recover good health. PMID:22849821

  20. 76 FR 30370 - National Institute of Dental and Craniofacial Research; Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-05-25

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Dental and Craniofacial Research... unwarranted invasion of personal privacy. Name of Committee: National Institute of Dental and...

  1. Biomaterials for Craniofacial Bone Engineering

    PubMed Central

    Tevlin, R.; McArdle, A.; Atashroo, D.; Walmsley, G.G.; Senarath-Yapa, K.; Zielins, E.R.; Paik, K.J.; Longaker, M.T.; Wan, D.C.

    2014-01-01

    Conditions such as congenital anomalies, cancers, and trauma can all result in devastating deficits of bone in the craniofacial skeleton. This can lead to significant alteration in function and appearance that may have significant implications for patients. In addition, large bone defects in this area can pose serious clinical dilemmas, which prove difficult to remedy, even with current gold standard surgical treatments. The craniofacial skeleton is complex and serves important functional demands. The necessity to develop new approaches for craniofacial reconstruction arises from the fact that traditional therapeutic modalities, such as autologous bone grafting, present myriad limitations and carry with them the potential for significant complications. While the optimal bone construct for tissue regeneration remains to be elucidated, much progress has been made in the past decade. Advances in tissue engineering have led to innovative scaffold design, complemented by progress in the understanding of stem cell–based therapy and growth factor enhancement of the healing cascade. This review focuses on the role of biomaterials for craniofacial bone engineering, highlighting key advances in scaffold design and development. PMID:25139365

  2. Bone Grafts in Craniofacial Surgery

    PubMed Central

    Elsalanty, Mohammed E.; Genecov, David G.

    2009-01-01

    Reconstruction of cranial and maxillofacial defects is a challenging task. The standard reconstruction method has been bone grafting. In this review, we shall describe the biological principles of bone graft healing, as pertinent to craniofacial reconstruction. Different types and sources of bone grafts will be discussed, as well as new methods of bone defect reconstruction. PMID:22110806

  3. Ribosomopathies: human disorders of ribosome dysfunction.

    PubMed

    Narla, Anupama; Ebert, Benjamin L

    2010-04-22

    Ribosomopathies compose a collection of disorders in which genetic abnormalities cause impaired ribosome biogenesis and function, resulting in specific clinical phenotypes. Congenital mutations in RPS19 and other genes encoding ribosomal proteins cause Diamond-Blackfan anemia, a disorder characterized by hypoplastic, macrocytic anemia. Mutations in other genes required for normal ribosome biogenesis have been implicated in other rare congenital syndromes, Schwachman-Diamond syndrome, dyskeratosis congenita, cartilage hair hypoplasia, and Treacher Collins syndrome. In addition, the 5q- syndrome, a subtype of myelodysplastic syndrome, is caused by a somatically acquired deletion of chromosome 5q, which leads to haploinsufficiency of the ribosomal protein RPS14 and an erythroid phenotype highly similar to Diamond-Blackfan anemia. Acquired abnormalities in ribosome function have been implicated more broadly in human malignancies. The p53 pathway provides a surveillance mechanism for protein translation as well as genome integrity and is activated by defects in ribosome biogenesis; this pathway appears to be a critical mediator of many of the clinical features of ribosomopathies. Elucidation of the mechanisms whereby selective abnormalities in ribosome biogenesis cause specific clinical syndromes will hopefully lead to novel therapeutic strategies for these diseases. PMID:20194897

  4. Hedgehog receptor function during craniofacial development.

    PubMed

    Xavier, Guilherme M; Seppala, Maisa; Barrell, William; Birjandi, Anahid A; Geoghegan, Finn; Cobourne, Martyn T

    2016-07-15

    The Hedgehog signalling pathway plays a fundamental role in orchestrating normal craniofacial development in vertebrates. In particular, Sonic hedgehog (Shh) is produced in three key domains during the early formation of the head; neuroectoderm of the ventral forebrain, facial ectoderm and the pharyngeal endoderm; with signal transduction evident in both ectodermal and mesenchymal tissue compartments. Shh signalling from the prechordal plate and ventral midline of the diencephalon is required for appropriate division of the eyefield and forebrain, with mutation in a number of pathway components associated with Holoprosencephaly, a clinically heterogeneous developmental defect characterized by a failure of the early forebrain vesicle to divide into distinct halves. In addition, signalling from the pharyngeal endoderm and facial ectoderm plays an essential role during development of the face, influencing cranial neural crest cells that migrate into the early facial processes. In recent years, the complexity of Shh signalling has been highlighted by the identification of multiple novel proteins that are involved in regulating both the release and reception of this protein. Here, we review the contributions of Shh signalling during early craniofacial development, focusing on Hedgehog receptor function and describing the consequences of disruption for inherited anomalies of this region in both mouse models and human populations. PMID:26875496

  5. Study on the performance of different craniofacial superimposition approaches (II): Best practices proposal.

    PubMed

    Damas, S; Wilkinson, C; Kahana, T; Veselovskaya, E; Abramov, A; Jankauskas, R; Jayaprakash, P T; Ruiz, E; Navarro, F; Huete, M I; Cunha, E; Cavalli, F; Clement, J; Lestón, P; Molinero, F; Briers, T; Viegas, F; Imaizumi, K; Humpire, D; Ibáñez, O

    2015-12-01

    Craniofacial superimposition, although existing for one century, is still a controversial technique within the scientific community. Objective and unbiased validation studies over a significant number of cases are required to establish a more solid picture on the reliability. However, there is lack of protocols and standards in the application of the technique leading to contradictory information concerning reliability. Instead of following a uniform methodology, every expert tends to apply his own approach to the problem, based on the available technology and deep knowledge on human craniofacial anatomy, soft tissues, and their relationships. The aim of this study was to assess the reliability of different craniofacial superimposition methodologies and the corresponding technical approaches to this type of identification. With all the data generated, some of the most representative experts in craniofacial identification joined in a discussion intended to identify and agree on the most important issues that have to be considered to properly employ the craniofacial superimposition technique. As a consequence, the consortium has produced the current manuscript, which can be considered the first standard in the field; including good and bad practices, sources of error and uncertainties, technological requirements and desirable features, and finally a common scale for the craniofacial matching evaluation. Such a document is intended to be part of a more complete framework for craniofacial superimposition, to be developed during the FP7-founded project MEPROCS, which will favour and standardize its proper application. PMID:26482539

  6. [Human skull development and voice disorders].

    PubMed

    Piron, A; Roch, J B

    2006-01-01

    The hominisation of the skull comes with the bipedic posture, due to a network of muscular and aponevrotic forces applied to the cranio-facial skeleton. A brief sight of the morphogenetic origine and issues of these forces help to understand more clearly the postural statement of the larynx, his functions, and his many extrinsic biomechanical bounds; then further his most frequently dysfunctions. The larynx is surrounded by several effective systems of protection: active, activo-passive, passive. The architectural features of the components of the laryngeal system allows us to consider the laryngeal function as an auto-balanced system. All the forces engaged are auto-balanced in a continuum of tension. This lead us to the concept of tensegrity system, neologism coming from tensional integrity described by Buckminster Fuller. The laryngeal employement by extrinsic system is pathological in case of chronicity. Any osteopathic treatment, which aims to restore the losses of laryngeal mobility, has to release first the peripherical structures involved in the laryngeal defense, before normalising the larynx itself Finally, the larynx recovers his functions in a tensegrity system. PMID:17425001

  7. Craniofacial reconstruction following oncologic resection.

    PubMed

    Hanasono, Matthew M; Hofstede, Theresa M

    2013-01-01

    The ability to reliably reconstruct complex and sizable wounds has decreased the morbidity of skull base surgery substantially, preventing major complications and allowing treatment of tumors previously considered inoperable. Addressing facial nerve function with static and dynamic procedures as well as fabrication of craniofacial prostheses to replace delicate facial landmarks has further increased surgeons' ability to restore the appearance and function of the face. PMID:23174362

  8. The oral and craniofacial relevance of chemically modified RNA therapeutics.

    PubMed

    Elangovan, Satheesh; Kormann, Michael S D; Khorsand, Behnoush; Salem, Aliasger K

    2016-01-01

    Several tissue engineering strategies in the form of protein therapy, gene therapy, cell therapy, and their combinations are currently being explored for oral and craniofacial regeneration and repair. Though each of these approaches has advantages, they all have common inherent drawbacks of being expensive and raising safety concerns. Using RNA (encoding therapeutic protein) has several advantages that have the potential to overcome these limitations. Chemically modifying the RNA improves its stability and mitigates immunogenicity allowing for the potential of RNA to become an alternative to protein and gene based therapies. This brief review article focuses on the potential of RNA therapeutics in the treatment of disorders in the oral and craniofacial regions. PMID:26896600

  9. National Institute of Dental and Craniofacial Research

    MedlinePlus

    ... and craniofacial health of our nation. Grants & Funding Funding Opportunity Announcements By Topic RFAs PAs See All Grants & Funding Application Forms and Deadlines Grant Application Forms Application ...

  10. Growth changes in internal and craniofacial flexion measurements.

    PubMed

    May, R; Sheffer, D B

    1999-09-01

    Growth changes in both internal and craniofacial flexion angles are presented for Pan troglodytes, Gorilla gorilla, and modern humans. The internal flexion angle (IFA) was measured from lateral radiographs, and the craniofacial flexion angle (CFA) was calculated from coordinate data. Stage of dental development is used as a baseline for examination of growth changes and nonparametric correlations between flexion angles and dental development stage are tested for significance. In Gorilla, the IFA increases during growth. The IFA is relatively stable in Pan and modern humans. Pan and Gorilla display an increase in the CFA. However, this angle decreases during growth in modern humans. Flexion angles were derived from coordinate data collected for several early hominid crania. Measurements for two robust australopithecine crania indicate strong internal flexion. It has been suggested that cerebellar expansion in this group may relate to derived features of the posterior cranial base. In general, australopithecine crania exhibit craniofacial flexion intermediate between great apes and modern humans. The "archaic" Homo sapiens specimen from Kabwe is most similar to modern humans. PMID:10490467

  11. Dental and craniofacial characteristics in a patient with Hutchinson-Gilford progeria syndrome.

    PubMed

    Reichert, Christoph; Gölz, Lina; Götz, Werner; Wolf, Michael; Deschner, James; Jäger, Andreas

    2014-07-01

    The Hutchinson-Gilford progeria syndrome (HGPS) is an exceptionally rare medical disorder caused by mutations in the lamin A/C gene. Affected patients display typical features of premature aging. Beside general medical disorders, these patients have several specific features related to the craniofacial phenotype and the oral cavity. In this article, the dental and craniofacial characteristics of a 9-year-old girl with HGPS are presented. It is the first report addressing orthodontic tooth movement and microbiological features in a HGPS patient. We describe and discuss pathologic findings and provide a detailed histology of the teeth which had to be extracted during initial treatment. PMID:25001855

  12. The Roles of RNA Polymerase I and III Subunits Polr1c and Polr1d in Craniofacial Development and in Zebrafish Models of Treacher Collins Syndrome.

    PubMed

    Noack Watt, Kristin E; Achilleos, Annita; Neben, Cynthia L; Merrill, Amy E; Trainor, Paul A

    2016-07-01

    Ribosome biogenesis is a global process required for growth and proliferation of all cells, yet perturbation of ribosome biogenesis during human development often leads to tissue-specific defects termed ribosomopathies. Transcription of the ribosomal RNAs (rRNAs) by RNA polymerases (Pol) I and III, is considered a rate limiting step of ribosome biogenesis and mutations in the genes coding for RNA Pol I and III subunits, POLR1C and POLR1D cause Treacher Collins syndrome, a rare congenital craniofacial disorder. Our understanding of the functions of individual RNA polymerase subunits, however, remains poor. We discovered that polr1c and polr1d are dynamically expressed during zebrafish embryonic development, particularly in craniofacial tissues. Consistent with this pattern of activity, polr1c and polr1d homozygous mutant zebrafish exhibit cartilage hypoplasia and cranioskeletal anomalies characteristic of humans with Treacher Collins syndrome. Mechanistically, we discovered that polr1c and polr1d loss-of-function results in deficient ribosome biogenesis, Tp53-dependent neuroepithelial cell death and a deficiency of migrating neural crest cells, which are the primary progenitors of the craniofacial skeleton. More importantly, we show that genetic inhibition of tp53 can suppress neuroepithelial cell death and ameliorate the skeletal anomalies in polr1c and polr1d mutants, providing a potential avenue to prevent the pathogenesis of Treacher Collins syndrome. Our work therefore has uncovered tissue-specific roles for polr1c and polr1d in rRNA transcription, ribosome biogenesis, and neural crest and craniofacial development during embryogenesis. Furthermore, we have established polr1c and polr1d mutant zebrafish as models of Treacher Collins syndrome together with a unifying mechanism underlying its pathogenesis and possible prevention. PMID:27448281

  13. The Roles of RNA Polymerase I and III Subunits Polr1c and Polr1d in Craniofacial Development and in Zebrafish Models of Treacher Collins Syndrome

    PubMed Central

    Achilleos, Annita; Neben, Cynthia L.; Merrill, Amy E.; Trainor, Paul A.

    2016-01-01

    Ribosome biogenesis is a global process required for growth and proliferation of all cells, yet perturbation of ribosome biogenesis during human development often leads to tissue-specific defects termed ribosomopathies. Transcription of the ribosomal RNAs (rRNAs) by RNA polymerases (Pol) I and III, is considered a rate limiting step of ribosome biogenesis and mutations in the genes coding for RNA Pol I and III subunits, POLR1C and POLR1D cause Treacher Collins syndrome, a rare congenital craniofacial disorder. Our understanding of the functions of individual RNA polymerase subunits, however, remains poor. We discovered that polr1c and polr1d are dynamically expressed during zebrafish embryonic development, particularly in craniofacial tissues. Consistent with this pattern of activity, polr1c and polr1d homozygous mutant zebrafish exhibit cartilage hypoplasia and cranioskeletal anomalies characteristic of humans with Treacher Collins syndrome. Mechanistically, we discovered that polr1c and polr1d loss-of-function results in deficient ribosome biogenesis, Tp53-dependent neuroepithelial cell death and a deficiency of migrating neural crest cells, which are the primary progenitors of the craniofacial skeleton. More importantly, we show that genetic inhibition of tp53 can suppress neuroepithelial cell death and ameliorate the skeletal anomalies in polr1c and polr1d mutants, providing a potential avenue to prevent the pathogenesis of Treacher Collins syndrome. Our work therefore has uncovered tissue-specific roles for polr1c and polr1d in rRNA transcription, ribosome biogenesis, and neural crest and craniofacial development during embryogenesis. Furthermore, we have established polr1c and polr1d mutant zebrafish as models of Treacher Collins syndrome together with a unifying mechanism underlying its pathogenesis and possible prevention. PMID:27448281

  14. GENETICS OF HUMAN AGE RELATED DISORDERS.

    PubMed

    Srivastava, I; Thukral, N; Hasija, Y

    2015-01-01

    Aging is an inevitable biological phenomenon. The incidence of age related disorders (ARDs) such as cardiovascular diseases, cancer, arthritis, dementia, osteoporosis, diabetes, neurodegenerative diseases increase rapidly with aging. ARDs are becoming a key social and economic trouble for the world's elderly population (above 60 years), which is expected to reach 2 billion by 2050. Advancement in understanding of genetic associations, particularly through genome wide association studies (GWAS), has revealed a substantial contribution of genes to human aging and ARDs. In this review, we have focused on the recent understanding of the extent to which genetic predisposition may influence the aging process. Further analysis of the genetic association studies through pathway analysis several genes associated with multiple ARDs have been highlighted such as apolipoprotein E (APOE), brain-derived neurotrophic factor (BDNF), cadherin 13 (CDH13), CDK5 regulatory subunit associated protein 1 (CDKAL-1), methylenetetrahydrofolate reductase (MTHFR), disrupted in schizophrenia 1 (DISC1), nitric oxide synthase 3 (NOS3), paraoxonase 1 (PON1), indicating that these genes could play a pivotal role in ARD causation. These genes were found to be significantly enriched in Jak-STAT signalling pathway, asthma and allograft rejection. Further, interleukin-6 (IL-6), insulin (INS), vascular endothelial growth factor A (VEGFA), estrogen receptor1 (ESR1), transforming growth factor, beta 1(TGFB1) and calmodulin 1 (CALM1) were found to be highly interconnected in network analysis. We believe that extensive research on the presence of common genetic variants among various ARDs may facilitate scientists to understand the biology behind ARDs causation. PMID:26856084

  15. Sf3b4-depleted Xenopus embryos: A model to study the pathogenesis of craniofacial defects in Nager syndrome.

    PubMed

    Devotta, Arun; Juraver-Geslin, Hugo; Gonzalez, Jose Antonio; Hong, Chang-Soo; Saint-Jeannet, Jean-Pierre

    2016-07-15

    Mandibulofacial dysostosis (MFD) is a human developmental disorder characterized by defects of the facial bones. It is the second most frequent craniofacial malformation after cleft lip and palate. Nager syndrome combines many features of MFD with a variety of limb defects. Mutations in SF3B4 (splicing factor 3b, subunit 4) gene, which encodes a component of the pre-mRNA spliceosomal complex, were recently identified as a cause of Nager syndrome, accounting for 60% of affected individuals. Nothing is known about the cellular pathogenesis underlying Nager type MFD. Here we describe the first animal model for Nager syndrome, generated by knocking down Sf3b4 function in Xenopus laevis embryos, using morpholino antisense oligonucleotides. Our results indicate that Sf3b4-depleted embryos show reduced expression of the neural crest genes sox10, snail2 and twist at the neural plate border, associated with a broadening of the neural plate. This phenotype can be rescued by injection of wild-type human SF3B4 mRNA but not by mRNAs carrying mutations that cause Nager syndrome. At the tailbud stage, morphant embryos had decreased sox10 and tfap2a expression in the pharyngeal arches, indicative of a reduced number of neural crest cells. Later in development, Sf3b4-depleted tadpoles exhibited hypoplasia of neural crest-derived craniofacial cartilages, phenocopying aspects of the craniofacial skeletal defects seen in Nager syndrome patients. With this animal model we are now poised to gain important insights into the etiology and pathogenesis of Nager type MFD, and to identify the molecular targets of Sf3b4. PMID:26874011

  16. Identification of novel craniofacial regulatory domains located far upstream of SOX9 and disrupted in Pierre Robin sequence

    PubMed Central

    Gordon, Christopher T.; Attanasio, Catia; Bhatia, Shipra; Benko, Sabina; Ansari, Morad; Tan, Tiong Y.; Munnich, Arnold; Pennacchio, Len A.; Abadie, Véronique; Temple, I. Karen; Goldenberg, Alice; van Heyningen, Veronica; Amiel, Jeanne; FitzPatrick, David; Kleinjan, Dirk A.; Visel, Axel; Lyonnet, Stanislas

    2015-01-01

    Mutations in the coding sequence of SOX9 cause campomelic dysplasia (CD), a disorder of skeletal development associated with 46,XY disorders of sex development (DSDs). Translocations, deletions and duplications within a ~2 Mb region upstream of SOX9 can recapitulate the CD-DSD phenotype fully or partially, suggesting the existence of an unusually large cis-regulatory control region. Pierre Robin sequence (PRS) is a craniofacial disorder that is frequently an endophenotype of CD and a locus for isolated PRS at ~1.2-1.5 Mb upstream of SOX9 has been previously reported. The craniofacial regulatory potential within this locus, and within the greater genomic domain surrounding SOX9, remains poorly defined. We report two novel deletions upstream of SOX9 in families with PRS, allowing refinement of the regions harbouring candidate craniofacial regulatory elements. In parallel, ChIP-Seq for p300 binding sites in mouse craniofacial tissue led to the identification of several novel craniofacial enhancers at the SOX9 locus, which were validated in transgenic reporter mice and zebrafish. Notably, some of the functionally validated elements fall within the PRS deletions. These studies suggest that multiple non-coding elements contribute to the craniofacial regulation of SOX9 expression, and that their disruption results in PRS. PMID:24934569

  17. RSK2 Is a Modulator of Craniofacial Development

    PubMed Central

    Laugel-Haushalter, Virginie; Paschaki, Marie; Marangoni, Pauline; Pilgram, Coralie; Langer, Arnaud; Kuntz, Thibaut; Demassue, Julie; Morkmued, Supawich; Choquet, Philippe; Constantinesco, André; Bornert, Fabien; Schmittbuhl, Matthieu; Pannetier, Solange; Viriot, Laurent; Hanauer, André; Dollé, Pascal; Bloch-Zupan, Agnès

    2014-01-01

    Background The RSK2 gene is responsible for Coffin-Lowry syndrome, an X-linked dominant genetic disorder causing mental retardation, skeletal growth delays, with craniofacial and digital abnormalities typically associated with this syndrome. Craniofacial and dental anomalies encountered in this rare disease have been poorly characterized. Methodology/Principal Findings We examined, using X-Ray microtomographic analysis, the variable craniofacial dysmorphism and dental anomalies present in Rsk2 knockout mice, a model of Coffin-Lowry syndrome, as well as in triple Rsk1,2,3 knockout mutants. We report Rsk mutation produces surpernumerary teeth midline/mesial to the first molar. This highly penetrant phenotype recapitulates more ancestral tooth structures lost with evolution. Most likely this leads to a reduction of the maxillary diastema. Abnormalities of molar shape were generally restricted to the mesial part of both upper and lower first molars (M1). Expression analysis of the four Rsk genes (Rsk1, 2, 3 and 4) was performed at various stages of odontogenesis in wild-type (WT) mice. Rsk2 is expressed in the mesenchymal, neural crest-derived compartment, correlating with proliferative areas of the developing teeth. This is consistent with RSK2 functioning in cell cycle control and growth regulation, functions potentially responsible for severe dental phenotypes. To uncover molecular pathways involved in the etiology of these defects, we performed a comparative transcriptomic (DNA microarray) analysis of mandibular wild-type versus Rsk2-/Y molars. We further demonstrated a misregulation of several critical genes, using a Rsk2 shRNA knock-down strategy in molar tooth germs cultured in vitro. Conclusions This study reveals RSK2 regulates craniofacial development including tooth development and patterning via novel transcriptional targets. PMID:24416220

  18. ARCN1 Mutations Cause a Recognizable Craniofacial Syndrome Due to COPI-Mediated Transport Defects.

    PubMed

    Izumi, Kosuke; Brett, Maggie; Nishi, Eriko; Drunat, Séverine; Tan, Ee-Shien; Fujiki, Katsunori; Lebon, Sophie; Cham, Breana; Masuda, Koji; Arakawa, Michiko; Jacquinet, Adeline; Yamazumi, Yusuke; Chen, Shu-Ting; Verloes, Alain; Okada, Yuki; Katou, Yuki; Nakamura, Tomohiko; Akiyama, Tetsu; Gressens, Pierre; Foo, Roger; Passemard, Sandrine; Tan, Ene-Choo; El Ghouzzi, Vincent; Shirahige, Katsuhiko

    2016-08-01

    Cellular homeostasis is maintained by the highly organized cooperation of intracellular trafficking systems, including COPI, COPII, and clathrin complexes. COPI is a coatomer protein complex responsible for intracellular protein transport between the endoplasmic reticulum and the Golgi apparatus. The importance of such intracellular transport mechanisms is underscored by the various disorders, including skeletal disorders such as cranio-lenticulo-sutural dysplasia and osteogenesis imperfect, caused by mutations in the COPII coatomer complex. In this article, we report a clinically recognizable craniofacial disorder characterized by facial dysmorphisms, severe micrognathia, rhizomelic shortening, microcephalic dwarfism, and mild developmental delay due to loss-of-function heterozygous mutations in ARCN1, which encodes the coatomer subunit delta of COPI. ARCN1 mutant cell lines were revealed to have endoplasmic reticulum stress, suggesting the involvement of ER stress response in the pathogenesis of this disorder. Given that ARCN1 deficiency causes defective type I collagen transport, reduction of collagen secretion represents the likely mechanism underlying the skeletal phenotype that characterizes this condition. Our findings demonstrate the importance of COPI-mediated transport in human development, including skeletogenesis and brain growth. PMID:27476655

  19. The human histaminergic system in neuropsychiatric disorders.

    PubMed

    Shan, Ling; Bao, Ai-Min; Swaab, Dick F

    2015-03-01

    Histaminergic neurons are exclusively located in the hypothalamic tuberomamillary nucleus, from where they project to many brain areas. The histaminergic system is involved in basic physiological functions, such as the sleep-wake cycle, energy and endocrine homeostasis, sensory and motor functions, cognition, and attention, which are all severely affected in neuropsychiatric disorders. Here, we present recent postmortem findings on the alterations in this system in neuropsychiatric disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), depression, and narcolepsy. In addition, we highlight the need to validate animal models for these diseases and also for Tourette's syndrome (TS) in relation to alterations in the histaminergic system. Moreover, we discuss the potential for, and concerns over, the use of novel histamine 3 receptor (H3R) antagonists/inverse agonists as treatment for such disorders. PMID:25575625

  20. Biomimetic approaches to complex craniofacial defects.

    PubMed

    Teven, Chad M; Fisher, Sean; Ameer, Guillermo A; He, Tong-Chuan; Reid, Russell R

    2015-01-01

    The primary goals of craniofacial reconstruction include the restoration of the form, function, and facial esthetics, and in the case of pediatric patients, respect for craniofacial growth. The surgeon, however, faces several challenges when attempting a reconstructive cranioplasty. For that reason, craniofacial defect repair often requires sophisticated treatment strategies and multidisciplinary input. In the ideal situation, autologous tissue similar in structure and function to that which is missing can be utilized for repair. In the context of the craniofacial skeleton, autologous cranial bone, or secondarily rib, iliac crest, or scapular bone, is most favorable. Often, this option is limited by the finite supply of available bone. Therefore, alternative strategies to repair craniofacial defects are necessary. In the field of regenerative medicine, tissue engineering has emerged as a promising concept, and several methods of bone engineering are currently under investigation. A growth factor-based approach utilizing bone morphogenetic proteins (BMPs) has demonstrated stimulatory effects on cranial bone and defect repair. When combined with cell-based and matrix-based models, regenerative goals can be optimized. This manuscript intends to review recent investigations of tissue engineering models used for the repair of craniofacial defects with a focus on the role of BMPs, scaffold materials, and novel cell lines. When sufficient autologous bone is not available, safe and effective strategies to engineer bone would allow the surgeon to meet the reconstructive goals of the craniofacial skeleton. PMID:26389027

  1. Biomimetic approaches to complex craniofacial defects

    PubMed Central

    Teven, Chad M.; Fisher, Sean; Ameer, Guillermo A.; He, Tong-Chuan; Reid, Russell R.

    2015-01-01

    The primary goals of craniofacial reconstruction include the restoration of the form, function, and facial esthetics, and in the case of pediatric patients, respect for craniofacial growth. The surgeon, however, faces several challenges when attempting a reconstructive cranioplasty. For that reason, craniofacial defect repair often requires sophisticated treatment strategies and multidisciplinary input. In the ideal situation, autologous tissue similar in structure and function to that which is missing can be utilized for repair. In the context of the craniofacial skeleton, autologous cranial bone, or secondarily rib, iliac crest, or scapular bone, is most favorable. Often, this option is limited by the finite supply of available bone. Therefore, alternative strategies to repair craniofacial defects are necessary. In the field of regenerative medicine, tissue engineering has emerged as a promising concept, and several methods of bone engineering are currently under investigation. A growth factor-based approach utilizing bone morphogenetic proteins (BMPs) has demonstrated stimulatory effects on cranial bone and defect repair. When combined with cell-based and matrix-based models, regenerative goals can be optimized. This manuscript intends to review recent investigations of tissue engineering models used for the repair of craniofacial defects with a focus on the role of BMPs, scaffold materials, and novel cell lines. When sufficient autologous bone is not available, safe and effective strategies to engineer bone would allow the surgeon to meet the reconstructive goals of the craniofacial skeleton. PMID:26389027

  2. Directory: Information Resources for Human Communication Disorders.

    ERIC Educational Resources Information Center

    National Inst. on Deafness and Other Communications Disorders, Bethesda, MD.

    This directory is designed to encourage networking among individuals and organizations that have an interest in deafness and communication disorders. The main body of the directory includes descriptions and publications of 122 organizations that are national in scope and that focus on health issues relating to hearing, balance, smell, taste,…

  3. Advances in Bioprinting Technologies for Craniofacial Reconstruction.

    PubMed

    Visscher, Dafydd O; Farré-Guasch, Elisabet; Helder, Marco N; Gibbs, Susan; Forouzanfar, Tymour; van Zuijlen, Paul P; Wolff, Jan

    2016-09-01

    Recent developments in craniofacial reconstruction have shown important advances in both the materials and methods used. While autogenous tissue is still considered to be the gold standard for these reconstructions, the harvesting procedure remains tedious and in many cases causes significant donor site morbidity. These limitations have subsequently led to the development of less invasive techniques such as 3D bioprinting that could offer possibilities to manufacture patient-tailored bioactive tissue constructs for craniofacial reconstruction. Here, we discuss the current technological and (pre)clinical advances of 3D bioprinting for use in craniofacial reconstruction and highlight the challenges that need to be addressed in the coming years. PMID:27113634

  4. Stem Cells in Teeth and Craniofacial Bones.

    PubMed

    Zhao, H; Chai, Y

    2015-11-01

    Stem cells are remarkable, and stem cell-based tissue engineering is an emerging field of biomedical science aiming to restore damaged tissue or organs. In dentistry and reconstructive facial surgery, it is of great interest to restore lost teeth or craniofacial bone defects using stem cell-mediated therapy. In the craniofacial region, various stem cell populations have been identified with regeneration potential. In this review, we provide an overview of the current knowledge concerning the various types of tooth- and craniofacial bone-related stem cells and discuss their in vivo identities and regulating mechanisms. PMID:26350960

  5. CRANIAL NEURAL CREST CELLS ON THE MOVE: THEIR ROLES IN CRANIOFACIAL DEVELOPMENT

    PubMed Central

    Cordero, Dwight R.; Brugmann, Samantha; Chu, Yvonne; Bajpai, Ruchi; Jame, Maryam; Helms, Jill A.

    2010-01-01

    The craniofacial region is assembled through the active migration of cells and the rearrangement and sculpting of facial prominences and pharyngeal arches, which consequently make it particularly susceptible to a large number of birth defects. Genetic, molecular, and cellular processes must be temporally and spatially regulated to culminate in the three-dimension structures of the face. The starting constituent for the majority of skeletal and connective tissues in the face is a pluripotent population of cells, the cranial neural crest cells (NCCs). In this review we discuss the newest scientific findings in the development of the craniofacial complex as related to NCCs. Furthermore, we present recent findings on NCC diseases called neurocristopathies and, in doing so, provide clinicians with new tools for understanding a growing number of craniofacial genetic disorders. PMID:21271641

  6. Cranial neural crest cells on the move: their roles in craniofacial development.

    PubMed

    Cordero, Dwight R; Brugmann, Samantha; Chu, Yvonne; Bajpai, Ruchi; Jame, Maryam; Helms, Jill A

    2011-02-01

    The craniofacial region is assembled through the active migration of cells and the rearrangement and sculpting of facial prominences and pharyngeal arches, which consequently make it particularly susceptible to a large number of birth defects. Genetic, molecular, and cellular processes must be temporally and spatially regulated to culminate in the three-dimension structures of the face. The starting constituent for the majority of skeletal and connective tissues in the face is a pluripotent population of cells, the cranial neural crest cells (NCCs). In this review we discuss the newest scientific findings in the development of the craniofacial complex as related to NCCs. Furthermore, we present recent findings on NCC diseases called neurocristopathies and, in doing so, provide clinicians with new tools for understanding a growing number of craniofacial genetic disorders. PMID:21271641

  7. Core issues in craniofacial myogenesis

    SciTech Connect

    Kelly, Robert G.

    2010-11-01

    Branchiomeric craniofacial muscles control feeding, breathing and facial expression. These muscles differ on multiple counts from all other skeletal muscles and originate in a progenitor cell population in pharyngeal mesoderm characterized by a common genetic program with an adjacent population of cardiac progenitor cells, the second heart field, that gives rise to much of the heart. The transcription factors and signaling molecules that trigger the myogenic program at sites of branchiomeric muscle formation are correspondingly distinct from those in somite-derived muscle progenitor cells. Here new insights into the regulatory hierarchies controlling branchiomeric myogenesis are discussed. Differences in embryological origin are reflected in the lineage, transcriptional program and proliferative and differentiation properties of branchiomeric muscle satellite cells. These recent findings have important implications for our understanding of the diverse myogenic strategies operative both in the embryo and adult and are of direct biomedical relevance to deciphering the mechanisms underlying the cause and progression of muscle restricted myopathies.

  8. Orthognathic Surgery in Craniofacial Microsomia: Treatment Algorithm

    PubMed Central

    Valladares, Salvador; Torrealba, Ramón; Nuñez, Marcelo; Uribe, Francisca

    2015-01-01

    Summary: Craniofacial microsomia is a broad term that covers a variety of craniofacial malformation conditions that are caused by alterations in the derivatives of the first and second pharyngeal arches. In general terms, diverse therapeutic alternatives are proposed according to the growth stage and the severity of the alteration. When craniofacial growth has concluded, conventional orthognathic surgery (Le Fort I osteotomy, bilateral sagittal split osteotomy, and genioplasty) provides good alternatives for MI and MIIA type cases. Reconstruction of the mandibular ramus and temporomandibular joint before orthognathic surgery is the indicated treatment for cases MIIB and MIII. The goal of this article is to establish a surgical treatment algorithm for orthognathic surgery on patients with craniofacial microsomia, analyzing the points that allow the ideal treatment for each patient to be chosen. PMID:25674375

  9. Genetic basis of human left-right asymmetry disorders.

    PubMed

    Deng, Hao; Xia, Hong; Deng, Sheng

    2015-01-01

    Humans and other vertebrates exhibit left-right (LR) asymmetric arrangement of the internal organs, and failure to establish normal LR asymmetry leads to internal laterality disorders, including situs inversus and heterotaxy. Situs inversus is complete mirror-imaged arrangement of the internal organs along LR axis, whereas heterotaxy is abnormal arrangement of the internal thoraco-abdominal organs across LR axis of the body, most of which are associated with complex cardiovascular malformations. Both disorders are genetically heterogeneous with reduced penetrance, presumably because of monogenic, polygenic or multifactorial causes. Research in genetics of LR asymmetry disorders has been extremely prolific over the past 17 years, and a series of loci and disease genes involved in situs inversus and heterotaxy have been described. The review highlights the classification, chromosomal abnormalities, pathogenic genes and the possible mechanism of human LR asymmetry disorders. PMID:26258520

  10. Shining evolutionary light on human sleep and sleep disorders.

    PubMed

    Nunn, Charles L; Samson, David R; Krystal, Andrew D

    2016-01-01

    Sleep is essential to cognitive function and health in humans, yet the ultimate reasons for sleep-i.e. 'why' sleep evolved-remain mysterious. We integrate findings from human sleep studies, the ethnographic record, and the ecology and evolution of mammalian sleep to better understand sleep along the human lineage and in the modern world. Compared to other primates, sleep in great apes has undergone substantial evolutionary change, with all great apes building a sleeping platform or 'nest'. Further evolutionary change characterizes human sleep, with humans having the shortest sleep duration, yet the highest proportion of rapid eye movement sleep among primates. These changes likely reflect that our ancestors experienced fitness benefits from being active for a greater portion of the 24-h cycle than other primates, potentially related to advantages arising from learning, socializing and defending against predators and hostile conspecifics. Perspectives from evolutionary medicine have implications for understanding sleep disorders; we consider these perspectives in the context of insomnia, narcolepsy, seasonal affective disorder, circadian rhythm disorders and sleep apnea. We also identify how human sleep today differs from sleep through most of human evolution, and the implications of these changes for global health and health disparities. More generally, our review highlights the importance of phylogenetic comparisons in understanding human health, including well-known links between sleep, cognitive performance and health in humans. PMID:27470330

  11. Shining evolutionary light on human sleep and sleep disorders

    PubMed Central

    Nunn, Charles L.; Samson, David R.; Krystal, Andrew D.

    2016-01-01

    Sleep is essential to cognitive function and health in humans, yet the ultimate reasons for sleep—i.e. ‘why’ sleep evolved—remain mysterious. We integrate findings from human sleep studies, the ethnographic record, and the ecology and evolution of mammalian sleep to better understand sleep along the human lineage and in the modern world. Compared to other primates, sleep in great apes has undergone substantial evolutionary change, with all great apes building a sleeping platform or ‘nest’. Further evolutionary change characterizes human sleep, with humans having the shortest sleep duration, yet the highest proportion of rapid eye movement sleep among primates. These changes likely reflect that our ancestors experienced fitness benefits from being active for a greater portion of the 24-h cycle than other primates, potentially related to advantages arising from learning, socializing and defending against predators and hostile conspecifics. Perspectives from evolutionary medicine have implications for understanding sleep disorders; we consider these perspectives in the context of insomnia, narcolepsy, seasonal affective disorder, circadian rhythm disorders and sleep apnea. We also identify how human sleep today differs from sleep through most of human evolution, and the implications of these changes for global health and health disparities. More generally, our review highlights the importance of phylogenetic comparisons in understanding human health, including well-known links between sleep, cognitive performance and health in humans. PMID:27470330

  12. The comparative psychopathology of affective disorders in animals and humans.

    PubMed

    Healy, D

    1987-01-01

    Reviews of animal models of affective disorders commonly concentrate on the behavioural features thereof, the supposed neurochemical substrates, the mode of production and the response to treatment of the state in question but ignore questions of psycho pathology. An attempt is made to deal critically with the psychopathology of human and animal affective disorders in the light of current operational criteria for the diagnosis of major depressive disorders. It is argued thatthe psychopathological tradition stemming from Jaspers may be more appropriate to a consideration of animal models of affective disorders than the psychopathological positions implicit in psychoanalysis, behaviourism or current cognitive psychologies and in addition more suited to meet these criteria. The adoption of such a perspective results in a shift of emphasis from abnormalities of psychological content to demonstrable neuropsychological deficits and a definition of affective disorders, whether in animals or humans, as psychosomatic illnesses, possibly involving a pathology of circadian rhythmicity. This perspective also suggests that animal models may be useful in the devel opment of more refined diagnostic criteria for affective disorders in humans. PMID:22158981

  13. The 50 Most Cited Papers in Craniofacial Anomalies and Craniofacial Surgery

    PubMed Central

    Joyce, Cormac W; Thomas, Sangeetha; Concannon, Elizabeth; Murray, Dylan

    2015-01-01

    Background Citation analysis is a recognized scientometric method of classifying cited articles according to the frequency of which they have been referenced. The total number of citations an article receives is considered to reflect it's significance among it's peers. Methods Until now, a bibliometric analysis has never been performed in the specialty of craniofacial anomalies and craniofacial surgery. This citation analysis generates an extensive list of the 50 most influential papers in this developing field. Journals specializing in craniofacial surgery, maxillofacial surgery, plastic surgery, neurosurgery, genetics and pediatrics were searched to demonstrate which articles have cultivated the specialty within the past 55 years. Results The results show an intriguing compilation of papers which outline the fundamental knowledge of craniofacial anomalies and the developments of surgical techniques to manage these patients. Conclusions This citation analysis provides a summation of the current most popular trends in craniofacial literature. These esteemed papers aid to direct our decision making today within this specialty. PMID:26430626

  14. Dental Approach to Craniofacial Syndromes: How Can Developmental Fields Show Us a New Way to Understand Pathogenesis?

    PubMed Central

    Kjær, Inger

    2012-01-01

    The paper consists of three parts. Part 1: Definition of Syndromes. Focus is given to craniofacial syndromes in which abnormal traits in the dentition are associated symptoms. In the last decade, research has concentrated on phenotype, genotype, growth, development, function, and treatment. Part 2: Syndromes before Birth. How can the initial malformation sites in these syndromes be studied and what can we learn from it? In this section, deviations observed in syndromes prenatally will be highlighted and compared to the normal human embryological craniofacial development. Specific focus will be given to developmental fields studied on animal tissue and transferred to human cranial development. Part 3: Developmental Fields Affected in Two Craniofacial Syndromes. Analysis of primary and permanent dentitions can determine whether a syndrome affects a single craniofacial field or several fields. This distinction is essential for insight into craniofacial syndromes. The dentition, thus, becomes central in diagnostics and evaluation of the pathogenesis. Developmental fields can explore and advance the concept of dental approaches to craniofacial syndromes. Discussion. As deviations in teeth persist and do not reorganize during growth and development, the dentition is considered useful for distinguishing between syndrome pathogenesis manifested in a single developmental field and in several fields. PMID:23091490

  15. Human embryonic stem cells carrying mutations for severe genetic disorders.

    PubMed

    Frumkin, Tsvia; Malcov, Mira; Telias, Michael; Gold, Veronica; Schwartz, Tamar; Azem, Foad; Amit, Ami; Yaron, Yuval; Ben-Yosef, Dalit

    2010-04-01

    Human embryonic stem cells (HESCs) carrying specific mutations potentially provide a valuable tool for studying genetic disorders in humans. One preferable approach for obtaining these cell lines is by deriving them from affected preimplantation genetically diagnosed embryos. These unique cells are especially important for modeling human genetic disorders for which there are no adequate research models. They can be further used to gain new insights into developmentally regulated events that occur during human embryo development and that are responsible for the manifestation of genetically inherited disorders. They also have great value for the exploration of new therapeutic protocols, including gene-therapy-based treatments and disease-oriented drug screening and discovery. Here, we report the establishment of 15 different mutant human embryonic stem cell lines derived from genetically affected embryos, all donated by couples undergoing preimplantation genetic diagnosis in our in vitro fertilization unit. For further information regarding access to HESC lines from our repository, for research purposes, please email dalitb@tasmc.health.gov.il. PMID:20186514

  16. Genesis of alcohol-induced craniofacial dysmorphism.

    PubMed

    Sulik, Kathleen K

    2005-06-01

    The initial diagnosis of fetal alcohol syndrome (FAS) in the United States was made because of the facial features common to the first cohort of patients. This article reviews the development of an FAS mouse model whose craniofacial features are remarkably similar to those of affected humans. The model is based on short-term maternal treatment with a high dosage of ethanol at stages of pregnancy that are equivalent to Weeks 3 and 4 of human gestation. At these early stages of development, alcohol's insult to the developing face is concurrent with that to the brain, eyes, and inner ear. That facial and central nervous system defects consistent with FAS can be induced by more "realistic" alcohol dosages as illustrated with data from an oral alcohol intake mouse model in which maternal blood alcohol levels do not exceed 200 mg/dl. The ethanol-induced pathogenesis involves apoptosis that occurs within 12 hrs of alcohol exposure in selected cell populations of Day 7, 8, and 9 mouse embryos. Experimental evidence from other species also shows that apoptosis underlies ethanol-induced malformations. With knowledge of sensitive and resistant cell populations at specific developmental stages, studies designed to identify the basis for these differing cellular responses and, therefore, to determine the primary mechanisms of ethanol's teratogenesis are possible. For example, microarray comparisons of sensitive and resistant embryonic cell populations have been made, as have in situ studies of gene expression patterns in the populations of interest. Studies that illustrate agents that are effective in diminishing or exacerbating ethanol's teratogenesis have also been helpful in determining mechanisms. Among these agents are antioxidants, sonic hedgehog protein, retinoids, and the peptides SAL and NAP. PMID:15956766

  17. 78 FR 50426 - National Institute of Dental & Craniofacial Research; Notice of Closed Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-08-19

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Dental & Craniofacial Research; Notice of Closed Meeting Pursuant to section 10(d) of the Federal Advisory Committee Act, as amended (5...

  18. 76 FR 57748 - National Institute of Dental & Craniofacial Research Notice of Closed Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-16

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Dental & Craniofacial Research Notice of Closed Meeting Pursuant to section 10(d) of the Federal Advisory Committee Act, as amended (5...

  19. 77 FR 29673 - National Institute of Dental & Craniofacial Research; Notice of Closed Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-05-18

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Dental & Craniofacial Research; Notice of Closed Meeting Pursuant to section 10(d) of the Federal Advisory Committee Act, as amended (5...

  20. 76 FR 79199 - National Institute of Dental & Craniofacial Research; Notice of Closed Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-21

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Dental & Craniofacial Research; Notice of Closed Meeting Pursuant to section 10(d) of the Federal Advisory Committee Act, as amended (5...

  1. 77 FR 50140 - National Institute of Dental & Craniofacial Research; Notice of Closed Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-08-20

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Dental & Craniofacial Research; Notice of Closed Meeting Pursuant to section 10(d) of the Federal Advisory Committee Act, as amended (5...

  2. 78 FR 65345 - National Institute of Dental & Craniofacial Research; Amended Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-10-31

    ... the Federal Register on August 19, 2013, 78 FR 50426. Meeting date has changed from October 17-18... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Dental & Craniofacial...

  3. 77 FR 11563 - National Institute of Dental and Craniofacial Research; Notice of Closed Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-02-27

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Dental and Craniofacial Research; Notice of Closed Meeting Pursuant to section 10(d) of the Federal Advisory Committee Act, as amended (5 U.S.C. App.), notice is hereby given of...

  4. 75 FR 28028 - National Institute of Dental and Craniofacial Research; Notice of Closed Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-05-19

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Dental and Craniofacial Research; Notice of Closed Meeting Pursuant to section 10(d) of the Federal Advisory Committee Act, as amended (5 U.S.C. App.), notice is hereby given of...

  5. 76 FR 58284 - National Institute of Dental and Craniofacial Research; Notice of Closed Meetings

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-20

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Dental and Craniofacial Research; Notice of Closed Meetings Pursuant to section 10(d) of the Federal Advisory Committee Act, as amended (5 U.S.C. App.), notice is hereby given of...

  6. 77 FR 35988 - National Institute of Dental and Craniofacial Research; Notice of Closed Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-06-15

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Dental and Craniofacial Research; Notice of Closed Meeting Pursuant to section 10(d) of the Federal Advisory Committee Act, as amended (5 U.S.C. App.), notice is hereby given of...

  7. 75 FR 82036 - National Institute of Dental and Craniofacial Research; Notice of Closed Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-12-29

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Dental and Craniofacial Research; Notice of Closed Meeting Pursuant to section 10(d) of the Federal Advisory Committee Act, as amended (5 U.S.C. App.), notice is hereby given of...

  8. 76 FR 78013 - National Institute of Dental and Craniofacial Research; Notice of Closed Meetings

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-15

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Dental and Craniofacial Research; Notice of Closed Meetings Pursuant to section 10(d) of the Federal Advisory Committee Act, as amended (5 U.S.C. App.), notice is hereby given of...

  9. 75 FR 67381 - National Institute of Dental and Craniofacial Research; Notice of Closed Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-11-02

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Dental and Craniofacial Research; Notice of Closed Meeting Pursuant to section 10(d) of the Federal Advisory Committee Act, as amended (5 U.S.C. App.), notice is hereby given of...

  10. 75 FR 1063 - National Institute of Dental & Craniofacial Research; Notice of Closed Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-01-08

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Dental & Craniofacial Research; Notice of Closed Meeting Pursuant to section 10(d) of the Federal Advisory Committee Act, as amended (5 U.S.C. App.), notice is hereby given of...

  11. Rare bone diseases and their dental, oral, and craniofacial manifestations.

    PubMed

    Foster, B L; Ramnitz, M S; Gafni, R I; Burke, A B; Boyce, A M; Lee, J S; Wright, J T; Akintoye, S O; Somerman, M J; Collins, M T

    2014-07-01

    Hereditary diseases affecting the skeleton are heterogeneous in etiology and severity. Though many of these conditions are individually rare, the total number of people affected is great. These disorders often include dental-oral-craniofacial (DOC) manifestations, but the combination of the rarity and lack of in-depth reporting often limit our understanding and ability to diagnose and treat affected individuals. In this review, we focus on dental, oral, and craniofacial manifestations of rare bone diseases. Discussed are defects in 4 key physiologic processes in bone/tooth formation that serve as models for the understanding of other diseases in the skeleton and DOC complex: progenitor cell differentiation (fibrous dysplasia), extracellular matrix production (osteogenesis imperfecta), mineralization (familial tumoral calcinosis/hyperostosis hyperphosphatemia syndrome, hypophosphatemic rickets, and hypophosphatasia), and bone resorption (Gorham-Stout disease). For each condition, we highlight causative mutations (when known), etiopathology in the skeleton and DOC complex, and treatments. By understanding how these 4 foci are subverted to cause disease, we aim to improve the identification of genetic, molecular, and/or biologic causes, diagnoses, and treatment of these and other rare bone conditions that may share underlying mechanisms of disease. PMID:24700690

  12. Rare Bone Diseases and Their Dental, Oral, and Craniofacial Manifestations

    PubMed Central

    Foster, B.L.; Ramnitz, M.S.; Gafni, R.I.; Burke, A.B.; Boyce, A.M.; Lee, J.S.; Wright, J.T.; Akintoye, S.O.; Somerman, M.J.; Collins, M.T.

    2014-01-01

    Hereditary diseases affecting the skeleton are heterogeneous in etiology and severity. Though many of these conditions are individually rare, the total number of people affected is great. These disorders often include dental-oral-craniofacial (DOC) manifestations, but the combination of the rarity and lack of in-depth reporting often limit our understanding and ability to diagnose and treat affected individuals. In this review, we focus on dental, oral, and craniofacial manifestations of rare bone diseases. Discussed are defects in 4 key physiologic processes in bone/tooth formation that serve as models for the understanding of other diseases in the skeleton and DOC complex: progenitor cell differentiation (fibrous dysplasia), extracellular matrix production (osteogenesis imperfecta), mineralization (familial tumoral calcinosis/hyperostosis hyperphosphatemia syndrome, hypophosphatemic rickets, and hypophosphatasia), and bone resorption (Gorham-Stout disease). For each condition, we highlight causative mutations (when known), etiopathology in the skeleton and DOC complex, and treatments. By understanding how these 4 foci are subverted to cause disease, we aim to improve the identification of genetic, molecular, and/or biologic causes, diagnoses, and treatment of these and other rare bone conditions that may share underlying mechanisms of disease. PMID:24700690

  13. Craniofacial ontogeny in Centrosaurus apertus

    PubMed Central

    Tumarkin-Deratzian, Allison R.

    2014-01-01

    Centrosaurus apertus, a large bodied ceratopsid from the Late Cretaceous of North America, is one of the most common fossils recovered from the Belly River Group. This fossil record shows a wide diversity in morphology and size, with specimens ranging from putative juveniles to fully-grown individuals. The goal of this study was to reconstruct the ontogenetic changes that occur in the craniofacial skeleton of C. apertus through a quantitative cladistic analysis. Forty-seven cranial specimens were independently coded in separate data matrices for 80 hypothetical multistate growth characters and 130 hypothetical binary growth characters. Both analyses yielded the max-limit of 100,000 most parsimonious saved trees and the strict consensus collapsed into large polytomies. In order to reduce conflict resulting from missing data, fragmentary individuals were removed and the analyses were rerun. Among both the complete and the reduced data sets the multistate analyses recovered a shorter tree with a higher consistency index (CI) than the additive binary data sets. The arrangement within the trees shows a progression of specimens with a recurved nasal horn in the least mature individuals, followed by specimens with straight nasal horns in relatively more mature individuals, and finally specimens with procurved nasal horns in the most mature individuals. The most mature individuals are further characterized by the reduction of the cranial horn ornamentations in late growth stages, a trait that similarly occurs in the growth of other dinosaurs. Bone textural changes were found to be sufficient proxies for relative maturity in individuals that have not reached adult size. Additionally, frill length is congruent with relative maturity status and makes an acceptable proxy for ontogenetic status, especially in smaller individuals. In adult-sized individuals, the fusion of the epiparietals and episquamosals and the orientation of the nasal horn are the best indicators of relative

  14. Craniofacial ontogeny in Centrosaurus apertus.

    PubMed

    Frederickson, Joseph A; Tumarkin-Deratzian, Allison R

    2014-01-01

    Centrosaurus apertus, a large bodied ceratopsid from the Late Cretaceous of North America, is one of the most common fossils recovered from the Belly River Group. This fossil record shows a wide diversity in morphology and size, with specimens ranging from putative juveniles to fully-grown individuals. The goal of this study was to reconstruct the ontogenetic changes that occur in the craniofacial skeleton of C. apertus through a quantitative cladistic analysis. Forty-seven cranial specimens were independently coded in separate data matrices for 80 hypothetical multistate growth characters and 130 hypothetical binary growth characters. Both analyses yielded the max-limit of 100,000 most parsimonious saved trees and the strict consensus collapsed into large polytomies. In order to reduce conflict resulting from missing data, fragmentary individuals were removed and the analyses were rerun. Among both the complete and the reduced data sets the multistate analyses recovered a shorter tree with a higher consistency index (CI) than the additive binary data sets. The arrangement within the trees shows a progression of specimens with a recurved nasal horn in the least mature individuals, followed by specimens with straight nasal horns in relatively more mature individuals, and finally specimens with procurved nasal horns in the most mature individuals. The most mature individuals are further characterized by the reduction of the cranial horn ornamentations in late growth stages, a trait that similarly occurs in the growth of other dinosaurs. Bone textural changes were found to be sufficient proxies for relative maturity in individuals that have not reached adult size. Additionally, frill length is congruent with relative maturity status and makes an acceptable proxy for ontogenetic status, especially in smaller individuals. In adult-sized individuals, the fusion of the epiparietals and episquamosals and the orientation of the nasal horn are the best indicators of relative

  15. Growth Hormone and Craniofacial Tissues. An update

    PubMed Central

    Litsas, George

    2015-01-01

    Growth hormone is an important regulator of bone homeostasis. In childhood, it determines the longitudinal bone growth, skeletal maturation, and acquisition of bone mass. In adulthood, it is necessary to maintain bone mass throughout life. Although an association between craniofacial and somatic development has been clearly established, craniofacial growth involves complex interactions of genes, hormones and environment. Moreover, as an anabolic hormone seems to have an important role in the regulation of bone remodeling, muscle enhancement and tooth development. In this paper the influence of growth hormone on oral tissues is reviewed. PMID:25674165

  16. Craniofacial reconstruction using rational cubic ball curves.

    PubMed

    Majeed, Abdul; Mt Piah, Abd Rahni; Gobithaasan, R U; Yahya, Zainor Ridzuan

    2015-01-01

    This paper proposes the reconstruction of craniofacial fracture using rational cubic Ball curve. The idea of choosing Ball curve is based on its robustness of computing efficiency over Bezier curve. The main steps are conversion of Digital Imaging and Communications in Medicine (Dicom) images to binary images, boundary extraction and corner point detection, Ball curve fitting with genetic algorithm and final solution conversion to Dicom format. The last section illustrates a real case of craniofacial reconstruction using the proposed method which clearly indicates the applicability of this method. A Graphical User Interface (GUI) has also been developed for practical application. PMID:25880632

  17. Craniofacial Reconstruction Using Rational Cubic Ball Curves

    PubMed Central

    Majeed, Abdul; Mt Piah, Abd Rahni; Gobithaasan, R. U.; Yahya, Zainor Ridzuan

    2015-01-01

    This paper proposes the reconstruction of craniofacial fracture using rational cubic Ball curve. The idea of choosing Ball curve is based on its robustness of computing efficiency over Bezier curve. The main steps are conversion of Digital Imaging and Communications in Medicine (Dicom) images to binary images, boundary extraction and corner point detection, Ball curve fitting with genetic algorithm and final solution conversion to Dicom format. The last section illustrates a real case of craniofacial reconstruction using the proposed method which clearly indicates the applicability of this method. A Graphical User Interface (GUI) has also been developed for practical application. PMID:25880632

  18. Homozygous frameshift mutation in TMCO1 causes a syndrome with craniofacial dysmorphism, skeletal anomalies, and mental retardation

    PubMed Central

    Xin, Baozhong; Puffenberger, Erik G.; Turben, Susan; Tan, Haiyan; Zhou, Aimin; Wang, Heng

    2009-01-01

    We identified an autosomal recessive condition in 11 individuals in the Old Order Amish of northeastern Ohio. The syndrome was characterized by distinctive craniofacial dysmorphism, skeletal anomalies, and mental retardation. The typical craniofacial dysmorphism included brachycephaly, highly arched bushy eyebrows, synophrys, long eyelashes, low-set ears, microdontism of primary teeth, and generalized gingival hyperplasia, whereas Sprengel deformity of scapula, fusion of spine, rib abnormities, pectus excavatum, and pes planus represented skeletal anomalies. The genome-wide homozygosity mapping using six affected individuals localized the disease gene to a 3.3-Mb region on chromosome 1q23.3-q24.1. Candidate gene sequencing identified a homozygous frameshift mutation, c.139_140delAG, in the transmembrane and coiled-coil domains 1 (TMCO1) gene, as the pathogenic change in all affected members of the extended pedigree. This mutation is predicted to result in a severely truncated protein (p.Ser47Ter) of only one-fourth the original length. The TMCO1 gene product is a member of DUF841 superfamily of several eukaryotic proteins with unknown function. The gene has highly conserved amino acid sequence and is universally expressed in all human tissues examined. The high degree of conservation and the ubiquitous expression pattern in human adult and fetal tissues suggest a critical role for TMCO1. This report shows a TMCO1 sequence variant being associated with a genetic disorder in human. We propose “TMCO1 defect syndrome” as the name of this condition. PMID:20018682

  19. Evolutionary conservation in genes underlying human psychiatric disorders.

    PubMed

    Ogawa, Lisa M; Vallender, Eric J

    2014-01-01

    Many psychiatric diseases observed in humans have tenuous or absent analogs in other species. Most notable among these are schizophrenia and autism. One hypothesis has posited that these diseases have arisen as a consequence of human brain evolution, for example, that the same processes that led to advances in cognition, language, and executive function also resulted in novel diseases in humans when dysfunctional. Here, the molecular evolution of the protein-coding regions of genes associated with these and other psychiatric disorders are compared among species. Genes associated with psychiatric disorders are drawn from the literature and orthologous sequences are collected from eleven primate species (human, chimpanzee, bonobo, gorilla, orangutan, gibbon, macaque, baboon, marmoset, squirrel monkey, and galago) and 34 non-primate mammalian species. Evolutionary parameters, including dN/dS, are calculated for each gene and compared between disease classes and among species, focusing on humans and primates compared to other mammals, and on large-brained taxa (cetaceans, rhinoceros, walrus, bear, and elephant) compared to their small-brained sister species. Evidence of differential selection in humans to the exclusion of non-human primates was absent, however elevated dN/dS was detected in catarrhines as a whole, as well as in cetaceans, possibly as part of a more general trend. Although this may suggest that protein changes associated with schizophrenia and autism are not a cost of the higher brain function found in humans, it may also point to insufficiencies in the study of these diseases including incomplete or inaccurate gene association lists and/or a greater role of regulatory changes or copy number variation. Through this work a better understanding of the molecular evolution of the human brain, the pathophysiology of disease, and the genetic basis of human psychiatric disease is gained. PMID:24834046

  20. Evolutionary conservation in genes underlying human psychiatric disorders

    PubMed Central

    Ogawa, Lisa M.; Vallender, Eric J.

    2014-01-01

    Many psychiatric diseases observed in humans have tenuous or absent analogs in other species. Most notable among these are schizophrenia and autism. One hypothesis has posited that these diseases have arisen as a consequence of human brain evolution, for example, that the same processes that led to advances in cognition, language, and executive function also resulted in novel diseases in humans when dysfunctional. Here, the molecular evolution of the protein-coding regions of genes associated with these and other psychiatric disorders are compared among species. Genes associated with psychiatric disorders are drawn from the literature and orthologous sequences are collected from eleven primate species (human, chimpanzee, bonobo, gorilla, orangutan, gibbon, macaque, baboon, marmoset, squirrel monkey, and galago) and 34 non-primate mammalian species. Evolutionary parameters, including dN/dS, are calculated for each gene and compared between disease classes and among species, focusing on humans and primates compared to other mammals, and on large-brained taxa (cetaceans, rhinoceros, walrus, bear, and elephant) compared to their small-brained sister species. Evidence of differential selection in humans to the exclusion of non-human primates was absent, however elevated dN/dS was detected in catarrhines as a whole, as well as in cetaceans, possibly as part of a more general trend. Although this may suggest that protein changes associated with schizophrenia and autism are not a cost of the higher brain function found in humans, it may also point to insufficiencies in the study of these diseases including incomplete or inaccurate gene association lists and/or a greater role of regulatory changes or copy number variation. Through this work a better understanding of the molecular evolution of the human brain, the pathophysiology of disease, and the genetic basis of human psychiatric disease is gained. PMID:24834046

  1. The FaceBase Consortium: a comprehensive resource for craniofacial researchers

    PubMed Central

    Brinkley, James F.; Fisher, Shannon; Harris, Matthew P.; Holmes, Greg; Hooper, Joan E.; Wang Jabs, Ethylin; Jones, Kenneth L.; Kesselman, Carl; Klein, Ophir D.; Maas, Richard L.; Marazita, Mary L.; Selleri, Licia; Spritz, Richard A.; van Bakel, Harm; Visel, Axel; Williams, Trevor J.; Wysocka, Joanna

    2016-01-01

    The FaceBase Consortium, funded by the National Institute of Dental and Craniofacial Research, National Institutes of Health, is designed to accelerate understanding of craniofacial developmental biology by generating comprehensive data resources to empower the research community, exploring high-throughput technology, fostering new scientific collaborations among researchers and human/computer interactions, facilitating hypothesis-driven research and translating science into improved health care to benefit patients. The resources generated by the FaceBase projects include a number of dynamic imaging modalities, genome-wide association studies, software tools for analyzing human facial abnormalities, detailed phenotyping, anatomical and molecular atlases, global and specific gene expression patterns, and transcriptional profiling over the course of embryonic and postnatal development in animal models and humans. The integrated data visualization tools, faceted search infrastructure, and curation provided by the FaceBase Hub offer flexible and intuitive ways to interact with these multidisciplinary data. In parallel, the datasets also offer unique opportunities for new collaborations and training for researchers coming into the field of craniofacial studies. Here, we highlight the focus of each spoke project and the integration of datasets contributed by the spokes to facilitate craniofacial research. PMID:27287806

  2. Reciprocal influence of masticatory apparatus, craniofacial structure and whole body homeostasis.

    PubMed

    Lee, Yong-Keun; Moon, Hyung-Joo

    2012-12-01

    There are evidences that the evolution into Homo erectus was partially induced by masticatory muscular dystrophy caused by a gene mutation, which in turn increased brain capacity and led to bipedalism. It is generally accepted that the morphology and function of mammalian skull are partially controlled by epigenetic mechanisms. Archeologic evidences support that the masticatory apparatus have influenced the mechanical stress distribution in hominin skull, and consequently changed craniofacial morphology and function. Even after evolution into H. erectus, alterations in food properties by civilization and cultural preferences have caused modification of human masticatory pattern and accordingly craniofacial structure. Since there are evidences that prehuman and human masticatory apparatus has been influenced the craniofacial and whole body morphology and function, this apparatus in turn might influence whole body homeostasis. Plausible reciprocal influencing mechanisms of the masticatory apparatus on the whole body homeostasis might be (1) direct mechanical influence on the craniofacial structure, (2) distortion of cerebrospinal fluid circulation, and/or (3) several neural/humoral routes. Based on these backgrounds, the hypothesis of the present study is that the morphology and function of masticatory apparatus influence the whole body homeostasis and these interactions are reciprocal. Therefore, human masticatory apparatus, at the present time, should be kept in its physiological status to maintain the whole body homeostasis. We recommend basic and clinical approaches to confirm this hypothesis. PMID:22981594

  3. The FaceBase Consortium: a comprehensive resource for craniofacial researchers.

    PubMed

    Brinkley, James F; Fisher, Shannon; Harris, Matthew P; Holmes, Greg; Hooper, Joan E; Jabs, Ethylin Wang; Jones, Kenneth L; Kesselman, Carl; Klein, Ophir D; Maas, Richard L; Marazita, Mary L; Selleri, Licia; Spritz, Richard A; van Bakel, Harm; Visel, Axel; Williams, Trevor J; Wysocka, Joanna; Chai, Yang

    2016-07-15

    The FaceBase Consortium, funded by the National Institute of Dental and Craniofacial Research, National Institutes of Health, is designed to accelerate understanding of craniofacial developmental biology by generating comprehensive data resources to empower the research community, exploring high-throughput technology, fostering new scientific collaborations among researchers and human/computer interactions, facilitating hypothesis-driven research and translating science into improved health care to benefit patients. The resources generated by the FaceBase projects include a number of dynamic imaging modalities, genome-wide association studies, software tools for analyzing human facial abnormalities, detailed phenotyping, anatomical and molecular atlases, global and specific gene expression patterns, and transcriptional profiling over the course of embryonic and postnatal development in animal models and humans. The integrated data visualization tools, faceted search infrastructure, and curation provided by the FaceBase Hub offer flexible and intuitive ways to interact with these multidisciplinary data. In parallel, the datasets also offer unique opportunities for new collaborations and training for researchers coming into the field of craniofacial studies. Here, we highlight the focus of each spoke project and the integration of datasets contributed by the spokes to facilitate craniofacial research. PMID:27287806

  4. Skeletal muscle disorders associated with selenium deficiency in humans.

    PubMed

    Chariot, Patrick; Bignani, Olivier

    2003-06-01

    Skeletal muscle disorders manifested by muscle pain, fatigue, proximal weakness, and serum creatine kinase (CK) elevation have been reported in patients with selenium deficiency. The object of this report was to review the conditions in which selenium deficiency is associated with human skeletal muscle disorders and to evaluate the importance of mitochondrial alterations in these disorders. A systematic literature review using the Medline database and Cochrane Library provided 38 relevant articles. The main conditions associated with selenium deficiency fell into three categories: (1) insufficient selenium intake in low soil-selenium areas; (2) parenteral or enteral nutrition, or malabsorption; and (3) chronic conditions associated with oxidative stress, such as chronic alcohol abuse and human immunodeficiency virus (HIV) infection. In low soil-selenium areas, reversibility of muscle symptoms was similar after selenium supplementation and placebo administration, suggesting a role for other factors in the development of disease. In parenteral or enteral nutrition, or malabsorption, muscle symptoms improved after selenium supplementation in 18 of 19 patients (median delay: 4 weeks). The reason that only a minority of selenium-deficient patients present with skeletal muscle disorders is unclear and is possibly related to cofactors, such as viral infections and drugs. Prospective studies of selenium-deficient myopathies would be useful in critically ill patients, alcohol abusers, and HIV-infected patients. PMID:12766976

  5. Bilateral lambdoid and sagittal synostosis (BLSS): a unique craniosynostosis syndrome or predictable craniofacial phenotype?

    PubMed

    Hing, Anne V; Click, Eleanor S; Holder, Ursula; Seto, Marianne L; Vessey, Kyle; Gruss, Joseph; Hopper, Richard; Cunningham, Michael L

    2009-05-01

    Multisutural craniosynostosis that includes bilateral lambdoid and sagittal synostosis (BLSS) results in a very characteristic head shape with frontal bossing, turribrachycephaly, biparietal narrowing, occipital concavity, and inferior displacement of the ears. This entity has been reported both in the genetics literature as craniofacial dyssynostosis and in the surgical literature as "Mercedes Benz" syndrome. Craniofacial dyssynostosis was first described in 1976 by Dr. Neuhauser when he presented a series of seven patients with synostosis of the sagittal and lambdoid sutures, short stature, and developmental delay. Over the past 30 years nine additional patients with craniofacial dyssynostosis have been reported in the literature adding to the growing evidence for a distinct craniosynostosis syndrome. The term "Mercedes Benz" syndrome was coined by Moore et al. in 1998 due to the characteristic appearance of the fused sutures on three-dimensional CT imaging. In contrast to the aforementioned reported cases of craniofacial dyssynostosis, all three patients had normal development. Recently, there have been several case reports of patients with BLSS and distinct chromosomal anomalies. These findings suggest that BLSS is a heterogeneous disorder perhaps with syndromic, chromosomal, and isolated forms. In this manuscript we will present the largest series of patients with BLSS and review clinical, CT, and molecular findings. PMID:19396832

  6. Dental and Craniofacial Anomalies Associated with Axenfeld-Rieger Syndrome with PITX2 Mutation

    PubMed Central

    Dressler, Simone; Meyer-Marcotty, Philipp; Weisschuh, Nicole; Jablonski-Momeni, Anahita; Pieper, Klaus; Gramer, Gwendolyn; Gramer, Eugen

    2010-01-01

    Axenfeld-Rieger syndrome (ARS) (OMIM Nr.: 180500) is a rare autosomal dominant disorder (1  :  200000) with genetic and morphologic variability. Glaucoma is associated in 50% of the patients. Craniofacial and dental anomalies are frequently reported with ARS. The present study was designed as a multidisciplinary analysis of orthodontic, ophthalmologic, and genotypical features. A three-generation pedigree was ascertained through a family with ARS. Clinically, radiographic and genetic analyses were performed. Despite an identical genotype in all patients, the phenotype varies in expressivity of craniofacial and dental morphology. Screening for PITX2 and FOXC1 mutations by direct DNA-sequencing revealed a P64L missense mutation in PITX2 in all family members, supporting earlier reports that PITX2 is an essential factor in morphogenesis of teeth and craniofacial skeleton. Despite the fact that the family members had identical mutations, morphologic differences were evident. The concomitant occurrence of rare dental and craniofacial anomalies may be early diagnostic indications of ARS. Early detection of ARS and elevated intraocular pressure (IOP) helps to prevent visual field loss. PMID:20339518

  7. EARLY CRANIOFACIAL DEVELOPMENT: LIFE AMONG THE SIGNALS

    EPA Science Inventory

    Early Craniofacial Development: Life Among the Signals. Sid Hunter and Keith Ward. Reproductive Toxicology Division, NHEERL, US EPA, RTP, NC, 27711

    Haloacetic acids (HAA) are chemicals formed during drinking water disinfection and present in finished tap water. Exposure o...

  8. Injectable Biomaterials for Regenerating Complex Craniofacial Tissues**

    PubMed Central

    Kretlow, James D.; Young, Simon; Klouda, Leda; Wong, Mark; Mikos, Antonios G.

    2009-01-01

    Engineering complex tissues requires a precisely formulated combination of cells, spatiotemporally released bioactive factors, and a specialized scaffold support system. Injectable materials, particularly those delivered in aqueous solution, are considered ideal delivery vehicles for cells and bioactive factors and can also be delivered through minimally invasive methods and fill complex 3D shapes. In this review, we examine injectable materials that form scaffolds or networks capable of both replacing tissue function early after delivery and supporting tissue regeneration over a time period of weeks to months. The use of these materials for tissue engineering within the craniofacial complex is challenging but ideal as many highly specialized and functional tissues reside within a small volume in the craniofacial structures and the need for minimally invasive interventions is desirable due to aesthetic considerations. Current biomaterials and strategies used to treat craniofacial defects are examined, followed by a review of craniofacial tissue engineering, and finally an examination of current technologies used for injectable scaffold development and drug and cell delivery using these materials. PMID:19750143

  9. Psychosocial adjustment and craniofacial malformations in childhood.

    PubMed

    Pertschuk, M J; Whitaker, L A

    1985-02-01

    Forty-three children between the ages of 6 and 13 years with congenital facial anomalies underwent psychosocial evaluation prior to surgery. Also evaluated were healthy children matched to the craniofacial subjects by sex, age, intelligence, and economic background. Relative to this comparison group, the craniofacial children were found to have poorer self-concept, greater anxiety at the time of evaluation, and more introversion. Parents of the craniofacial children noted more frequent negative social encounters for their children and more hyperactive behavior at home. Teachers reported more problematic classroom behavior. Examination of these results revealed craniofacial malformations to be associated with psychosocial limitations rather than marked deficits. These children tended to function less well than the comparison children, but with few exceptions, they were not functioning in a psychosocially deviant range. Explanations for the observed circumscribed impact of facial deformity include the use of denial as a coping mechanism, possible diminished significance of appearance for younger children, and the restricted environment experienced by most of the subjects. It can be predicted that time would render these protective influences ineffective, so that adolescent and young adult patients could be at far greater psychosocial risk. PMID:3969404

  10. Family Members as Participants on Craniofacial Teams.

    ERIC Educational Resources Information Center

    Andrews, James; Seaver, Earl; Stevens, George; Whiteley, Joseph

    1998-01-01

    Family members (N=83) who participated in professional team staffing concerning treatment plans for their child with a craniofacial difference (typically, cleft lip and/or palate) were surveyed. Ninety-seven percent of respondents said they would choose to meet with the team on their next visit to the clinic. The role of early interventionists on…

  11. Discrimination among adults with craniofacial conditions.

    PubMed

    Roberts, Rachel M

    2014-01-01

    The primary goal of this study was to establish the level of perceived discrimination experienced by adults with congenital craniofacial conditions in Australia and to examine predictors of discrimination. Specifically, this study tested whether social support mediates the relationship between discrimination and health. Adults (n = 93) who had been treated at the Australian Craniofacial Unit, Women's and Children's Hospital, Adelaide for congenital craniofacial conditions (not including cleft lip and/or palate) completed questionnaires examining satisfaction with life, quality of life, anxiety and depression, self-esteem, satisfaction with social support, and satisfaction with appearance. A substantial minority of adults with congenital craniofacial conditions reported that they experience discrimination almost every day in a range of areas. Higher reports of discrimination were related to older age, being male, and less education. Other factors related to higher discrimination included lower levels of satisfaction with life, self-esteem, satisfaction with appearance and mental quality of life, as well as higher levels of anxiety and depression. Social support partially mediated the relationship between discrimination and mental health outcomes. The current study shows that discrimination experiences continue into adulthood confirming the importance of ensuring patients are well supported both by psychosocial services as well as within their own social support networks. PMID:24240765

  12. The emerging roles of ribosome biogenesis in craniofacial development.

    PubMed

    Ross, Adam P; Zarbalis, Konstantinos S

    2014-01-01

    Neural crest cells (NCCs) are a transient, migratory cell population, which originates during neurulation at the neural folds and contributes to the majority of tissues, including the mesenchymal structures of the craniofacial skeleton. The deregulation of the complex developmental processes that guide migration, proliferation, and differentiation of NCCs may result in a wide range of pathological conditions grouped together as neurocristopathies. Recently, due to their multipotent properties neural crest stem cells have received considerable attention as a possible source for stem cell based regenerative therapies. This exciting prospect underlines the need to further explore the developmental programs that guide NCC differentiation. This review explores the particular importance of ribosome biogenesis defects in this context since a specific interface between ribosomopathies and neurocristopathies exists as evidenced by disorders such as Treacher-Collins-Franceschetti syndrome (TCS) and Diamond-Blackfan anemia (DBA). PMID:24550838

  13. Wnt Signaling and Its Contribution to Craniofacial Tissue Homeostasis.

    PubMed

    Yin, X; Li, J; Salmon, B; Huang, L; Lim, W H; Liu, B; Hunter, D J; Ransom, R C; Singh, G; Gillette, M; Zou, S; Helms, J A

    2015-11-01

    A new field of dental medicine seeks to exploit nature's solution for repairing damaged tissues, through the process of regeneration. Most adult mammalian tissues have limited regenerative capacities, but in lower vertebrates, the molecular machinery for regeneration is an elemental part of their genetic makeup. Accumulating data suggest that the molecular pathways responsible for the regenerative capacity of teleosts, amphibians, and reptiles have fallen into disuse in mammals but that they can be "jumpstarted" by the selective activation of key molecules. The Wnt family of secreted proteins constitutes one such critical pathway: Wnt proteins rank among the most potent and ubiquitous stem cell self-renewing factors, with tremendous potential for promoting human tissue regeneration. Wnt reporter and lineage-tracing strains of mice have been employed to create molecular maps of Wnt responsiveness in the craniofacial tissues, and these patterns of Wnt signaling colocalize with stem/progenitor populations in the rodent incisor apex, the dental pulp, the alveolar bone, the periodontal ligament, the cementum, and oral mucosa. The importance of Wnt signaling in both the maintenance and healing of these craniofacial tissues is summarized, and the therapeutic potential of Wnt-based strategies to accelerate healing through activation of endogenous stem cells is highlighted. PMID:26285808

  14. Thymus, kidney and craniofacial abnormalities in Six 1 deficient mice.

    PubMed

    Laclef, Christine; Souil, Evelyne; Demignon, Josiane; Maire, Pascal

    2003-06-01

    Six genes are widely expressed during vertebrate embryogenesis, suggesting that they are implicated in diverse differentiation processes. To determine the functions of the Six1 gene, we constructed Six1-deficient mice by replacing its first exon by the beta-galactosidase gene. We have previously shown that mice lacking Six1 die at birth due to thoracic skeletal defects and severe muscle hypoplasia affecting most of the body muscles. Here, we report that Six1(-/-) neonates also lack a kidney and thymus, as well as displaying a strong disorganisation of craniofacial structures, namely the inner ear, the nasal cavity, the craniofacial skeleton, and the lacrimal and parotid glands. These organ defects can be correlated with Six1 expression in the embryonic primordium structures as revealed by X-Gal staining at different stages of embryogenesis. Thus, the fetal abnormalities of Six1(-/-) mice appear to result from the absence of the Six 1 homeoprotein during early stages of organogenesis. Interestingly, these Six1 defects are very similar to phenotypes caused by mutations of Eya 1, which are responsible for the BOR syndrome in humans. Close comparison of Six1 and Eya 1 deficient mice strongly suggests a functional link between these two factors. Pax gene mutations also lead to comparable phenotypes, suggesting that a regulatory network including the Pax, Six and Eya genes is required for several types of organogenesis in mammals. PMID:12834866

  15. Reliability of Craniofacial Superimposition Using Three-Dimension Skull Model.

    PubMed

    Gaudio, Daniel; Olivieri, Lara; De Angelis, Danilo; Poppa, Pasquale; Galassi, Andrea; Cattaneo, Cristina

    2016-01-01

    Craniofacial superimposition is a technique potentially useful for the identification of unidentified human remains if a photo of the missing person is available. We have tested the reliability of the 2D-3D computer-aided nonautomatic superimposition techniques. Three-dimension laser scans of five skulls and ten photographs were overlaid with an imaging software. The resulting superimpositions were evaluated using three methods: craniofacial landmarks, morphological features, and a combination of the two. A 3D model of each skull without its mandible was tested for superimposition; we also evaluated whether separating skulls by sex would increase correct identifications. Results show that the landmark method employing the entire skull is the more reliable one (5/5 correct identifications, 40% false positives [FP]), regardless of sex. However, the persistence of a high percentage of FP in all the methods evaluated indicates that these methods are unreliable for positive identification although the landmark-only method could be useful for exclusion. PMID:26335587

  16. Ellis Van Creveld2 is Required for Postnatal Craniofacial Bone Development.

    PubMed

    Badri, Mohammed K; Zhang, Honghao; Ohyama, Yoshio; Venkitapathi, Sundharamani; Kamiya, Nobuhiro; Takeda, Haruko; Ray, Manas; Scott, Greg; Tsuji, Takehito; Kunieda, Tetsuo; Mishina, Yuji; Mochida, Yoshiyuki

    2016-08-01

    Ellis-van Creveld (EvC) syndrome is a genetic disorder with mutations in either EVC or EVC2 gene. Previous case studies reported that EvC patients underwent orthodontic treatment, suggesting the presence of craniofacial bone phenotypes. To investigate whether a mutation in EVC2 gene causes a craniofacial bone phenotype, Evc2 knockout (KO) mice were generated and cephalometric analysis was performed. The heads of wild type (WT), heterozygous (Het) and homozygous Evc2 KO mice (1-, 3-, and 6-week-old) were prepared and cephalometric analysis based on the selected reference points on lateral X-ray radiographs was performed. The linear and angular bone measurements were then calculated, compared between WT, Het and KO and statistically analyzed at each time point. Our data showed that length of craniofacial bones in KO was significantly lowered by ∼20% to that of WT and Het, the growth of certain bones, including nasal bone, palatal length, and premaxilla was more affected in KO, and the reduction in these bone length was more significantly enhanced at later postnatal time points (3 and 6 weeks) than early time point (1 week). Furthermore, bone-to-bone relationship to cranial base and cranial vault in KO was remarkably changed, i.e. cranial vault and nasal bone were depressed and premaxilla and mandible were developed in a more ventral direction. Our study was the first to show the cause-effect relationship between Evc2 deficiency and craniofacial defects in EvC syndrome, demonstrating that Evc2 is required for craniofacial bone development and its deficiency leads to specific facial bone growth defect. Anat Rec, 299:1110-1120, 2016. © 2016 Wiley Periodicals, Inc. PMID:27090777

  17. Screening for obstructive sleep apnea in children treated at a major craniofacial center.

    PubMed

    Paliga, J Thomas; Tahiri, Youssef; Silvestre, Jason; Taylor, Jesse A

    2014-09-01

    Timely diagnosis of obstructive sleep apnea (OSA) in patients with craniofacial disorders may help prevent long-term adverse sequelae of upper airway obstruction, namely pulmonary hypertension, failure to thrive, and impaired neurocognitive development. Currently, little is known about the incidence of OSA in this high-risk population. A prospective study examining the incidence of positive screening for OSA in patients cared for by the craniofacial team at a large, urban referral center was performed. From January 2011 to August 2013, all patient families were asked to complete the Pediatric Sleep Questionnaire. This validated tool has a sensitivity of 85% and specificity of 87% in predicting a positive sleep study when the ratio of positive-total responses is 0.33 or greater. Screening results were evaluated via Chi-squared and Fisher tests according to demographic and clinical variables. A total of 234 children seen in our craniofacial clinic completed the Pediatric Sleep Questionnaire. The mean screening age was 8.38 years, and 47% were male (110/234). Total incidence of positive OSA screening was 28.2% (66/234). Of the total population, 128 patients had an underlying syndrome (54.7%), whereas 106 patients were nonsyndromic (45.3%). Both groups were at equivalent risk for screening positive for OSA (28.1% versus 28.3%, P = 1.0). Among children with a craniofacial diagnosis, patients with a cleft lip and/or palate were at equivalent risk for screening positive for OSA as patients without a cleft (25.5% versus 32.6%, P = 0.24). The OSA symptoms affect almost one third of patients seen by our craniofacial team. Syndromic and nonsyndromic patients seem to be at equivalent risk as those patients with and without an oropharyngeal cleft. Future work will correlate these findings with formal polysomnography and may serve to heighten awareness of OSA in this at-risk population. PMID:25162551

  18. The ADAMTS(L) family and human genetic disorders.

    PubMed

    Le Goff, Carine; Cormier-Daire, Valérie

    2011-10-15

    ADAMTS designates a family of 19 secreted enzymes, whose the first member ADAMTS1 was described in 1997. The ADAMTS family has a role in extracellular matrix degradation and turn over and has previously been involved in various human biological processes, including connective tissue structure, cancer, coagulation, arthritis, angiogenesis and cell migration. More recently, the ADAMTS(L) family has been described, sharing the same ancillary domain but distinct by the absence of any enzyme activity. Mutations in ADAMTS13, ADAMTS2, ADAMTS10, ADAMTS17, ADAMTSL2 and ADAMTSL4 have been identified in distinct human genetic disorders ranging from thrombotic thrombocytopenic purpura to acromelic dysplasia. The aim of our review was to emphasize the role of this family in the extracellular matrix based on human phenotypes so far identified in relation with ADAMTS(L) mutations. PMID:21880666

  19. Etiology of craniofacial malformations in mouse models of blepharophimosis, ptosis and epicanthus inversus syndrome.

    PubMed

    Heude, Églantine; Bellessort, Brice; Fontaine, Anastasia; Hamazaki, Manatsu; Treier, Anna-Corina; Treier, Mathias; Levi, Giovanni; Narboux-Nême, Nicolas

    2015-03-15

    Blepharophimosis, ptosis, epicanthus-inversus syndrome (BPES) is an autosomal dominant genetic disorder characterized by narrow palpebral fissures and eyelid levator muscle defects. BPES is often associated to premature ovarian insufficiency (BPES type I). FOXL2, a member of the forkhead transcription factor family, is the only gene known to be mutated in BPES. Foxl2 is essential for maintenance of ovarian identity, but the developmental origin of the facial malformations of BPES remains, so far, unexplained. In this study, we provide the first detailed account of the developmental processes leading to the craniofacial malformations associated to Foxl2. We show that, during development, Foxl2 is expressed both by Cranial Neural Crest Cells (CNCCs) and by Cranial Mesodermal Cells (CMCs), which give rise to skeletal (CNCCs and CMCs) and muscular (CMCs) components of the head. Using mice in which Foxl2 is selectively inactivated in either CNCCs or CMCs, we reveal that expression of Foxl2 in CNCCs is essential for the development of extraocular muscles. Indeed, inactivation of Foxl2 in CMCs has only minor effects on muscle development, whereas its inactivation in CNCCs provokes a severe hypoplasia of the levator palpabrae superioris and of the superior and inferior oblique muscles. We further show that Foxl2 deletion in either CNCCs or CMCs prevents eyelid closure and induces subtle skeletal developmental defects. Our results provide new insights in the complex developmental origin of human BPES and could help to understand the origin of other ocular anomalies associated to this syndrome. PMID:25416281

  20. Sh3pxd2b Mice Are a Model for Craniofacial Dysmorphology and Otitis Media

    PubMed Central

    Yang, Bin; Tian, Cong; Zhang, Zhi-guang; Han, Feng-chan; Azem, Rami; Yu, Heping; Zheng, Ye; Jin, Ge; Arnold, James E.; Zheng, Qing Y.

    2011-01-01

    Craniofacial defects that occur through gene mutation during development increase vulnerability to eustachian tube dysfunction. These defects can lead to an increased incidence of otitis media. We examined the effects of a mutation in the Sh3pxd2b gene (Sh3pxd2bnee) on the progression of otitis media and hearing impairment at various developmental stages. We found that all mice that had the Sh3pxd2bnee mutation went on to develop craniofacial dysmorphologies and subsequently otitis media, by as early as 11 days of age. We found noteworthy changes in cilia and goblet cells of the middle ear mucosa in Sh3pxd2bnee mutant mice using scanning electronic microscopy. By measuring craniofacial dimensions, we determined for the first time in an animal model that this mouse has altered eustachian tube morphology consistent with a more horizontal position of the eustachian tube. All mutants were found to have hearing impairment. Expression of TNF-α and TLR2, which correlates with inflammation in otitis media, was up-regulated in the ears of mutant mice when examined by immunohistochemistry and semi-quantitative RT-PCR. The mouse model with a mutation in the Sh3pxd2b gene (Sh3pxd2bnee) mirrors craniofacial dysmorphology and otitis media in humans. PMID:21818352

  1. Sh3pxd2b mice are a model for craniofacial dysmorphology and otitis media.

    PubMed

    Yang, Bin; Tian, Cong; Zhang, Zhi-guang; Han, Feng-chan; Azem, Rami; Yu, Heping; Zheng, Ye; Jin, Ge; Arnold, James E; Zheng, Qing Y

    2011-01-01

    Craniofacial defects that occur through gene mutation during development increase vulnerability to eustachian tube dysfunction. These defects can lead to an increased incidence of otitis media. We examined the effects of a mutation in the Sh3pxd2b gene (Sh3pxd2b(nee)) on the progression of otitis media and hearing impairment at various developmental stages. We found that all mice that had the Sh3pxd2b(nee) mutation went on to develop craniofacial dysmorphologies and subsequently otitis media, by as early as 11 days of age. We found noteworthy changes in cilia and goblet cells of the middle ear mucosa in Sh3pxd2b(nee) mutant mice using scanning electronic microscopy. By measuring craniofacial dimensions, we determined for the first time in an animal model that this mouse has altered eustachian tube morphology consistent with a more horizontal position of the eustachian tube. All mutants were found to have hearing impairment. Expression of TNF-α and TLR2, which correlates with inflammation in otitis media, was up-regulated in the ears of mutant mice when examined by immunohistochemistry and semi-quantitative RT-PCR. The mouse model with a mutation in the Sh3pxd2b gene (Sh3pxd2b(nee)) mirrors craniofacial dysmorphology and otitis media in humans. PMID:21818352

  2. Applications of Mesenchymal Stem Cells and Neural Crest Cells in Craniofacial Skeletal Research

    PubMed Central

    Ouchi, Takehito; Shibata, Shinsuke; Fujimura, Takumi; Kawana, Hiromasa; Okano, Hideyuki; Nakagawa, Taneaki

    2016-01-01

    Craniofacial skeletal tissues are composed of tooth and bone, together with nerves and blood vessels. This composite material is mainly derived from neural crest cells (NCCs). The neural crest is transient embryonic tissue present during neural tube formation whose cells have high potential for migration and differentiation. Thus, NCCs are promising candidates for craniofacial tissue regeneration; however, the clinical application of NCCs is hindered by their limited accessibility. In contrast, mesenchymal stem cells (MSCs) are easily accessible in adults, have similar potential for self-renewal, and can differentiate into skeletal tissues, including bones and cartilage. Therefore, MSCs may represent good sources of stem cells for clinical use. MSCs are classically identified under adherent culture conditions, leading to contamination with other cell lineages. Previous studies have identified mouse- and human-specific MSC subsets using cell surface markers. Additionally, some studies have shown that a subset of MSCs is closely related to neural crest derivatives and endothelial cells. These MSCs may be promising candidates for regeneration of craniofacial tissues from the perspective of developmental fate. Here, we review the fundamental biology of MSCs in craniofacial research. PMID:27006661

  3. CT and MR Imaging in a Large Series of Patients with Craniofacial Fibrous Dysplasia

    PubMed Central

    Atalar, Mehmet Haydar; Salk, Ismail; Savas, Recep; Uysal, Ismail Onder; Egilmez, Hulusi

    2015-01-01

    Summary Background In this retrospective review of patients with craniofacial fibrous dysplasia (FD), the clinical and radiological findings of CT and MR scan were analyzed. Material/Methods The study material included 32 patients, at 9 to 68 years of age that were directed for differential diagnostics of several disorders in the head. We recorded CT and MRI data related to the lesion number, location, sidedness, appearance, and sex of the cases with craniofacial FD. Results Of 32 patients involved in this study, 17 had monostotic and 15 had polyostotic involvement pattern. Bones most commonly involved by monostotic involvement in females were, in descending order, mandibular, maxillary, and sphenoid bones, while the sphenoid bone was involved the most in males. Leontiasis ossea was observed in 2 patients. Sclerotic and mixed lesion types were more common in both females and males. In T1- and T2-weighted MRI sequences, hypointensity was more common compared to hyperintensity or heterogeneous intensity. The type of enhancement of lesions was found similar after contrast medium administration. Conclusions In the presence of craniofacial FD during CT or MRI imaging of the head, a detailed description of FD lesions may provide an important clinical benefit by increasing radiological experience during the diagnostics of this rare disorder. PMID:26000068

  4. Craniofacial malformation among endemic cretins in Ecuador.

    PubMed

    Israel, H; Johnson, G F; Fierro-Benitez, R

    1983-01-01

    Nearly 6% of the inhabitants of two villages in Ecuador are deaf-mute and mentally retarded cretins. These communities are situated in the Andean highlands where environmental and dietary stores of iodine are extremely scarce. Endemic goiter and cretinism are widespread, and 10% of the cretins are additionally burdened with dwarfism and facial dysmorphia. Those with obvious involvement of the skeletal system were selected in order to study the extent of craniofacial malformation. Their appearance is characterized by midface hypoplasia, a broad nose with a depressed bridge, and a conspicuous circumoral prominence. Radiographic evaluation demonstrates a vertical displacement of the cranial base with an associated upward tilt of the midface. The flattened frontal bone, reduced frontal sinus pneumatization, and diminutive nasal bones collectively create a backward sloping face. The defect in the craniofacial skeleton of these Ecuadorian cretins is characteristic, and it readily sets them apart from the dysmorphism of those cretins with myxedema. PMID:6874895

  5. The concept of pattern in craniofacial growth.

    PubMed

    Moyers, R E; Bookstein, F L; Guire, K E

    1979-08-01

    1. There are semantic and associated problems with the word pattern in biology, particularly in orthodontics and facial growth. 2. Pattern, as we use the term, is invariance of relationships--"a set of constraints operating to preserve the integration of parts under varying conditions and through time." 3. Craniofacial pattern can be described and quantified by the identification of craniofacial constants, measures that are relatively invariant. 4. Growth is change and is best identified by studying those measures of size and shape that vary most sensitively through time over development stages. 5. The many traditional cephalometric measures that represent well neither pattern nor growth (mixed) are of less clinical utility than either pure pattern indices or growth indices. 6. The analytical and conceptual separation of pattern and growth seems useful in analysis of morphology, analysis of growth, prediction of growth, and clinical treatment planning. PMID:289292

  6. Antimicrobial potentials and structural disorder of human and animal defensins.

    PubMed

    Mattar, Ehab H; Almehdar, Hussein A; Yacoub, Haitham A; Uversky, Vladimir N; Redwan, Elrashdy M

    2016-04-01

    Defensins are moonlighting peptides which are broadly distributed throughout all the living kingdoms. They play a multitude of important roles in human health and disease, possessing several immunoregulatory functions and manifesting broad antimicrobial activities against viruses, bacteria, and fungi. Based on their patterns of intramolecular disulfide bridges, these small cysteine-rich cationic proteins are divided into three major types, α-, β-, and θ-defensins, with the α- and β-defensins being further subdivided into a number of subtypes. The various roles played by the defensins in the innate (especially mucosal) and adoptive immunities place these polypeptides at the frontiers of the defense against the microbial invasions. Current work analyzes the antimicrobial activities of human and animal defensins in light of their intrinsic disorder propensities. PMID:26598808

  7. Imaging findings in craniofacial childhood rhabdomyosarcoma

    PubMed Central

    Merks, Johannes H. M.; Saeed, Peerooz; Balm, Alfons J. M.; Bras, Johannes; Pieters, Bradley R.; Adam, Judit A.; van Rijn, Rick R.

    2010-01-01

    Rhabdomyosarcoma (RMS) is the commonest paediatric soft-tissue sarcoma constituting 3–5% of all malignancies in childhood. RMS has a predilection for the head and neck area and tumours in this location account for 40% of all childhood RMS cases. In this review we address the clinical and imaging presentations of craniofacial RMS, discuss the most appropriate imaging techniques, present characteristic imaging features and offer an overview of differential diagnostic considerations. Post-treatment changes will be briefly addressed. PMID:20725831

  8. Holoprosencephaly with Multiple Anomalies of the Craniofacial Bones-An Autopsy Report

    PubMed Central

    Aruna, E.; Chakravarthy, V. Kalyan; Rao, D. Naveen Chandar; Rao, D. Ranga

    2013-01-01

    Holoprosencephaly (HPE), a disorder which results from a failure of cleavage or the incomplete differentiation of the forebrain structures at various levels or to various degrees, is related to hereditary factors, chromosomal anomalies, cytogenetic abnormalities, and environmental teratogenic factors. We are reporting a case of a multiparous woman who was G3,P3,L2, who delivered a full term foetus with holoprosencephaly and multiple craniofacial anomalies. An autopsy was conducted. Multiple anomalies of the craniofacial bones, which include hypoplasia and synostosis of the frontal bone, anophthalmia, absence of the anterior cranial fossa, hypoplasia of the maxillae, an absent antrum, cleft palate, a central hare lip and arrhinia which includes absence of the nostrils and hypotelorism of the eye placodes, were noted. This case is being reported for its rarity and the available literature was reviewed in this respect. PMID:24086891

  9. [Mechanisms of growth, development and disease of the craniofacial skeleton].

    PubMed

    Yamashiro, Takashi

    2016-01-01

    Craniofacial skeleton is derived from several pieces of bone, which hold the brain and house the sensory organ of vision, hearing, taste and smell. It also serves as an entrance of the digestive and respiratory tracts. Hence, craniofacial complex develops under sophisticated balance between the shape and the function. Disruption of such balance leads to various types of malformation and/or deformation of the face. This review focuses on the molecular aspects of growth and developments of the craniofacial structures and also on the genetic basis of congenital craniofacial malformations. PMID:26728542

  10. Hypomorphic PCNA mutation underlies a human DNA repair disorder

    PubMed Central

    Baple, Emma L.; Chambers, Helen; Cross, Harold E.; Fawcett, Heather; Nakazawa, Yuka; Chioza, Barry A.; Harlalka, Gaurav V.; Mansour, Sahar; Sreekantan-Nair, Ajith; Patton, Michael A.; Muggenthaler, Martina; Rich, Phillip; Wagner, Karin; Coblentz, Roselyn; Stein, Constance K.; Last, James I.; Taylor, A. Malcolm R.; Jackson, Andrew P.; Ogi, Tomoo; Lehmann, Alan R.; Green, Catherine M.; Crosby, Andrew H.

    2014-01-01

    Numerous human disorders, including Cockayne syndrome, UV-sensitive syndrome, xeroderma pigmentosum, and trichothiodystrophy, result from the mutation of genes encoding molecules important for nucleotide excision repair. Here, we describe a syndrome in which the cardinal clinical features include short stature, hearing loss, premature aging, telangiectasia, neurodegeneration, and photosensitivity, resulting from a homozygous missense (p.Ser228Ile) sequence alteration of the proliferating cell nuclear antigen (PCNA). PCNA is a highly conserved sliding clamp protein essential for DNA replication and repair. Due to this fundamental role, mutations in PCNA that profoundly impair protein function would be incompatible with life. Interestingly, while the p.Ser228Ile alteration appeared to have no effect on protein levels or DNA replication, patient cells exhibited marked abnormalities in response to UV irradiation, displaying substantial reductions in both UV survival and RNA synthesis recovery. The p.Ser228Ile change also profoundly altered PCNA’s interaction with Flap endonuclease 1 and DNA Ligase 1, DNA metabolism enzymes. Together, our findings detail a mutation of PCNA in humans associated with a neurodegenerative phenotype, displaying clinical and molecular features common to other DNA repair disorders, which we showed to be attributable to a hypomorphic amino acid alteration. PMID:24911150

  11. Venous air embolism during a craniofacial procedure.

    PubMed

    Phillips, R J; Mulliken, J B

    1988-07-01

    The possibility of venous air embolism exists whenever the craniofacial operative field is above the level of the heart. Craniotomy with the high-torque craniotome is hypothesized to have produced venous air embolism in the patient described in this report. The diagnosis of venous air embolism is determined by transesophageal Doppler probe, transesophageal echocardiogram or external echocardiogram, and end-tidal N2 and CO2 determinations. Treatment includes control of the air entry sites, aspiration of air from the right atrium via a catheter placed prior to operation, and discontinuing nitrous oxide. If these measures are unsuccessful, the operative field should be transposed below heart level and the procedure terminated. In the event of significant hemodynamic compromise, closed cardiac massage should be tried; if that fails, open cardiac massage and direct aspiration are necessary. The true incidence of venous air embolism in craniofacial operations may be much higher than previously suspected. We therefore recommend placement of appropriate monitoring equipment to detect intracardiac air in those major craniofacial procedures in which there is a potential for intravascular air ingress. PMID:3289061

  12. Craniofacial abnormalities among patients with Edwards Syndrome

    PubMed Central

    Rosa, Rafael Fabiano M.; Rosa, Rosana Cardoso M.; Lorenzen, Marina Boff; Zen, Paulo Ricardo G.; Graziadio, Carla; Paskulin, Giorgio Adriano

    2013-01-01

    OBJECTIVE To determine the frequency and types of craniofacial abnormalities observed in patients with trisomy 18 or Edwards syndrome (ES). METHODS This descriptive and retrospective study of a case series included all patients diagnosed with ES in a Clinical Genetics Service of a reference hospital in Southern Brazil from 1975 to 2008. The results of the karyotypic analysis, along with clinical data, were collected from medical records. RESULTS: The sample consisted of 50 patients, of which 66% were female. The median age at first evaluation was 14 days. Regarding the karyotypes, full trisomy of chromosome 18 was the main alteration (90%). Mosaicism was observed in 10%. The main craniofacial abnormalities were: microretrognathia (76%), abnormalities of the ear helix/dysplastic ears (70%), prominent occiput (52%), posteriorly rotated (46%) and low set ears (44%), and short palpebral fissures/blepharophimosis (46%). Other uncommon - but relevant - abnormalities included: microtia (18%), orofacial clefts (12%), preauricular tags (10%), facial palsy (4%), encephalocele (4%), absence of external auditory canal (2%) and asymmetric face (2%). One patient had an initial suspicion of oculo-auriculo-vertebral spectrum (OAVS) or Goldenhar syndrome. CONCLUSIONS: Despite the literature description of a characteristic clinical presentation for ES, craniofacial alterations may be variable among these patients. The OAVS findings in this sample are noteworthy. The association of ES with OAVS has been reported once in the literature. PMID:24142310

  13. Midline Anterior Craniofacial Approach for Malignancy

    PubMed Central

    Wellman, Bryan John; Traynelis, Vincent C.; McCulloch, Timothy M.; Funk, Gerry F.; Menezes, Arnold H.; Hoffman, Henry T.

    1999-01-01

    Thirty consecutive cases of midline anterior craniofacial procedures for the treatment of malignant neoplasms arising from the paranasal sinuses were reviewed. Posterior and lateral base craniofacial procedures were specifically excluded. This review compares the results, in terms of survival and major complication rate, between en bloc and piecemeal resections. The average follow-up was 4 years and 3 months. Sixteen patients were treated with an en bloc resection. The major complication rate was 31%. One-year survival rate was 94% for the en bloc resection group, 67% for patients with positive margins, and 100% for patients with clear margins. Three-year survival for en bloc resection dropped to 56, 33, and 67%, respectively. Fourteen patients were treated with piecemeal resections. The major complication rate was 21%. One-year survival rate was 83% for the piecemeal resection group, 60% for patients with positive margins, and 100% for patients with clear margins. Three-year survival dropped to 70, 60, and 80%, respectively. Although it is considered desirable to obtain an en bloc resection in some craniofacial procedures, we conclude that a piecemeal resection is a viable alternative in situations where an en bloc procedure is difficult to obtain safely. ImagesFigure 1p43-bFigure 2p44-b PMID:17171080

  14. Fuz Regulates Craniofacial Development through Tissue Specific Responses to Signaling Factors

    PubMed Central

    Zhang, Zichao; Wlodarczyk, Bogdan J.; Niederreither, Karen; Venugopalan, Shankar; Florez, Sergio; Finnell, Richard H.; Amendt, Brad A.

    2011-01-01

    The planar cell polarity effector gene Fuz regulates ciliogenesis and Fuz loss of function studies reveal an array of embryonic phenotypes. However, cilia defects can affect many signaling pathways and, in humans, cilia defects underlie several craniofacial anomalies. To address this, we analyzed the craniofacial phenotype and signaling responses of the Fuz−/− mice. We demonstrate a unique role for Fuz in regulating both Hedgehog (Hh) and Wnt/β-catenin signaling during craniofacial development. Fuz expression first appears in the dorsal tissues and later in ventral tissues and craniofacial regions during embryonic development coincident with cilia development. The Fuz−/− mice exhibit severe craniofacial deformities including anophthalmia, agenesis of the tongue and incisors, a hypoplastic mandible, cleft palate, ossification/skeletal defects and hyperplastic malformed Meckel's cartilage. Hh signaling is down-regulated in the Fuz null mice, while canonical Wnt signaling is up-regulated revealing the antagonistic relationship of these two pathways. Meckel's cartilage is expanded in the Fuz−/− mice due to increased cell proliferation associated with the up-regulation of Wnt canonical target genes and decreased non-canonical pathway genes. Interestingly, cilia development was decreased in the mandible mesenchyme of Fuz null mice, suggesting that cilia may antagonize Wnt signaling in this tissue. Furthermore, expression of Fuz decreased expression of Wnt pathway genes as well as a Wnt-dependent reporter. Finally, chromatin IP experiments demonstrate that β-catenin/TCF-binding directly regulates Fuz expression. These data demonstrate a new model for coordination of Hh and Wnt signaling and reveal a Fuz-dependent negative feedback loop controlling Wnt/β-catenin signaling. PMID:21935430

  15. Cranio-facial remodeling in domestic dogs is associated with changes in larynx position.

    PubMed

    Plotsky, Kyle; Rendall, Drew; Chase, Kevin; Riede, Tobias

    2016-06-01

    The hyo-laryngeal complex is a multi-segmented structure integrating the oral and pharyngeal cavities and thus a variety of critical functions related to airway control, feeding, and vocal communication. Currently, we lack a complete understanding of how the hyoid complex, and the functions it mediates, can also be affected by changes in surrounding cranio-facial dimensions. Here, we explore these relationships in a breed of domestic dog, the Portuguese Water Dog, which is characterized by strong cranio-facial variation. We used radiographic images of the upper body and head of 55 adult males and 51 adult females to obtain detailed measures of cranio-facial variation and hyoid anatomy. Principal components analysis revealed multiple orthogonal dimensions of cranio-facial variation, some of which were associated with significant differences in larynx position: the larynx occupied a more descended position in individuals with shorter, broader faces than in those with longer, narrower faces. We then tested the possibility that caudal displacement of the larynx in brachycephalic individuals might reflect a degree of tongue crowding resulting from facial shortening and reduction of oral and pharyngeal spaces. A cadaver sample was used to obtain detailed measurements of constituent bones of the hyoid skeleton and of the tongue body, and their relationships to cranio-facial size and shape and overall body size supported the tongue-crowding hypothesis. Considering the presence of descended larynges in numerous mammalian taxa, our findings establish an important precedent for the possibility that laryngeal descent can be initiated, and even sustained, in part in response to remodeling of the face and cranium for selective pressures unrelated to vocal production. These integrated changes could also have been involved in hominin evolution, where the different laryngeal positions in modern humans compared with nonhuman primates have been traditionally linked to the evolution

  16. Similar impressions of humanness for human and artificial singing voices in autism spectrum disorders.

    PubMed

    Kuriki, Shinji; Tamura, Yuri; Igarashi, Miki; Kato, Nobumasa; Nakano, Tamami

    2016-08-01

    People with autism spectrum disorder (ASD) exhibit impairments in the perception of and orientation to social information related to humans, and some people with ASD show higher preference toward human-like robots than other humans. We speculated that this behavioural bias in people with ASD is caused by a weakness in their perception of humanness. To address this issue, we investigated whether people with ASD detect a subtle difference between the same song sung by human and artificial voices even when the lyrics, melody and rhythm are identical. People without ASD answered that the songs sung by a human voice evoked more impressions of humanness (human-likeness, animateness, naturalness, emotion) and more positive feelings (warmth, familiarity, comfort) than those sung by an artificial voice. In contrast, people with ASD had similar impressions of humanness and positive feelings for the songs sung by the human and artificial voices. The evaluations of musical characteristics (complexity, regularity, brightness) did not differ between people with and without ASD. These results suggest that people with ASD are weak in their ability to perceive psychological attributes of humanness. PMID:27107740

  17. Transferrin receptor facilitates TGF-β and BMP signaling activation to control craniofacial morphogenesis.

    PubMed

    Lei, R; Zhang, K; Liu, K; Shao, X; Ding, Z; Wang, F; Hong, Y; Zhu, M; Li, H; Li, H

    2016-01-01

    The Pierre Robin Sequence (PRS), consisting of cleft palate, glossoptosis and micrognathia, is a common human birth defect. However, how this abnormality occurs remains largely unknown. Here we report that neural crest cell (NCC)-specific knockout of transferrin receptor (Tfrc), a well known transferrin transporter protein, caused micrognathia, cleft palate, severe respiratory distress and inability to suckle in mice, which highly resemble human PRS. Histological and anatomical analysis revealed that the cleft palate is due to the failure of palatal shelves elevation that resulted from a retarded extension of Meckel's cartilage. Interestingly, Tfrc deletion dramatically suppressed both transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) signaling in cranial NCCs-derived mandibular tissues, suggesting that Tfrc may act as a facilitator of these two signaling pathways during craniofacial morphogenesis. Together, our study uncovers an unknown function of Tfrc in craniofacial development and provides novel insight into the etiology of PRS. PMID:27362800

  18. Proteomic analysis of human osteoprogenitor response to disordered nanotopography

    PubMed Central

    Kantawong, Fahsai; Burchmore, Richard; Gadegaard, Nikolaj; Oreffo, Richard O. C.; Dalby, Matthew J.

    2009-01-01

    Previous studies have shown that microgroove-initiated contact guidance can induce bone formation in osteoprogenitor cells (OPGs) and produce changes in the cell proteome. For proteomic analysis, differential in-gel electrophoresis (DIGE) can be used as a powerful diagnostic method to provide comparable data between the proteomic profiles of cells cultured in different conditions. This study focuses on the response of OPGs to a novel nanoscale pit topography with osteoinductive properties compared with planar controls. Disordered near-square nanopits with 120 nm diameter and 100 nm depth with an average 300 nm centre-to-centre spacing (300 nm spaced pits in square pattern, but with ±50 nm disorder) were fabricated on 1×1 cm2 polycaprolactone sheets. Human OPGs were seeded onto the test materials. DIGE analysis revealed changes in the expression of a number of distinct proteins, including upregulation of actin isoforms, beta-galectin1, vimentin and procollagen-proline, 2-oxoglutarate 4-dioxygenase and prolyl 4-hydroxylase. Downregulation of enolase, caldesmon, zyxin, GRASP55, Hsp70 (BiP/GRP78), RNH1, cathepsin D and Hsp27 was also observed. The differences in cell morphology and mineralization are also reported using histochemical techniques. PMID:19068473

  19. Human Genetic Disorders and Knockout Mice Deficient in Glycosaminoglycan

    PubMed Central

    2014-01-01

    Glycosaminoglycans (GAGs) are constructed through the stepwise addition of respective monosaccharides by various glycosyltransferases and maturated by epimerases and sulfotransferases. The structural diversity of GAG polysaccharides, including their sulfation patterns and sequential arrangements, is essential for a wide range of biological activities such as cell signaling, cell proliferation, tissue morphogenesis, and interactions with various growth factors. Studies using knockout mice of enzymes responsible for the biosynthesis of the GAG side chains of proteoglycans have revealed their physiological functions. Furthermore, mutations in the human genes encoding glycosyltransferases, sulfotransferases, and related enzymes responsible for the biosynthesis of GAGs cause a number of genetic disorders including chondrodysplasia, spondyloepiphyseal dysplasia, and Ehlers-Danlos syndromes. This review focused on the increasing number of glycobiological studies on knockout mice and genetic diseases caused by disturbances in the biosynthetic enzymes for GAGs. PMID:25126564

  20. OCT imaging of craniofacial anatomy in xenopus embryos (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Deniz, Engin; Jonas, Stephan M.; Griffin, John; Hooper, Michael C.; Choma, Michael A.; Khokha, Mustafa K.

    2016-03-01

    The etiology of craniofacial defects is incompletely understood. The ability to obtain large amounts of gene sequence data from families affected by craniofacial defects is opening up new ways to understand molecular genetic etiological factors. One important link between gene sequence data and clinical relevance is biological research into candidate genes and molecular pathways. We present our recent research using OCT as a nondestructive phenotyping modality of craniofacial morphology in Xenopus embryos, an important animal model for biological research in gene and pathway discovery. We define 2D and 3D scanning protocols for a standardized approach to craniofacial imaging in Xenopus embryos. We define standard views and planar reconstructions for visualizing normal anatomy and landmarks. We compare these views and reconstructions to traditional histopathology using alcian blue staining. In addition to being 3D, nondestructive, and having much faster throughout, OCT can identify craniofacial features that are lost during traditional histopathological preparation. We also identify quantitative morphometric parameters to define normative craniofacial anatomy. We also note that craniofacial and cardiac defects are not infrequently present in the same patient (e.g velocardiofacial syndrome). Given that OCT excels at certain aspects of cardiac imaging in Xenopus embryos, our work highlights the potential of using OCT and Xenopus to study molecular genetic factors that impact both cardiac and craniofacial development.

  1. Craniofacial dysmorphology: Studies in honor of Samuel Pruzansky

    SciTech Connect

    Cohen, M.M.; Rollnick, B.R.

    1985-01-01

    This book contains 31 chapters. Some of the chapter titles are: Regional Specification of Cell-Specific Gene Expression During Craniofacial Development; Timing Cleft Palate Closure - Age Should Not Be the Sole Determinant; Excess of Parental Non-Righthandedness in Children with Right-Sided Cleft Lip: A Preliminary Report; and The Application of Roentgencephalometry to the Study of Craniofacial Anomalies.

  2. Neural Crest-Specific TSC1 Deletion in Mice Leads to Sclerotic Craniofacial Bone Lesion.

    PubMed

    Fang, Fang; Sun, Shaogang; Wang, Li; Guan, Jun-Lin; Giovannini, Marco; Zhu, Yuan; Liu, Fei

    2015-07-01

    Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in either TSC1 or TSC2. TSC has high frequency of osseous manifestations such as sclerotic lesions in the craniofacial region. However, an animal model that replicates TSC craniofacial bone lesions has not yet been described. The roles of Tsc1 and the sequelae of Tsc1 dysfunction in bone are unknown. In this study, we generated a mouse model of TSC with a deletion of Tsc1 in neural crest-derived (NCD) cells that recapitulated the sclerotic craniofacial bone lesions in TSC. Analysis of this mouse model demonstrated that TSC1 deletion led to enhanced mTORC1 signaling in NCD bones and the increase in bone formation is responsible for the aberrantly increased bone mass. Lineage mapping revealed that TSC1 deficient NCD cells overpopulated the NCD bones. Mechanistically, hyperproliferation of osteoprogenitors at an early postnatal stage accounts for the increased osteoblast pool. Intriguingly, early postnatal treatment with rapamycin, an mTORC1 inhibitor, can completely rescue the aberrant bone mass, but late treatment cannot. Our data suggest that enhanced mTOR signaling in NCD cells can increase bone mass through enlargement of the osteoprogenitor pool, which likely explains the sclerotic bone lesion observed in TSC patients. PMID:25639352

  3. VEGF stimulates intramembranous bone formation during craniofacial skeletal development.

    PubMed

    Duan, Xuchen; Bradbury, Seth R; Olsen, Bjorn R; Berendsen, Agnes D

    2016-01-01

    Deficiency of vascular endothelial growth factor A (VEGF) has been associated with severe craniofacial anomalies in both humans and mice. Cranial neural crest cell (NCC)-derived VEGF regulates proliferation, vascularization and ossification of cartilage and membranous bone. However, the function of VEGF derived from specific subpopulations of NCCs in controlling unique aspects of craniofacial morphogenesis is not clear. In this study a conditional knockdown strategy was used to genetically delete Vegfa expression in Osterix (Osx) and collagen II (Col2)-expressing NCC descendants. No major defects in calvaria and mandibular morphogenesis were observed upon knockdown of VEGF in the Col2(+) cell population. In contrast, loss of VEGF in Osx(+) osteoblast progenitor cells led to reduced ossification of calvarial and mandibular bones without affecting the formation of cartilage templates in newborn mice. The early stages of ossification in the developing jaw revealed decreased initial mineralization levels and a reduced thickness of the collagen I (Col1)-positive bone template upon loss of VEGF in Osx(+) precursors. Increased numbers of proliferating cells were detected within the jaw mesenchyme of mutant embryos. Explant culture assays revealed that mandibular osteogenesis occurred independently of paracrine VEGF action and vascular development. Reduced VEGF expression in mandibles coincided with increased phospho-Smad1/5 (P-Smad1/5) levels and bone morphogenetic protein 2 (Bmp2) expression in the jaw mesenchyme. We conclude that VEGF derived from Osx(+) osteoblast progenitor cells is required for optimal ossification of developing mandibular bones and modulates mechanisms controlling BMP-dependent specification and expansion of the jaw mesenchyme. PMID:26899202

  4. Craniofacial Reconstruction with Induced Pluripotent Stem Cells

    PubMed Central

    Wan, Derrick C.; Wong, Victor W.; Longaker, Michael T.

    2012-01-01

    Induced pluripotent stem cells (iPSCs) hold enormous promise for the treatment of complex tissue defects throughout the entire body. The ability for iPSCs to form all tissue types makes them an ideal autogenous cellular building block for tissue engineering strategies designed to replace any combination of skin, muscle, nerve, and bone deficiencies in the craniofacial region. Several obstacles to their use remain, however, chief among which include concerns over insertional mutagenesis and tumorigenicity. As studies continue to develop strategies minimizing these risks, the potential for development of patient-specific regenerative therapies has become tantalizingly close. PMID:22627398

  5. Stature estimation from craniofacial anthropometry in Bangladeshi Garo adult females.

    PubMed

    Akhter, Z; Banu, L A; Alam, M M; Rahman, M F

    2012-07-01

    Estimation of stature is an important tool in forensic examination especially in unknown, highly decomposed, fragmentary and mutilated human remains. When the evidences are skeletal remains; forensic anthropology has put forward means to estimate the stature from the skeletal and even from fragmentary bones. Sometimes, craniofacial remains are brought in for forensic and postmortem examination. In such a situation, estimation of stature becomes equally important along with other parameters like age, sex, race, etc. Today, anthropometry plays an important role in industrial design, clothing design, ergonomics and architecture where statistical data about the distribution of body dimensions in the population are used to optimize products. It is well established that a single standard of craniofacial aesthetics is not appropriate for application to diverse racial and ethnic groups. Bangladesh is a country not only for the Bengalis; the country harbours many cultures and people of different races because of the colonial rules of the past regimes. Like other ethnic groups, the Garos (study subjects) have their own set of language, social structure, cultures and economic activities and religious values. In the above context, the present study was attempted to establish ethnic specific anthropometric data for the Bangladeshi Garo adult females. The study also attempted to find out the correlation of the craniofacial dimensions with stature and to determine multiplication factors. The study was an observational, cross-sectional and primarily descriptive in nature with some analytical components. The study was carried out with a total number of one hundred Garo adult females, aged between 25-45 years. Craniofacial dimension such as head circumference, head length, facial height from 'nasion' to 'gnathion', bizygomatic breadth and stature were measured using a measuring tape, spreading caliper, steel plate and steel tape and sliding caliper. The data were then statistically

  6. The chick embryo as a model for the effects of prenatal exposure to alcohol on craniofacial development.

    PubMed

    Kiecker, Clemens

    2016-07-15

    Prenatal exposure to ethanol results in fetal alcohol spectrum disorder (FASD), a syndrome characterised by a broad range of clinical manifestations including craniofacial dysmorphologies and neurological defects. The characterisation of the mechanisms by which ethanol exerts its teratogenic effects is difficult due to the pleiotropic nature of its actions. Different experimental model systems have been employed to investigate the aetiology of FASD. Here, I will review studies using these different model organisms that have helped to elucidate how ethanol causes the craniofacial abnormalities characteristic of FASD. In these studies, ethanol was found to impair the prechordal plate-an important embryonic signalling centre-during gastrulation and to negatively affect the induction, migration and survival of the neural crest, a cell population that generates the cartilage and most of the bones of the skull. At the cellular level, ethanol appears to inhibit Sonic hedgehog signalling, alter levels of retionoic acid activity, trigger a Ca(2+)-CamKII-dependent pathway that antagonises WNT signalling, affect cytoskeletal dynamics and increase oxidative stress. Embryos of the domestic chick Gallus gallus domesticus have played a central role in developing a working model for the effects of ethanol on craniofacial development because they are easily accessible and because key steps in craniofacial development are particularly well established in the avian embryo. I will finish this review by highlighting some potential future avenues of fetal alcohol research. PMID:26777098

  7. Genomic factors that shape craniofacial outcome and neural crest vulnerability in FASD

    PubMed Central

    Smith, Susan M.; Garic, Ana; Berres, Mark E.; Flentke, George R.

    2014-01-01

    Prenatal alcohol exposure (PAE) causes distinctive facial characteristics in some pregnancies and not others; genetic factors may contribute to this differential vulnerability. Ethanol disrupts multiple events of neural crest development, including induction, survival, migration, and differentiation. Animal models and genomic approaches have substantially advanced our understanding of the mechanisms underlying these facial changes. PAE during gastrulation produces craniofacial changes corresponding with human fetal alcohol syndrome. These result because PAE reduces prechordal plate extension and suppresses sonic hedgehog, leading to holoprosencephaly and malpositioned facial primordia. Haploinsufficiency in sonic hedgehog signaling increases vulnerability to facial deficits and may influence some PAE pregnancies. In contrast, PAE during early neurogenesis produces facial hypoplasia, preceded by neural crest reductions due to significant apoptosis. Factors mediating this apoptosis include intracellular calcium mobilization, elevated reactive oxygen species, and loss of trophic support from β-catenin/calcium, sonic hedgehog, and mTOR signaling. Genome-wide SNP analysis links PDGFRA with facial outcomes in human PAE. Multiple genomic-level comparisons of ethanol-sensitive and – resistant early embryos, in both mouse and chick, independently identify common candidate genes that may potentially modify craniofacial vulnerability, including ribosomal proteins, proteosome, RNA splicing, and focal adhesion. In summary, research using animal models with genome-level differences in ethanol vulnerability, as well as targeted loss-and gain-of-function mutants, has clarified the mechanisms mediating craniofacial change in PAE. The findings additionally suggest that craniofacial deficits may represent a gene–ethanol interaction for some affected individuals. Genetic-level changes may prime individuals toward greater sensitivity or resistance to ethanol’s neurotoxicity

  8. Genomic factors that shape craniofacial outcome and neural crest vulnerability in FASD.

    PubMed

    Smith, Susan M; Garic, Ana; Berres, Mark E; Flentke, George R

    2014-01-01

    Prenatal alcohol exposure (PAE) causes distinctive facial characteristics in some pregnancies and not others; genetic factors may contribute to this differential vulnerability. Ethanol disrupts multiple events of neural crest development, including induction, survival, migration, and differentiation. Animal models and genomic approaches have substantially advanced our understanding of the mechanisms underlying these facial changes. PAE during gastrulation produces craniofacial changes corresponding with human fetal alcohol syndrome. These result because PAE reduces prechordal plate extension and suppresses sonic hedgehog, leading to holoprosencephaly and malpositioned facial primordia. Haploinsufficiency in sonic hedgehog signaling increases vulnerability to facial deficits and may influence some PAE pregnancies. In contrast, PAE during early neurogenesis produces facial hypoplasia, preceded by neural crest reductions due to significant apoptosis. Factors mediating this apoptosis include intracellular calcium mobilization, elevated reactive oxygen species, and loss of trophic support from β-catenin/calcium, sonic hedgehog, and mTOR signaling. Genome-wide SNP analysis links PDGFRA with facial outcomes in human PAE. Multiple genomic-level comparisons of ethanol-sensitive and - resistant early embryos, in both mouse and chick, independently identify common candidate genes that may potentially modify craniofacial vulnerability, including ribosomal proteins, proteosome, RNA splicing, and focal adhesion. In summary, research using animal models with genome-level differences in ethanol vulnerability, as well as targeted loss-and gain-of-function mutants, has clarified the mechanisms mediating craniofacial change in PAE. The findings additionally suggest that craniofacial deficits may represent a gene-ethanol interaction for some affected individuals. Genetic-level changes may prime individuals toward greater sensitivity or resistance to ethanol's neurotoxicity. PMID

  9. Using 501c3 Foundations in the Care of Cleft and Craniofacial Children.

    PubMed

    Smith, Kevin S; Henry, Byron T

    2016-05-01

    This article relates to the use of 501c3 foundations in the care of patients with cleft and craniofacial disorders. Both authors are medical directors and founders of foundations that serve these children: A Smile for a Child Foundation was set up to help children locally; Free to Smile was set up as an international missions foundation. This article explores the advantages and disadvantages of each type of foundation as well as the struggles and successes foundations face to help children locally and internationally. PMID:27150307

  10. Translational genetic approaches to substance use disorders: bridging the gap between mice and humans

    PubMed Central

    Palmer, Abraham A.; de Wit, Harriet

    2012-01-01

    While substance abuse disorders only occur in humans, mice and other model organisms can make valuable contributions to genetic studies of these disorders. In this review, we consider a few specific examples of how model organisms have been used in conjunction with studies in humans to study the role of genetic factors in substance use disorders. In some examples genes that were first discovered in mice were subsequently studied in humans. In other examples genes or specific polymorphisms in genes were first studied in humans and then modeled in mice. Using anatomically and temporally specific genetic, pharmacological and other environmental manipulations in conjunction with histological analyses, mechanistic insights that would be difficult to obtain in humans have been obtained in mice. We hope these examples illustrate how novel biological insights about the effect of genes on substance use disorders can be obtained when mouse and human genetic studies are successfully integrated. PMID:22170288

  11. Pacific Craniofacial Team and Cleft Prevention Program.

    PubMed

    Tolarová, Marie M; Poulton, Donald; Aubert, Maryse M; Oh, HeeSoo; Ellerhorst, Thomas; Mosby, Terezie; Tolar, Miroslav; Boyd, Robert L

    2006-10-01

    There is no doubt modern genetics have greatly influenced our professional and personal lives during the last decade. Uncovering genetic causes of many medical and dental pathologies is helping to narrow the diagnosis and select a treatment plan that would provide the best outcome. Importantly, having an understanding of multifactorial etiology helps direct our attention toward prevention. We now understand much better our own health problems. In some cases, we can modify our lifestyle and diet in order to prevent "environmental factors" from triggering the mutated genes inherited from our parents. Good examples are diabetes and cardiovascular diseases. If we realize we might have inherited genes for cardiovascular problems from several ancestors who had heart attacks, we already know that these genes will make us only "susceptible" for disease. Those who exercise, watch one's weight, diet, and carefully monitor one's lifestyle will very likely--though possessing "susceptibility genes"--stay healthier and, maybe, will never experience any cardiovascular problems. In principle, the same applies for craniofacial anomalies, especially for nonsyndromic cleft lip and palate. One needs to understand genetic and environmental causes of nonsyndromic orofacial clefts in order to prevent them. With all this in mind, the Pacific Craniofacial Team and Cleft Prevention Program have been established at the Department of Orthodontics, University of the Pacific Arthur A. Dugoni School of Dentistry in San Francisco. A partnership with Rotaplast International, Inc., has made it possible for the faculty, orthodontic residents, and students to participate in 27 multidisciplinary cleft medical missions in underdeveloped and developing countries by donating professional and educational services, and, last but not least, by collecting valuable data and specimens to further research. A significant number of research studies, including 15 master of science theses, have been accomplished in

  12. In vivo impact of Dlx3 conditional inactivation in Neural Crest-Derived Craniofacial Bones

    PubMed Central

    Duverger, Olivier; Isaac, Juliane; Zah, Angela; Hwang, Joonsung; Berdal, Ariane; Lian, Jane B.; Morasso, Maria I.

    2012-01-01

    Mutations in DLX3 in humans lead to defects in craniofacial and appendicular bones, yet the in vivo activity related to Dlx3 function during normal skeletal development have not been fully elucidated. Here we used a conditional knockout approach to analyze the effects of neural crest deletion of Dlx3 on craniofacial bones development. At birth, mutant mice exhibit a normal overall positioning of the skull bones, but a change in the shape of the calvaria was observed. Molecular analysis of the genes affected in the frontal bones and mandibles from these mice identified several bone markers known to affect bone development, with a strong prediction for increased bone formation and mineralization in vivo. Interestingly, while a subset of these genes were similarly affected in frontal bones and mandibles (Sost, Mepe, Bglap, Alp, Ibsp, Agt), several genes, including Lect1 and Calca, were specifically affected in frontal bones. Consistent with these molecular alterations, cells isolated from the frontal bone of mutant mice exhibited increased differentiation and mineralization capacities ex vivo, supporting cell autonomous defects in neural crest cells. However, adult mutant animals exhibited decreased bone mineral density in both mandibles and calvaria, as well as a significant increase in bone porosity. Together, these observations suggest that mature osteoblasts in the adult respond to signals that regulate adult bone mass and remodeling. This study provides new downstream targets for Dlx3 in craniofacial bone, and gives additional evidence of the complex regulation of bone formation and homeostasis in the adult skeleton. PMID:22886599

  13. In vivo impact of Dlx3 conditional inactivation in neural crest-derived craniofacial bones.

    PubMed

    Duverger, Olivier; Isaac, Juliane; Zah, Angela; Hwang, Joonsung; Berdal, Ariane; Lian, Jane B; Morasso, Maria I

    2013-03-01

    Mutations in DLX3 in humans lead to defects in craniofacial and appendicular bones, yet the in vivo activities related to Dlx3 function during normal skeletal development have not been fully elucidated. Here we used a conditional knockout approach to analyze the effects of neural crest deletion of Dlx3 on craniofacial bones development. At birth, mutant mice exhibit a normal overall positioning of the skull bones, but a change in the shape of the calvaria was observed. Molecular analysis of the genes affected in the frontal bones and mandibles from these mice identified several bone markers known to affect bone development, with a strong prediction for increased bone formation and mineralization in vivo. Interestingly, while a subset of these genes were similarly affected in frontal bones and mandibles (Sost, Mepe, Bglap, Alp, Ibsp, Agt), several genes, including Lect1 and Calca, were specifically affected in frontal bones. Consistent with these molecular alterations, cells isolated from the frontal bone of mutant mice exhibited increased differentiation and mineralization capacities ex vivo, supporting cell autonomous defects in neural crest cells. However, adult mutant animals exhibited decreased bone mineral density in both mandibles and calvaria, as well as a significant increase in bone porosity. Together, these observations suggest that mature osteoblasts in the adult respond to signals that regulate adult bone mass and remodeling. This study provides new downstream targets for Dlx3 in craniofacial bone, and gives additional evidence of the complex regulation of bone formation and homeostasis in the adult skeleton. PMID:22886599

  14. Face Scanning in Autism Spectrum Disorder and Attention Deficit/Hyperactivity Disorder: Human Versus Dog Face Scanning

    PubMed Central

    Muszkat, Mauro; de Mello, Claudia Berlim; Muñoz, Patricia de Oliveira Lima; Lucci, Tania Kiehl; David, Vinicius Frayze; Siqueira, José de Oliveira; Otta, Emma

    2015-01-01

    This study used eye tracking to explore attention allocation to human and dog faces in children and adolescents with autism spectrum disorder (ASD), attention deficit/hyperactivity disorder (ADHD), and typical development (TD). Significant differences were found among the three groups. TD participants looked longer at the eyes than ASD and ADHD ones, irrespective of the faces presented. In spite of this difference, groups were similar in that they looked more to the eyes than to the mouth areas of interest. The ADHD group gazed longer at the mouth region than the other groups. Furthermore, groups were also similar in that they looked more to the dog than to the human faces. The eye-tracking technology proved to be useful for behavioral investigation in different neurodevelopmental disorders. PMID:26557097

  15. Reforming craniofacial orthodontics via stem cells

    PubMed Central

    Mohanty, Pritam; Prasad, N.K.K.; Sahoo, Nivedita; Kumar, Gunjan; Mohanty, Debapreeti; Sah, Sushila

    2015-01-01

    Stem cells are the most interesting cells in cell biology. They have the potential to evolve as one of the most powerful technologies in the future. The future refers to an age where it will be used extensively in various fields of medical and dental sciences. Researchers have discovered a number of sources from which stem cells can be derived. Craniofacial problems are very common and occur at all ages. Stem cells can be used therapeutically in almost every field of health science. In fact, many procedures will be reformed after stem cells come into play. This article is an insight into the review of the current researches being carried out on stem cells and its use in the field of orthodontics, which is a specialized branch of dentistry. Although the future is uncertain, there is a great possibility that stem cells will be used extensively in almost all major procedures of orthodontics. PMID:25767761

  16. Application of Digital Anthropometry for Craniofacial Assessment

    PubMed Central

    Jayaratne, Yasas S. N.; Zwahlen, Roger A.

    2014-01-01

    Craniofacial anthropometry is an objective technique based on a series of measurements and proportions, which facilitate the characterization of phenotypic variation and quantification of dysmorphology. With the introduction of stereophotography, it is possible to acquire a lifelike three-dimensional (3D) image of the face with natural color and texture. Most of the traditional anthropometric landmarks can be identified on these 3D photographs using specialized software. Therefore, it has become possible to compute new digital measurements, which were not feasible with traditional instruments. The term “digital anthropometry” has been used by researchers based on such systems to separate their methods from conventional manual measurements. Anthropometry has been traditionally used as a research tool. With the advent of digital anthropometry, this technique can be employed in several disciplines as a noninvasive tool for quantifying facial morphology. The aim of this review is to provide a broad overview of digital anthropometry and discuss its clinical applications. PMID:25050146

  17. The Dlx5 and Dlx6 homeobox genes are essential for craniofacial, axial, and appendicular skeletal development.

    PubMed

    Robledo, Raymond F; Rajan, Lakshmi; Li, Xue; Lufkin, Thomas

    2002-05-01

    Dlx homeobox genes are mammalian homologs of the Drosophila Distal-less (Dll) gene. The Dlx/Dll gene family is of ancient origin and appears to play a role in appendage development in essentially all species in which it has been identified. In Drosophila, Dll is expressed in the distal portion of the developing appendages and is critical for the development of distal structures. In addition, human Dlx5 and Dlx6 homeobox genes have been identified as possible candidate genes for the autosomal dominant form of the split-hand/split-foot malformation (SHFM), a heterogeneous limb disorder characterized by missing central digits and claw-like distal extremities. Targeted inactivation of Dlx5 and Dlx6 genes in mice results in severe craniofacial, axial, and appendicular skeletal abnormalities, leading to perinatal lethality. For the first time, Dlx/Dll gene products are shown to be critical regulators of mammalian limb development, as combined loss-of-function mutations phenocopy SHFM. Furthermore, spatiotemporal-specific transgenic overexpression of Dlx5, in the apical ectodermal ridge of Dlx5/6 null mice can fully rescue Dlx/Dll function in limb outgrowth. PMID:12000792

  18. The eye as an organizer of craniofacial development

    PubMed Central

    Kish, Phillip E.; Bohnsack, Brenda L; Gallina, Donika D.; Kasprick, Daniel S.

    2013-01-01

    The formation and invagination of the optic stalk coincides with the migration of cranial neural crest (CNC) cells, and a growing body of data reveals that the optic stalk and CNC cells communicate to lay the foundations for periocular and craniofacial development. Following migration, the interaction between the developing eye and surrounding periocular mesenchyme (POM) continues, leading to induction of transcriptional regulatory cascades that regulate craniofacial morphogenesis. Studies in chick, mice and zebrafish have revealed a remarkable level of genetic and mechanistic conservation, affirming the power of each animal model to shed light on the broader morphogenic process. This review will focus on the role of the developing eye in orchestrating craniofacial morphogenesis, utilizing morphogenic gradients, paracrine signaling, and transcriptional regulatory cascades to establish an evolutionarily-conserved facial architecture. We propose that in addition to the forebrain, the eye functions during early craniofacial morphogenesis as a key organizer of facial development, independent of its role in vision. PMID:21309065

  19. Impact of Stem Cells in Craniofacial Regenerative Medicine

    PubMed Central

    Sanchez-Lara, Pedro A.; Zhao, Hu; Bajpai, Ruchi; Abdelhamid, Alaa I.; Warburton, David

    2012-01-01

    Interest regarding stem cell based therapies for the treatment of congenital or acquired craniofacial deformities is rapidly growing. Craniofacial problems such as periodontal disease, cleft lip and palate, ear microtia, craniofacial microsomia, and head and neck cancers are not only common but also some of the most burdensome surgical problems worldwide. Treatments often require a multi-staged multidisciplinary team approach. Current surgical therapies attempt to reduce the morbidity and social/emotional impact, yet outcomes can still be unpredictable and unsatisfactory. The concept of harvesting stem cells followed by expansion, differentiation, seeding onto a scaffold and re-transplanting them is likely to become a clinical reality. In this review, we will summarize the translational applications of stem cell therapy in tissue regeneration for craniofacial defects. PMID:22737127

  20. [Personal identification using information from cranio-facial region].

    PubMed

    Minaguchi, Kiyoshi

    2007-11-01

    Much of Forensic Odontology is concerned with personal identification, through examination of cranio-facial region. This paper describes several studies in which we worked with materials derived from cranio-facial region. The following topics are addressed : (1) Human saliva contains proteins specific to salivary glands, proteins which are highly polymorphic compared with those found in other body fluids. In particular, six genes for proline-rich proteins coded many proteins found in human saliva, and we found several of them. At least five kinds of cystatin are secreted in saliva. We constructed recombinant polymorphic proteins, cystatin SAl and SA2. Using these proteins, we compared effects of amino acid mutation on protease inhibitor activity, and demonstrated a novel function for type-2 cystatin cytokine-inducing activity. (2) Among autosomal STR loci, we identified the D12S67 locus as highly polymorphic, with a heterozygosity of 95%, by investigating differences in nucleotide repeat units. Highly polymorphic autosomal STR loci offer an effective forensic tool under certain conditions, in addition to multiplex PCR, and therefore merit further study in forensic practice. (3) Although digitalization is prevalent in photography, analog images are preferable in certain circumstances as they offer better resolution. (4) Usually, information on mtDNA polymorphisms from HV1 and HV2 in the control region is used in forensic practice. However, information from the coding region considerably increases the discrimination power of mtDNA polymorphisms. It is important to increase the volume of coding region information available with regard to mtDNA polymorphisms for future forensic practice. (5) Y-STR polymorphisms are closely associated with binary haplogroups, and it is possible to estimate a binary haplogroup from an STR haplotype. (6) Mitochondrial DNA and Y-chromosomal polymorphisms can be used to determine geographic origin in individuals from East Asia, something

  1. Normalized Shape and Location of Perturbed Craniofacial Structures in the Xenopus Tadpole Reveal an Innate Ability to Achieve Correct Morphology

    PubMed Central

    Vandenberg, Laura N.; Adams, Dany S.; Levin, Michael

    2012-01-01

    Background Embryonic development can often adjust its morphogenetic processes to counteract external perturbation. The existence of self-monitoring responses during pattern formation is of considerable importance to the biomedicine of birth defects, but has not been quantitatively addressed. To understand the computational capabilities of biological tissues in a molecularly-tractable model system, we induced craniofacial defects in Xenopus embryos, then tracked tadpoles with craniofacial deformities and used geometric morphometric techniques to characterize changes in the shape and position of the craniofacial structures. Results Canonical variate analysis revealed that the shapes and relative positions of perturbed jaws and branchial arches were corrected during the first few months of tadpole development. Analysis of the relative movements of the anterior-most structures indicates that misplaced structures move along the anterior-posterior and left-right axes in ways that are significantly different from their normal movements. Conclusions Our data suggest a model in which craniofacial structures utilize a measuring mechanism to assess and adjust their location relative to other local organs. Understanding the correction mechanisms at work in this system could lead to the better understanding of the adaptive decision-making capabilities of living tissues and suggest new approaches to correct birth defects in humans. PMID:22411736

  2. Adult psychological functioning of individuals born with craniofacial anomalies.

    PubMed

    Sarwer, D B; Bartlett, S P; Whitaker, L A; Paige, K T; Pertschuk, M J; Wadden, T A

    1999-02-01

    This study represents an initial investigation into the adult psychological functioning of individuals born with craniofacial disfigurement. A total of 24 men and women born with a craniofacial anomaly completed paper and pencil measures of body image dissatisfaction, self-esteem, quality of life, and experiences of discrimination. An age- and gender-matched control group of 24 non-facially disfigured adults also completed the measures. As expected, craniofacially disfigured adults reported greater dissatisfaction with their facial appearance than did the control group. Craniofacially disfigured adults also reported significantly lower levels of self-esteem and quality of life. Dissatisfaction with facial appearance, self-esteem, and quality of life were related to self-ratings of physical attractiveness. More than one-third of craniofacially disfigured adults (38 percent) reported experiences of discrimination in employment or social settings. Among disfigured adults, psychological functioning was not related to number of surgeries, although the degree of residual facial deformity was related to increased dissatisfaction with facial appearance and greater experiences of discrimination. Results suggest that adults who were born with craniofacial disfigurement, as compared with non-facially disfigured adults, experience greater dissatisfaction with facial appearance and lower self-esteem and quality of life; however, these experiences do not seem to be universal. PMID:9950526

  3. The Aponeurotic Tension Model of Craniofacial Growth in Man

    PubMed Central

    Standerwick, Richard G; Roberts, W. Eugene

    2009-01-01

    Craniofacial growth is a scientific crossroad for the fundamental mechanisms of musculoskeletal physiology. Better understanding of growth and development will provide new insights into repair, regeneration and adaptation to applied loads. Traditional craniofacial growth concepts are insufficient to explain the dynamics of airway/vocal tract development, cranial rotation, basicranial flexion and the role of the cranial base in expression of facial proportions. A testable hypothesis is needed to explore the physiological pressure propelling midface growth and the role of neural factors in expression of musculoskeletal adaptation after the cessation of anterior cranial base growth. A novel model for craniofacial growth is proposed for: 1. brain growth and craniofacial adaptation up to the age of 20; 2. explaining growth force vectors; 3. defining the role of muscle plasticity as a conduit for craniofacial growth forces; and 4. describing the effect of cranial rotation in the expression of facial form. Growth of the viscerocranium is believed to be influenced by the superficial musculoaponeurotic systems (SMAS) of the head through residual tension in the occipitofrontalis muscle as a result of cephalad brain growth and cranial rotation. The coordinated effects of the regional SMAS develop a craniofacial musculoaponeurotic system (CFMAS), which is believed to affect maxillary and mandibular development. PMID:19572022

  4. Antimicrobial surfaces for craniofacial implants: state of the art

    PubMed Central

    Actis, Lisa; Gaviria, Laura; Guda, Teja

    2013-01-01

    In an attempt to regain function and aesthetics in the craniofacial region, different biomaterials, including titanium, hydroxyapatite, biodegradable polymers and composites, have been widely used as a result of the loss of craniofacial bone. Although these materials presented favorable success rates, osseointegration and antibacterial properties are often hard to achieve. Although bone-implant interactions are highly dependent on the implant's surface characteristics, infections following traumatic craniofacial injuries are common. As such, poor osseointegration and infections are two of the many causes of implant failure. Further, as increasingly complex dental repairs are attempted, the likelihood of infection in these implants has also been on the rise. For these reasons, the treatment of craniofacial bone defects and dental repairs for long-term success remains a challenge. Various approaches to reduce the rate of infection and improve osseointegration have been investigated. Furthermore, recent and planned tissue engineering developments are aimed at improving the implants' physical and biological properties by improving their surfaces in order to develop craniofacial bone substitutes that will restore, maintain and improve tissue function. In this review, the commonly used biomaterials for craniofacial bone restoration and dental repair, as well as surface modification techniques, antibacterial surfaces and coatings are discussed. PMID:24471018

  5. Neutral versus Emotional Human Stimuli Processing in Children with Pervasive Developmental Disorders not Otherwise Specified

    ERIC Educational Resources Information Center

    Vannetzel, Leonard; Chaby, Laurence; Cautru, Fabienne; Cohen, David; Plaza, Monique

    2011-01-01

    Pervasive developmental disorder not otherwise specified (PDD-NOS) represents up to two-thirds of autism spectrum disorders; however, it is usually described in terms of the symptoms not shared by autism. The study explores processing of neutral and emotional human stimuli (by auditory, visual and multimodal channels) in children with PDD-NOS (n =…

  6. The Ticking Clock of Cayo Santiago Macaques and Its Implications for Understanding Human Circadian Rhythm Disorders

    PubMed Central

    Rogers, Jeffrey; Gonzalez-Martinez, Janis; Farrer, Lindsay A.

    2016-01-01

    The circadian clock disorders in humans remain poorly understood. However, their impact on the development and progression of major human conditions, from cancer to insomnia, metabolic or mental illness becomes increasingly apparent. Addressing human circadian disorders in animal models is, in part, complicated by inverse temporal relationship between the core clock and specific physiological or behavioral processes in diurnal and nocturnal animals. Major advantages of a macaque model for translational circadian research, as a diurnal vertebrate phylogenetically close to humans, are further emphasized by the discovery of the first familial circadian disorder in non-human primates among the rhesus monkeys originating from Cayo Santiago. The remarkable similarity of their pathological phenotypes to human Delayed Sleep Phase Disorder (DSPD), high penetrance of the disorder within one branch of the colony and the large number of animals available provide outstanding opportunities for studying the mechanisms of circadian disorders, their impact on other pathological conditions, and for the development of novel and effective treatment strategies. PMID:25940511

  7. Animal Models of Psychiatric Disorders That Reflect Human Copy Number Variation

    PubMed Central

    Nomura, Jun; Takumi, Toru

    2012-01-01

    The development of genetic technologies has led to the identification of several copy number variations (CNVs) in the human genome. Genome rearrangements affect dosage-sensitive gene expression in normal brain development. There is strong evidence associating human psychiatric disorders, especially autism spectrum disorders (ASDs) and schizophrenia to genetic risk factors and accumulated CNV risk loci. Deletions in 1q21, 3q29, 15q13, 17p12, and 22q11, as well as duplications in 16p11, 16p13, and 15q11-13 have been reported as recurrent CNVs in ASD and/or schizophrenia. Chromosome engineering can be a useful technology to reflect human diseases in animal models, especially CNV-based psychiatric disorders. This system, based on the Cre/loxP strategy, uses large chromosome rearrangement such as deletion, duplication, inversion, and translocation. Although it is hard to reflect human pathophysiology in animal models, some aspects of molecular pathways, brain anatomy, cognitive, and behavioral phenotypes can be addressed. Some groups have created animal models of psychiatric disorders, ASD, and schizophrenia, which are based on human CNV. These mouse models display some brain anatomical and behavioral abnormalities, providing insight into human neuropsychiatric disorders that will contribute to novel drug screening for these devastating disorders. PMID:22900207

  8. Cloning, characterization, localization, and mutational screening of the human BARX1 gene.

    PubMed

    Gould, D B; Walter, M A

    2000-09-15

    The Bar subclass of homeodomain proteins was first identified for its role in Drosophila eye development. The Bar subclass homolog, Barx1, has since been cloned in mouse and in chick. The expression of Barx1 in developing teeth and craniofacial mesenchyme of neural crest origin makes it a strong candidate for the related human disorders of Axenfeld-Reiger syndrome (ARS) and iridogoniodysgenesis syndrome (IGDS). Here we report the cloning and characterization of a novel human Bar class gene, human BARX1. Screening of a human fetal craniofacial library resulted in the isolation of a 1.6-kb full-length transcript. Sequence analysis indicated that human BARX1, mouse Barx1, and chick Barx1 show 100% identity at the amino acid level within their homeodomains. Human BARX1 is expressed in a number of tissues including testis and heart by Northern analysis and in iris and craniofacial tissues by PCR of cDNA libraries. BARX1 chromosomal localization to 9q12 was determined by radiation hybrid mapping. Intron/exon boundaries were established, and primers were generated to PCR amplify all four exons. A mutation screen was conducted in 55 patients affected with ARS, IGDS, or related ocular malformations. While six sequence polymorphisms were detected, no disease-causing mutations of BARX1 were observed. PMID:10995576

  9. Autism Spectrum Disorders: Translating human deficits into mouse behavior.

    PubMed

    Pasciuto, E; Borrie, S C; Kanellopoulos, A K; Santos, A R; Cappuyns, E; D'Andrea, L; Pacini, L; Bagni, C

    2015-10-01

    Autism Spectrum Disorders are a heterogeneous group of neurodevelopmental disorders, with rising incidence but little effective therapeutic intervention available. Currently two main clinical features are described to diagnose ASDs: impaired social interaction and communication, and repetitive behaviors. Much work has focused on understanding underlying causes of ASD by generating animal models of the disease, in the hope of discovering signaling pathways and cellular targets for drug intervention. Here we review how ASD behavioral phenotypes can be modeled in the mouse, the most common animal model currently in use in this field, and discuss examples of genetic mouse models of ASD with behavioral features that recapitulate various symptoms of ASD. PMID:26220900

  10. The bite force and craniofacial morphology in patients with acromegaly: A pilot study

    PubMed Central

    Aktas-Yılmaz, Banu; Dogan, Arife; Yetkin, Ilhan; Bek, Bulent

    2014-01-01

    Objectives: Acromegaly is a metabolic disorder caused by increased growth hormone secretion. As a consequence of acromegaly some typical craniofacial morphology changes appear. This pilot study was conducted to compare the bite force and the characteristic size and shape of the craniofacial components of acromegalic patients with the healthy Turkish individuals. In additon, the correlations between bite force and craniofacial morphology of patients with acromegaly and control individuals were evaluated. Study Design: The maximum bite force of the participants was recorded with strain-gage transducer. Lateral x-ray scans were made under standard conditions, in centric occlusion. On cephalograms, the linear and angular measurements was performed. Results: Patients with acromegaly showed increased anterior and posterior total face height, ramus length, width of frontal sinuse, gonial angle and a negative difference between maxillary and mandibular protrusions. In addition, females with acromegaly showed larger lower anterior face height and sella turcica, decreased facial angle, increased mandibular plane angle. The cephalometric measurements, except one did not showed correlation with the bite force in acromegalic patients. In control group, significant correlations were observed between anterior total face height and anterior lower face height, mandibular plane angle and gonial angle. Conclusions: The greater changes were observed in the mandible. The maximum bite force of patients with acromegaly showed no difference from healthy individuals. The non-significant difference of bite force between healthy participants and acromegalic patients provide important information for dental treatment and prosthetic rehabilitation of acromegalic patients. Key words:Acromegaly, bite force, cephalometric analysis, mandibular prognathism. PMID:23986010

  11. Human Sexual Desire Disorder: Do We Have a Problem?

    ERIC Educational Resources Information Center

    McNab, Warren L.; Henry, Jean

    2006-01-01

    Hypoactive Sexual Desire Disorder (HSDD), loss of sexual desire for sexual activity, is one of the most common sexual dysfunctions of men and women in the United States. This article presents an overview of this specific sexual dysfunction including incidence, possible causes, treatment options, and the role of the health educator in addressing…

  12. Morphometrics, 3D Imaging, and Craniofacial Development.

    PubMed

    Hallgrimsson, Benedikt; Percival, Christopher J; Green, Rebecca; Young, Nathan M; Mio, Washington; Marcucio, Ralph

    2015-01-01

    Recent studies have shown how volumetric imaging and morphometrics can add significantly to our understanding of morphogenesis, the developmental basis for variation, and the etiology of structural birth defects. On the other hand, the complex questions and diverse imaging data in developmental biology present morphometrics with more complex challenges than applications in virtually any other field. Meeting these challenges is necessary in order to understand the mechanistic basis for variation in complex morphologies. This chapter reviews the methods and theory that enable the application of modern landmark-based morphometrics to developmental biology and craniofacial development, in particular. We discuss the theoretical foundations of morphometrics as applied to development and review the basic approaches to the quantification of morphology. Focusing on geometric morphometrics, we discuss the principal statistical methods for quantifying and comparing morphological variation and covariation structure within and among groups. Finally, we discuss the future directions for morphometrics in developmental biology that will be required for approaches that enable quantitative integration across the genotype-phenotype map. PMID:26589938

  13. Applying Craniofacial Principles to Neurosurgical Exposures in Cerebrovascular Aneurysm Repair.

    PubMed

    Alperovich, Michael; Frey, Jordan D; Potts, Matthew B; Riina, Howard A; Staffenberg, David A

    2016-06-01

    The subspecialty of craniofacial surgery emphasizes skeletal exposure, preservation of critical structures, and provision of a superior cosmetic result. In recent decades, an emphasis on minimally invasive neurosurgical exposure has paved the way for increased collaboration between neurosurgeons and craniofacial surgeons.The 1990s saw the growing popularity of an eyebrow incision for orbital roof craniotomies in neurosurgery to address lesions in the anterior skull base. Disadvantages of this approach included conspicuous scarring above the brow skin, risk of injury to the frontal branch of the facial nerve, and numbness from supraorbital or supratrochlear nerve transection.A transpalpebral approach was first described in 2008 in the neurosurgical literature. An approach familiar to the craniofacial surgeon, transpalpebral exposure is used for zygomaticomaxillary complex fractures as well as aesthetic brow and periorbital surgery.In conjunction with neurosurgery, the authors have applied craniofacial principles to address the major pitfalls of the transpalpebral craniotomy. The authors present their patient series experience. Hopefully, in the future, other institutions will have increased collaboration between craniofacial surgeons and neurosurgeons. PMID:27192638

  14. Zebrafish Craniofacial Development: A Window into Early Patterning

    PubMed Central

    Mork, Lindsey; Crump, Gage

    2016-01-01

    The formation of the face and skull involves a complex series of developmental events mediated by cells derived from the neural crest, endoderm, mesoderm, and ectoderm. Although vertebrates boast an enormous diversity of adult facial morphologies, the fundamental signaling pathways and cellular events that sculpt the nascent craniofacial skeleton in the embryo have proven to be highly conserved from fish to man. The zebrafish Danio rerio, a small freshwater cyprinid fish from eastern India, has served as a popular model of craniofacial development since the 1990s. Unique strengths of the zebrafish model include a simplified skeleton during larval stages, access to rapidly developing embryos for live imaging, and amenability to transgenesis and complex genetics. In this chapter, we describe the anatomy of the zebrafish craniofacial skeleton; its applications as models for the mammalian jaw, middle ear, palate, and cranial sutures; the superior imaging technology available in fish that has provided unprecedented insights into the dynamics of facial morphogenesis; the use of the zebrafish to decipher the genetic underpinnings of craniofacial biology; and finally a glimpse into the most promising future applications of zebrafish craniofacial research. PMID:26589928

  15. Genetic Analysis of Craniofacial Traits in the Medaka

    PubMed Central

    Kimura, Tetsuaki; Shimada, Atsuko; Sakai, Noriyoshi; Mitani, Hiroshi; Naruse, Kiyoshi; Takeda, Hiroyuki; Inoko, Hidetoshi; Tamiya, Gen; Shinya, Minori

    2007-01-01

    Family and twin studies suggest that a substantial genetic component underlies individual differences in craniofacial morphology. In the current study, we quantified 444 craniofacial traits in 100 individuals from two inbred medaka (Oryzias latipes) strains, HNI and Hd-rR. Relative distances between defined landmarks were measured in digital images of the medaka head region. A total of 379 traits differed significantly between the two strains, indicating that many craniofacial traits are controlled by genetic factors. Of these, 89 traits were analyzed via interval mapping of 184 F2 progeny from an intercross between HNI and Hd-rR. We identified quantitative trait loci for 66 craniofacial traits. The highest logarithm of the odds score was 6.2 for linkage group (LG) 9 and 11. Trait L33, which corresponds to the ratio of head length to head height at eye level, mapped to LG9; trait V15, which corresponds to the ratio of snout length to head width measured behind the eyes, mapped to LG11. Our initial results confirm the potential of the medaka as a model system for the genetic analysis of complex traits such as craniofacial morphology. PMID:18073435

  16. Cranio-facial clefts in pre-hispanic America.

    PubMed

    Marius-Nunez, A L; Wasiak, D T

    2015-10-01

    Among the representations of congenital malformations in Moche ceramic art, cranio-facial clefts have been portrayed in pottery found in Moche burials. These pottery vessels were used as domestic items during lifetime and funerary offerings upon death. The aim of this study was to examine archeological evidence for representations of cranio-facial cleft malformations in Moche vessels. Pottery depicting malformations of the midface in Moche collections in Lima-Peru were studied. The malformations portrayed on pottery were analyzed using the Tessier classification. Photographs were authorized by the Larco Museo.Three vessels were observed to have median cranio-facial dysraphia in association with midline cleft of the lower lip with cleft of the mandible. ML001489 portrays a median cranio-facial dysraphia with an orbital cleft and a midline cleft of the lower lip extending to the mandible. ML001514 represents a median facial dysraphia in association with an orbital facial cleft and a vertical orbital dystopia. ML001491 illustrates a median facial cleft with a soft tissue cleft. Three cases of midline, orbital and lateral facial clefts have been portrayed in Moche full-figure portrait vessels. They represent the earliest registries of congenital cranio-facial malformations in ancient Peru. PMID:26010214

  17. Emotion Recognition in Animated Compared to Human Stimuli in Adolescents with Autism Spectrum Disorder

    ERIC Educational Resources Information Center

    Brosnan, Mark; Johnson, Hilary; Grawmeyer, Beate; Chapman, Emma; Benton, Laura

    2015-01-01

    There is equivocal evidence as to whether there is a deficit in recognising emotional expressions in Autism spectrum disorder (ASD). This study compared emotion recognition in ASD in three types of emotion expression media (still image, dynamic image, auditory) across human stimuli (e.g. photo of a human face) and animated stimuli (e.g. cartoon…

  18. Puberty as a critical risk period for eating disorders: a review of human and animal studies.

    PubMed

    Klump, Kelly L

    2013-07-01

    This article is part of a Special Issue "Puberty and Adolescence". Puberty is one of the most frequently discussed risk periods for the development of eating disorders. Prevailing theories propose environmentally mediated sources of risk arising from the psychosocial effects (e.g., increased body dissatisfaction, decreased self-esteem) of pubertal development in girls. However, recent research highlights the potential role of ovarian hormones in phenotypic and genetic risk for eating disorders during puberty. The goal of this paper is to review data from human and animal studies in support of puberty as a critical risk period for eating disorders and evaluate the evidence for hormonal contributions. Data are consistent in suggesting that both pubertal status and pubertal timing significantly impact risk for most eating disorders in girls, such that advanced pubertal development and early pubertal timing are associated with increased rates of eating disorders and their symptoms in both cross-sectional and longitudinal research. Findings in boys have been much less consistent and suggest a smaller role for puberty in risk for eating disorders in boys. Twin and animal studies indicate that at least part of the female-specific risk is due to genetic factors associated with estrogen activation at puberty. In conclusion, data thus far support a role for puberty in risk for eating disorders and highlight the need for additional human and animal studies of hormonal and genetic risk for eating disorders during puberty. PMID:23998681

  19. Cephalometric Assessment of Upper Airway Effects on Craniofacial Morphology.

    PubMed

    Ardehali, Mojtaba Mohamadi; Zarch, Varasteh Vakili; Joibari, Mohammad-Esmaeil; Kouhi, Ali

    2016-03-01

    To investigate craniofacial growth deformities in children with upper airway obstruction, this controlled study was performed. Cephalometry is used as a screening test for anatomic abnormalities in patients with obstructive sleep apnea syndrome. Therefore, the current work selected this method to investigate the effect of upper airway obstruction on craniofacial morphology.Patients with upper airway obstruction (104) were compared with 71 controls. Patients with upper airway compromise had mandibular hypoplasia, mandibular retrognathism, and higher hard palates in comparison with controls with no history of airway obstruction. The difference was higher in the older age group.Airway obstruction has significant correlation craniofacial morphology. Our findings support the idea of early assessment and thorough management of mouth breathing in children. PMID:26967073

  20. The chromatin remodeling protein CHD7, mutated in CHARGE syndrome, is necessary for proper craniofacial and tracheal development

    PubMed Central

    Sperry, Ethan D.; Hurd, Elizabeth A.; Durham, Mark A.; Reamer, Elyse N.; Stein, Adam B.; Martin, Donna M.

    2014-01-01

    Background Heterozygous mutations in the chromatin remodeling gene CHD7 cause CHARGE syndrome, a developmental disorder with variable craniofacial dysmorphisms and respiratory difficulties. The molecular etiologies of these malformations are not well understood. Homozygous Chd7 null mice die by E11, whereas Chd7Gt/+ heterozygous null mice are a viable and excellent model of CHARGE. We explored skeletal phenotypes in Chd7Gt/+ and Chd7 conditional knockout mice, using Foxg1-Cre to delete Chd7 (Foxg1-CKO) in the developing eye, ear, nose, pharyngeal pouch, forebrain, and gut and Wnt1-Cre (Wnt1-CKO) to delete Chd7 in migrating neural crest cells. Results Foxg1-CKO mice exhibited postnatal respiratory distress and death, dysplasia of the eye, concha, and frontal bone, hypoplastic maxillary shelves and nasal epithelia, and reduced tracheal rings. Wnt1-CKO mice exhibited frontal and occipital bone dysplasia, hypoplasia of the maxillary shelves and mandible, and cleft palate. In contrast, heterozygous Chd7Gt/+ mice had apparently normal skeletal development. Conclusions Conditional deletion of Chd7 in ectodermal and endodermal derivatives (Foxg1-Cre) or migrating neural crest cells (Wnt1-Cre) results in varied and more severe craniofacial defects than in Chd7Gt/+ mice. These studies indicate that CHD7 has an important, dosage-dependent role in development of several different craniofacial tissues. PMID:24975120

  1. MEPE Localization in the Craniofacial Complex and Function in Tooth Dentin Formation.

    PubMed

    Gullard, Angela; Gluhak-Heinrich, Jelica; Papagerakis, Silvana; Sohn, Philip; Unterbrink, Aaron; Chen, Shuo; MacDougall, Mary

    2016-04-01

    Matrix extracellular phosphoglycoprotein (MEPE) is an extracellular matrix protein found in dental and skeletal tissues. Although information regarding the role of MEPE in bone and disorders of phosphate metabolism is emerging, the role of MEPE in dental tissues remains unclear. We performed RNA in situ hybridization and immunohistochemistry analyses to delineate the expression pattern of MEPE during embryonic and postnatal development in craniofacial mineralizing tissues.MepeRNA expression was seen within teeth from cap through root formation in association with odontoblasts and cellular cementoblasts. More intense expression was seen in the alveolar bone within the osteoblasts and osteocytes. MEPE immunohistochemistry showed biphasic dentin staining in incisors and more intense staining in alveolar bone matrix and in forming cartilage. Analysis ofMepenull mouse molars showed overall mineralized tooth volume and density of enamel and dentin comparable with that of wild-type samples. However,Mepe(-/-)molars exhibited increased thickness of predentin, dentin, and enamel over controls and decreased gene expression ofEnam,Bsp,Dmp1,Dspp, andOpnby RT-PCR. In vitroMepeoverexpression in odontoblasts led to significant reductions inDsppreporter activity. These data suggest MEPE may be instrumental in craniofacial and dental matrix maturation, potentially functioning in the maintenance of non-mineralized matrix. PMID:26927967

  2. Alcohol use in pregnancy, craniofacial features, and fetal growth.

    PubMed Central

    Rostand, A; Kaminski, M; Lelong, N; Dehaene, P; Delestret, I; Klein-Bertrand, C; Querleu, D; Crepin, G

    1990-01-01

    STUDY OBJECTIVE--The aim was to study the relationship between the level of alcohol consumption in pregnancy and craniofacial characteristics of the neonate. DESIGN--This was a prospective survey of a sample of pregnant women, stratified on prepregnancy level of alcohol consumption. SETTING--The study was carried out at the public antenatal clinic of Roubaix maternity hospital. PARTICIPANTS--During an eight month period, 684 women (89% of those eligible) were interviewed in a standardised way at their first antenatal clinic visit. Of these, all who were suspected of being alcoholic or heavy drinkers (at least 21 drinks per week) were selected for follow up, as was a subsample of light (0-6 drinks per week) and moderate (7-20 drinks per week) drinkers. Of 347 women selected in this way, 202 had their infants assessed by a standardised morphological examination. MEASUREMENTS AND AND MAIN RESULTS--Suggestive craniofacial characteristics of the infants, present either in isolation or in association with growth retardation ("fetal alcohol effects"), were compared in relation to maternal alcohol consumption (alcoholic 12%; heavy drinking 24%; moderate drinking 28%; light drinking 36%). No differences were found between light and moderate drinkers. Infants born to alcoholics had a greater number of craniofacial characteristics and the proportion with features compatible with fetal alcohol effects was higher. There was a similar trend for infants of heavy drinkers. Infants of heavy drinkers who had decreased their alcohol consumption during pregnancy had fewer craniofacial features. Infants of heavy smokers were also found to have increased numbers of craniofacial characteristics. CONCLUSIONS--Craniofacial morphology could be a sensitive indicator of alcohol exposure in utero. Altered morphology is usually considered specific for alcohol exposure, but the relation observed with smoking needs further exploration. PMID:2277252

  3. Craniofacial Asymmetry in Adults With Neglected Congenital Muscular Torticollis

    PubMed Central

    Jeong, Kil-Yong; Min, Kyung-Jay; Woo, Jieun

    2015-01-01

    Objective To evaluate the craniofacial asymmetry in adults with neglected congenital muscular torticollis (CMT) by quantitative assessment based on craniofacial three-dimensional computed tomography (3D-CT). Methods Preoperative craniofacial asymmetry was measured by 3D-CT for 31 CMT subjects ≥18 years of age who visited a tertiary medical center and underwent 3D-CT between January 2009 and December 2013. The relationship between the age and the severity of craniofacial asymmetry was analyzed in reference to anteroposterior length asymmetry of the frontal bone and zygomatic arch, vertical and lateral displacements of the facial landmarks, and mandibular axis rotation. Results The age at CT was 27.71±7.02 years (range, 18-44 years). All intra-class correlation coefficients were higher than 0.7, suggesting good inter-rater reliability (p<0.05) of all the measurements. The frontal and the zygomatic length ratio (i.e., the anteroposterior length asymmetry on the axial plane) was 1.06±0.03 and 1.07±0.03, respectively, which was increased significantly with age in the linear regression analysis (r2=0.176, p=0.019 and r2=0.188, p=0.015, respectively). The vertical or lateral displacement of the facial landmarks and rotation of the mandibular axis did not significantly correlate with age (p>0.05). Conclusion Craniofacial asymmetry of neglected CMT became more severe with age in terms of anteroposterior length asymmetry of the ipsilateral frontal bone and zygomatic arch on the axial plane even after growth cessation. This finding may enhance the understanding of therapeutic strategies for craniofacial asymmetry in adults with neglected CMT. PMID:26161351

  4. Distinguishing Goldenhar Syndrome from Craniofacial Microsomia.

    PubMed

    Tuin, Jorien; Tahiri, Youssef; Paliga, James T; Taylor, Jesse A; Bartlett, Scott P

    2015-09-01

    Goldenhar syndrome is characterized by the typical features of craniofacial microsomia (CFM) with the addition of epibulbar dermoids and vertebral anomalies. The aim of this study is to examine the objective differences between patients carrying a diagnosis of Goldenhar syndrome to those diagnosed with CFM. Thus, we performed an Institutional Review Board-approved retrospective chart review on all patients who presented with a diagnosis of CFM or Goldenhar syndrome from January 1990 to December 2012. Demographic, diagnosis, OMENS+ classification, accompanying diagnoses, and radiographic data were collected. For subjective analysis, subgroups were designed based on the diagnosis Goldenhar syndrome or CFM per history. For objective analysis, subgroups were designed based on the presence of epibulbar dermoids and/or vertebral anomalies. The cohorts were compared with respect to associated medical abnormalities and severity of CFM features. One hundred thirty eight patients met inclusion criteria. Epibulbar dermoids and vertebral anomalies were seen in 17% and 34% of the patients, respectively. Only 10 patients (7.2%) had both epibulbar dermoids and vertebral anomalies. The subjective "Goldenhar" group (N = 44, 32%) was found to have a higher percentage of bilaterally affected patients (P = 0.001), a more severe mandibular deformity (P = <0.001), a more severe soft tissue deformity (P = 0.01), and a higher incidence of macrostomia (P = 0.003). In the objective subgroup analysis, the only significant difference was found in the degree of soft tissue deficiency (P = 0.049). The diagnostic criteria of Goldenhar syndrome remain unclear, thereby making clinical use of the term "Goldenhar" inconsequential. Goldenhar syndrome is over diagnosed subjectively in patients who show more severe CFM features. PMID:26267577

  5. Cell lineage in mammalian craniofacial mesenchyme.

    PubMed

    Yoshida, Toshiyuki; Vivatbutsiri, Philaiporn; Morriss-Kay, Gillian; Saga, Yumiko; Iseki, Sachiko

    2008-01-01

    We have analysed the contributions of neural crest and mesoderm to mammalian craniofacial mesenchyme and its derivatives by cell lineage tracing experiments in mouse embryos, using the permanent genetic markers Wnt1-cre for neural crest and Mesp1-cre for mesoderm, combined with the Rosa26 reporter. At the end of neural crest cell migration (E9.5) the two patterns are reciprocal, with a mutual boundary just posterior to the eye. Mesodermal cells expressing endothelial markers (angioblasts) are found not to respect this boundary; they are associated with the migrating neural crest from the 5-somite stage, and by E9.5 they form a pre-endothelial meshwork throughout the cranial mesenchyme. Mesodermal cells of the myogenic lineage also migrate with neural crest cells, as the branchial arches form. By E17.5 the neural crest-mesoderm boundary in the subectodermal mesenchyme becomes out of register with that of the underlying skeletogenic layer, which is between the frontal and parietal bones. At E13.5 the primordia of these bones lie basolateral to the brain, extending towards the vertex of the skull during the following 4-5 days. We used DiI labelling of the bone primordia in ex-utero E13.5 embryos to distinguish between two possibilities for the origin of the frontal and parietal bones: (1) recruitment from adjacent connective tissue or (2) proliferation of the original primordia. The results clearly demonstrated that the bone primordia extend vertically by intrinsic growth, without detectable recruitment of adjacent mesenchymal cells. PMID:18617001

  6. Obstructive sleep apnoea in children with craniofacial syndromes

    PubMed Central

    Cielo, Christopher M.

    2014-01-01

    Summary Obstructive sleep apnoea syndrome (OSAS) is common in children. Craniofacial anomalies such as cleft palate are among the most common congenital conditions. Children with a variety of craniofacial conditions, including cleft palate, micrognathia, craniosynostosis, and midface hypoplasia are at increased risk for OSAS. Available evidence, which is largely limited to surgical case series and retrospective studies, suggests that OSAS can be successfully managed in these children through both surgical and non-surgical techniques. Prospective studies using larger cohorts of patients and including polysomnograms are needed to better understand the risk factors for this patient population and the efficacy of treatment options for OSAS and their underlying conditions. PMID:25555676

  7. Human Genetic Disorders Caused by Mutations in Genes Encoding Biosynthetic Enzymes for Sulfated Glycosaminoglycans*

    PubMed Central

    Mizumoto, Shuji; Ikegawa, Shiro; Sugahara, Kazuyuki

    2013-01-01

    A number of genetic disorders are caused by mutations in the genes encoding glycosyltransferases and sulfotransferases, enzymes responsible for the synthesis of sulfated glycosaminoglycan (GAG) side chains of proteoglycans, including chondroitin sulfate, dermatan sulfate, and heparan sulfate. The phenotypes of these genetic disorders reflect disturbances in crucial biological functions of GAGs in human. Recent studies have revealed that mutations in genes encoding chondroitin sulfate and dermatan sulfate biosynthetic enzymes cause various disorders of connective tissues. This minireview focuses on growing glycobiological studies of recently described genetic diseases caused by disturbances in biosynthetic enzymes for sulfated GAGs. PMID:23457301

  8. Craniofacial Birth Defects: The Role of Neural Crest Cells in the Etiology and Pathogenesis of Treacher Collins Syndrome and the Potential for Prevention

    PubMed Central

    Trainor, Paul A.

    2013-01-01

    Of all the babies born with birth defects, approximately one-third display anomalies of the head and face [Gorlin et al., 1990] including cleft lip, cleft palate, small or absent facial and skull bones and improperly formed nose, eyes, ears, and teeth. Craniofacial disorders are a primary cause of infant mortality and have serious lifetime functional, esthetic, and social consequences that are devastating to both children and parents alike. Comprehensive surgery, dental care, psychological counseling, and rehabilitation can help ameliorate-specific problems but at great cost over many years which dramatically affects national health care budgets. For example, the Center for Disease Control and Prevention estimates that the lifetime cost of treating the children born each year with cleft lip and/or cleft palate alone to be US$697 million. Treating craniofacial malformations, of which in excess of 700 distinct syndromes have been described, through comprehensive, well-coordinated and integrated strategies can provide satisfactory management of individual conditions, however, the results are often variable and rarely fully corrective. Therefore, better techniques for tissue repair and regeneration need to be developed and therapeutic avenues of prevention need to be explored in order to eliminate the devastating consequences of head and facial birth defects. To do this requires a thorough understanding of the normal events that control craniofacial development during embryogenesis. This review therefore focuses on recent advances in our understanding of the basic etiology and pathogenesis of a rare craniofacial disorder known as Treacher Collins syndrome and emerging prospects for prevention that may have broad application to congenital craniofacial birth defects. PMID:20734335

  9. The human microbiome in hematopoiesis and hematologic disorders

    PubMed Central

    Manzo, Veronica E.

    2015-01-01

    Humans are now understood to be in complex symbiosis with a diverse ecosystem of microbial organisms, including bacteria, viruses, and fungi. Efforts to characterize the role of these microorganisms, commonly referred as the microbiota, in human health have sought to answer the fundamental questions of what organisms are present, how are they functioning to interact with human cells, and by what mechanism are these interactions occurring. In this review, we describe recent efforts to describe the microbiota in healthy and diseased individuals, summarize the role of various molecular technologies (ranging from 16S ribosomal RNA to shotgun metagenomic sequencing) in enumerating the community structure of the microbiota, and explore known interactions between the microbiota and humans, with a focus on the microbiota’s role in hematopoiesis and hematologic diseases. PMID:26012569

  10. Insights into synaptic function from mouse models of human cognitive disorders.

    PubMed

    Banko, Jessica L; Trotter, Justin; Weeber, Edwin J

    2011-01-01

    Modern approaches to the investigation of the molecular mechanisms underlying human cognitive disease often include multidisciplinary examination of animal models engineered with specific mutations that spatially and temporally restrict expression of a gene of interest. This approach not only makes possible the development of animal models that demonstrate phenotypic similarities to their respective human disorders, but has also allowed for significant progress towards understanding the processes that mediate synaptic function and memory formation in the nondiseased state. Examples of successful mouse models where genetic manipulation of the mouse resulted in recapitulation of the symptomatology of the human disorder and was used to significantly expand our understanding of the molecular mechanisms underlying normal synaptic plasticity and memory formation are discussed in this article. These studies have broadened our knowledge of several signal transduction cascades that function throughout life to mediate synaptic physiology. Defining these events is key for developing therapies to address disorders of cognitive ability. PMID:25083141

  11. Insights from human congenital disorders of intestinal lipid metabolism

    PubMed Central

    Levy, Emile

    2015-01-01

    The intestine must challenge the profuse daily flux of dietary fat that serves as a vital source of energy and as an essential component of cell membranes. The fat absorption process takes place in a series of orderly and interrelated steps, including the uptake and translocation of lipolytic products from the brush border membrane to the endoplasmic reticulum, lipid esterification, Apo synthesis, and ultimately the packaging of lipid and Apo components into chylomicrons (CMs). Deciphering inherited disorders of intracellular CM elaboration afforded new insight into the key functions of crucial intracellular proteins, such as Apo B, microsomal TG transfer protein, and Sar1b GTPase, the defects of which lead to hypobetalipoproteinemia, abetalipoproteinemia, and CM retention disease, respectively. These “experiments of nature” are characterized by fat malabsorption, steatorrhea, failure to thrive, low plasma levels of TGs and cholesterol, and deficiency of liposoluble vitamins and essential FAs. After summarizing and discussing the functions and regulation of these proteins for reader’s comprehension, the current review focuses on their specific roles in malabsorptions and dyslipidemia-related intestinal fat hyperabsorption while dissecting the spectrum of clinical manifestations and managements. The influence of newly discovered proteins (proprotein convertase subtilisin/kexin type 9 and angiopoietin-like 3 protein) on fat absorption has also been provided. Finally, it is stressed how the overexpression or polymorphism status of the critical intracellular proteins promotes dyslipidemia and cardiometabolic disorders. PMID:25387865

  12. Mechanisms of interstrand DNA crosslink repair and human disorders.

    PubMed

    Hashimoto, Satoru; Anai, Hirofumi; Hanada, Katsuhiro

    2016-01-01

    Interstrand DNA crosslinks (ICLs) are the link between Watson-Crick strands of DNAs with the covalent bond and prevent separation of DNA strands. Since the ICL lesion affects both strands of the DNA, the ICL repair is not simple. So far, nucleotide excision repair (NER), structure-specific endonucleases, translesion DNA synthesis (TLS), homologous recombination (HR), and factors responsible for Fanconi anemia (FA) are identified to be involved in ICL repair. Since the presence of ICL lesions causes severe defects in transcription and DNA replication, mutations in these DNA repair pathways give rise to a various hereditary disorders. NER plays an important role for the ICL recognition and removal in quiescent cells, and defects of NER causes congential progeria syndrome, such as xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy. On the other hand, the ICL repair in S phase requires more complicated orchestration of multiple factors, including structure-specific endonucleases, and TLS, and HR. Disturbed this ICL repair orchestration in S phase causes genome instability resulting a cancer prone disease, Fanconi anemia. So far more than 30 factors in ICL repair have already identified. Recently, a new factor, UHRF1, was discovered as a sensor of ICLs. In addition to this, numbers of nucleases that are involved in the first incision, also called unhooking, of ICL lesions have also been identified. Here we summarize the recent studies of ICL associated disorders and repair mechanism, with emphasis in the first incision of ICLs. PMID:27350828

  13. Microgravity reduces sleep-disordered breathing in humans

    NASA Technical Reports Server (NTRS)

    Elliott, A. R.; Shea, S. A.; Dijk, D. J.; Wyatt, J. K.; Riel, E.; Neri, D. F.; Czeisler, C. A.; West, J. B.; Prisk, G. K.

    2001-01-01

    To understand the factors that alter sleep quality in space, we studied the effect of spaceflight on sleep-disordered breathing. We analyzed 77 8-h, full polysomnographic recordings (PSGs) from five healthy subjects before spaceflight, on four occasions per subject during either a 16- or 9-d space shuttle mission and shortly after return to earth. Microgravity was associated with a 55% reduction in the apnea-hypopnea index (AHI), which decreased from a preflight value of 8.3 +/- 1.6 to 3.4 +/- 0.8 events/h inflight. This reduction in AHI was accompanied by a virtual elimination of snoring, which fell from 16.5 +/- 3.0% of total sleep time preflight to 0.7 +/- 0.5% inflight. Electroencephalogram (EEG) arousals also decreased in microgravity (by 19%), and this decrease was almost entirely a consequence of the reduction in respiratory-related arousals, which fell from 5.5 +/- 1.2 arousals/h preflight to 1.8 +/- 0.6 inflight. Postflight there was a return to near or slightly above preflight levels in these variables. We conclude that sleep quality during spaceflight is not degraded by sleep-disordered breathing. This is the first direct demonstration that gravity plays a dominant role in the generation of apneas, hypopneas, and snoring in healthy subjects.

  14. A computerized tomography study of the morphological interrelationship between the temporal bones and the craniofacial complex

    PubMed Central

    Costa, Helder Nunes; Slavicek, Rudolf; Sato, Sadao

    2012-01-01

    The hypothesis that the temporal bones are at the center of the dynamics of the craniofacial complex, directly influencing facial morphology, has been put forward long ago. This study examines the role of the spatial positioning of temporal bones (frontal and sagittal inclination) in terms of influencing overall facial morphology. Several 3D linear, angular and orthogonal measurements obtained through computerized analysis of virtual models of 163 modern human skulls reconstructed from cone-beam computed tomography images were analyzed and correlated. Additionally, the sample was divided into two subgroups based on the median value of temporal bone sagittal inclination [anterior rotation group (n = 82); posterior rotation group (n = 81)], and differences between groups evaluated. Correlation coefficients showed that sagittal inclination of the temporal bone was significantly (P < 0.01) related to midline flexion, transversal width and anterior–posterior length of the basicranium, to the anterior–posterior positioning of the mandible and maxilla, and posterior midfacial height. Frontal inclination of the temporal bone was significantly related (P < 0.01) to basicranium anterior–posterior and transversal dimensions, and to posterior midfacial height. In comparison with the posterior rotation group, the anterior rotation group presented a less flexed and anterior–posteriorly longer cranial base, a narrower skull, porion and the articular eminence located more superiorly and posteriorly, a shorter posterior midfacial height, the palatal plane rotated clockwise, a more retrognathic maxilla and mandible, and the upper posterior occlusal plane more inclined and posteriorly located. The results suggest that differences in craniofacial morphology are highly integrated with differences in the positional relationship of the temporal bones. The sagittal inclination of the temporal bone seems to have a greater impact on the 3D morphology of the craniofacial complex than

  15. Exclusion of the PAX2 gene as a candidate gene for Crouzon craniofacial dysostosis

    SciTech Connect

    Preston, R.A.; Gorry, M.C.; Warman, M.

    1994-09-01

    Crouzon craniofacial dysostosis (CFD, MIM 123500) is an abnormality of craniofacial development characterized by premature craniosynostosis, maxillary hypoplasia, and shallow orbits. We have mapped the CFD gene locus using a candidate gene approach to a 7 centiMorgan region on chromosome 10q in three CFD families. A maximal multipoint LOD score of 12.33 was achieved for a locus 2 cM distal to the microsatellite marker D10S209. A comparison of several physical, cytogenetic, and linkage maps revealed that the cytogenetic bands, 10q25-q26, most likely contain this CFD locus. The PAX2 gene, which has been mapped near another marker which in turn has been mapped to 10q25, was analyzed as a candidate gene. PAX2 was chosen for analysis because mutations in other members of the PAX gene family have been identified with human craniofacial abnormalities (e.g. Waardenburg syndrome). A YAC contig, consisting of 5 overlapping groups and composed of 11 YACs that spans the entire 7 cM region, was assembled for PAX2 analyses. None of these YACs supported PAX2-specific amplification using primer sets for both the second and third PAX2 exons. Control amplifications for YAC vector sequences produced robust amplifications in all cases. In addition, SSCP analyses of amplification products generated from the second and third PAX2 exons and the 3{prime} untranslated region of the PAX2 gene from both affected and unaffected family members in two of the kindreds failed to reveal any polymorphisms. Although it remains theoretically possible, due to artifacts in the YAC contigs, it is unlikely that PAX2 is the CFD gene.

  16. Mutations in mouse Ift144 model the craniofacial, limb and rib defects in skeletal ciliopathies.

    PubMed

    Ashe, Alyson; Butterfield, Natalie C; Town, Liam; Courtney, Andrew D; Cooper, Ashley N; Ferguson, Charles; Barry, Rachael; Olsson, Fredrik; Liem, Karel F; Parton, Robert G; Wainwright, Brandon J; Anderson, Kathryn V; Whitelaw, Emma; Wicking, Carol

    2012-04-15

    Mutations in components of the intraflagellar transport (IFT) machinery required for assembly and function of the primary cilium cause a subset of human ciliopathies characterized primarily by skeletal dysplasia. Recently, mutations in the IFT-A gene IFT144 have been described in patients with Sensenbrenner and Jeune syndromes, which are associated with short ribs and limbs, polydactyly and craniofacial defects. Here, we describe an N-ethyl-N-nitrosourea-derived mouse mutant with a hypomorphic missense mutation in the Ift144 gene. The mutant twinkle-toes (Ift144(twt)) phenocopies a number of the skeletal and craniofacial anomalies seen in patients with human skeletal ciliopathies. Like other IFT-A mouse mutants, Ift144 mutant embryos display a generalized ligand-independent expansion of hedgehog (Hh) signalling, in spite of defective ciliogenesis and an attenuation of the ability of mutant cells to respond to upstream stimulation of the pathway. This enhanced Hh signalling is consistent with cleft palate and polydactyly phenotypes in the Ift144(twt) mutant, although extensive rib branching, fusion and truncation phenotypes correlate with defects in early somite patterning and may reflect contributions from multiple signalling pathways. Analysis of embryos harbouring a second allele of Ift144 which represents a functional null, revealed a dose-dependent effect on limb outgrowth consistent with the short-limb phenotypes characteristic of these ciliopathies. This allelic series of mouse mutants provides a unique opportunity to uncover the underlying mechanistic basis of this intriguing subset of ciliopathies. PMID:22228095

  17. The questionable contribution of the Neolithic and the Bronze Age to European craniofacial form

    PubMed Central

    Brace, C. Loring; Seguchi, Noriko; Quintyn, Conrad B.; Fox, Sherry C.; Nelson, A. Russell; Manolis, Sotiris K.; Qifeng, Pan

    2006-01-01

    Many human craniofacial dimensions are largely of neutral adaptive significance, and an analysis of their variation can serve as an indication of the extent to which any given population is genetically related to or differs from any other. When 24 craniofacial measurements of a series of human populations are used to generate neighbor-joining dendrograms, it is no surprise that all modern European groups, ranging all of the way from Scandinavia to eastern Europe and throughout the Mediterranean to the Middle East, show that they are closely related to each other. The surprise is that the Neolithic peoples of Europe and their Bronze Age successors are not closely related to the modern inhabitants, although the prehistoric/modern ties are somewhat more apparent in southern Europe. It is a further surprise that the Epipalaeolithic Natufian of Israel from whom the Neolithic realm was assumed to arise has a clear link to Sub-Saharan Africa. Basques and Canary Islanders are clearly associated with modern Europeans. When canonical variates are plotted, neither sample ties in with Cro-Magnon as was once suggested. The data treated here support the idea that the Neolithic moved out of the Near East into the circum-Mediterranean areas and Europe by a process of demic diffusion but that subsequently the in situ residents of those areas, derived from the Late Pleistocene inhabitants, absorbed both the agricultural life way and the people who had brought it. PMID:16371462

  18. The questionable contribution of the Neolithic and the Bronze Age to European craniofacial form.

    PubMed

    Brace, C Loring; Seguchi, Noriko; Quintyn, Conrad B; Fox, Sherry C; Nelson, A Russell; Manolis, Sotiris K; Qifeng, Pan

    2006-01-01

    Many human craniofacial dimensions are largely of neutral adaptive significance, and an analysis of their variation can serve as an indication of the extent to which any given population is genetically related to or differs from any other. When 24 craniofacial measurements of a series of human populations are used to generate neighbor-joining dendrograms, it is no surprise that all modern European groups, ranging all of the way from Scandinavia to eastern Europe and throughout the Mediterranean to the Middle East, show that they are closely related to each other. The surprise is that the Neolithic peoples of Europe and their Bronze Age successors are not closely related to the modern inhabitants, although the prehistoric/modern ties are somewhat more apparent in southern Europe. It is a further surprise that the Epipalaeolithic Natufian of Israel from whom the Neolithic realm was assumed to arise has a clear link to Sub-Saharan Africa. Basques and Canary Islanders are clearly associated with modern Europeans. When canonical variates are plotted, neither sample ties in with Cro-Magnon as was once suggested. The data treated here support the idea that the Neolithic moved out of the Near East into the circum-Mediterranean areas and Europe by a process of demic diffusion but that subsequently the in situ residents of those areas, derived from the Late Pleistocene inhabitants, absorbed both the agricultural life way and the people who had brought it. PMID:16371462

  19. Mutations in mouse Ift144 model the craniofacial, limb and rib defects in skeletal ciliopathies

    PubMed Central

    Ashe, Alyson; Butterfield, Natalie C.; Town, Liam; Courtney, Andrew D.; Cooper, Ashley N.; Ferguson, Charles; Barry, Rachael; Olsson, Fredrik; Liem, Karel F.; Parton, Robert G.; Wainwright, Brandon J.; Anderson, Kathryn V.; Whitelaw, Emma; Wicking, Carol

    2012-01-01

    Mutations in components of the intraflagellar transport (IFT) machinery required for assembly and function of the primary cilium cause a subset of human ciliopathies characterized primarily by skeletal dysplasia. Recently, mutations in the IFT-A gene IFT144 have been described in patients with Sensenbrenner and Jeune syndromes, which are associated with short ribs and limbs, polydactyly and craniofacial defects. Here, we describe an N-ethyl-N-nitrosourea-derived mouse mutant with a hypomorphic missense mutation in the Ift144 gene. The mutant twinkle-toes (Ift144twt) phenocopies a number of the skeletal and craniofacial anomalies seen in patients with human skeletal ciliopathies. Like other IFT-A mouse mutants, Ift144 mutant embryos display a generalized ligand-independent expansion of hedgehog (Hh) signalling, in spite of defective ciliogenesis and an attenuation of the ability of mutant cells to respond to upstream stimulation of the pathway. This enhanced Hh signalling is consistent with cleft palate and polydactyly phenotypes in the Ift144twt mutant, although extensive rib branching, fusion and truncation phenotypes correlate with defects in early somite patterning and may reflect contributions from multiple signalling pathways. Analysis of embryos harbouring a second allele of Ift144 which represents a functional null, revealed a dose-dependent effect on limb outgrowth consistent with the short-limb phenotypes characteristic of these ciliopathies. This allelic series of mouse mutants provides a unique opportunity to uncover the underlying mechanistic basis of this intriguing subset of ciliopathies. PMID:22228095

  20. The relationship between nasal obstruction and craniofacial growth.

    PubMed

    Smith, R M; Gonzalez, C

    1989-12-01

    The relationship between nasal obstruction and craniofacial growth is unclear. The literature indicates that upper-airway compromise produces chronic mouth breathing, especially in the dolichocephalic (narrow-faced) child. It has been shown that a greater tendency exists toward the skeletal pattern associated with long face syndrome in dolichocephalic head types. Therefore, it becomes difficult to assess whether the long face syndrome is a cause or an effect of increased nasal airway resistance. Nevertheless, animal studies have demonstrated the development of typical craniofacial anomalies in experimentally induced nasal obstruction. Some of these changes are also noted to be reversed by removing the nasal obstruction. Although much of the concern for nasal obstruction and abnormal dentofacial growth has centered around adenotonsillar hypertrophy, other causes for nasal obstruction should be sought. Allergic rhinitis and choanal atresia also should be considered. Longitudinal data are lacking to support conclusively abnormal dentofacial growth as an indication for surgical intervention. Available literature would suggest, however, that relief of nasal obstruction should be attempted in an effort to establish a patent airway and decrease the possibility of abnormal craniofacial development. The more information we gain about nasal obstruction and abnormal dentofacial development, the greater our diagnostic ability becomes. We can now incorporate information from a thorough nasal-oral examination with rhinomanometry and cephalometrics to provide a rational treatment plan for these children. Future directions should investigate genetic influences on craniofacial morphology and growth. PMID:2587086

  1. The genesis of craniofacial biology as a health science discipline.

    PubMed

    Sperber, G H; Sperber, S M

    2014-06-01

    The craniofacial complex encapsulates the brain and contains the organs for key functions of the body, including sight, hearing and balance, smell, taste, respiration and mastication. All these systems are intimately integrated within the head. The combination of these diverse systems into a new field was dictated by the dental profession's desire for a research branch of basic science devoted and attuned to its specific needs. The traditional subjects of genetics, embryology, anatomy, physiology, biochemistry, dental materials, odontology, molecular biology and palaeoanthropology pertaining to dentistry have been drawn together by many newly emerging technologies. These new technologies include gene sequencing, CAT scanning, MRI imaging, laser scanning, image analysis, ultrasonography, spectroscopy and visualosonics. A vibrant unitary discipline of investigation, craniofacial biology, has emerged that builds on the original concept of 'oral biology' that began in the 1960s. This paper reviews some of the developments that have led to the genesis of craniofacial biology as a fully-fledged health science discipline of significance in the advancement of clinical dental practice. Some of the key figures and milestones in craniofacial biology are identified. PMID:24495071

  2. Hutchinson-Gilford progeria syndrome: Oral and craniofacial phenotypes

    PubMed Central

    Domingo, D.L.; Trujillo, M.I.; Council, S.E.; Merideth, M.A.; Gordon, L.B.; Wu, T.; Introne, W.J.; Gahl, W.A.; Hart, T.C.

    2008-01-01

    OBJECTIVE Hutchinson-Gilford progeria syndrome (HGPS) is a rare early-onset accelerated senescence syndrome. In HGPS, a recently identified de novo dominant mutation of the lamin A gene (LMNA) produces abnormal lamin A, resulting in compromised nuclear membrane integrity. Clinical features include sclerotic skin, cardiovascular and bone abnormalities, and marked growth retardation. Craniofacial features include “bird-like” facies, alopecia, craniofacial disproportion and dental crowding. Our prospective study describes dental, oral soft tissue, and craniofacial bone features in HGPS. METHODS Fifteen patients with confirmed p.G608G LMNA mutation (1–17 years, 7 males, 8 females) received comprehensive oral evaluations. Anomalies of oral soft tissue, gnathic bones and dentition were identified. RESULTS Radiographic findings included hypodontia (n=7), dysmorphic teeth (n=5), steep mandibular angles (n=11), and thin basal bone (n=11). Soft tissue findings included ogival palatal arch (n=8), median sagittal palatal fissure (n=7), and ankyloglossia (n=7). Calculated dental ages (9months–11y2m) were significantly lower than chronological ages (1y6m–17y8m) (p=0.002). Eleven children manifested a shorter mandibular body, anterior/posterior cranial base and ramus, but a larger gonial angle, compared to age/gender/race norms. CONCLUSION Novel oral-craniofacial phenotypes and quantification of previously reported features are presented. Our findings expand the HGPS phenotype and provide additional insight into the complex pathogenesis of HGPS. PMID:19236595

  3. Analysis of the 50 most cited papers in craniofacial surgery.

    PubMed

    Tahiri, Youssef; Fleming, Tara M; Greathouse, Travis; Tholpady, Sunil S

    2015-12-01

    The intent of this study is to discuss the most prominent literature in craniofacial surgery. To do so, using the ISI Web of Science, a ranking by average number of citations per year of the top 50 craniofacial surgery articles was compiled. All plastic surgery journals listed in the "Surgery" category in the ISI Web of Knowledge Journal Citation Reports 2013 Science Edition were considered. Journal of publication, country of origin, collaborating institutions, topic of interest, and level of evidence were analyzed. The total number of citations ranged from 47 to 1017. Average number of citations per year ranged from 46.2 to 8.6. The oldest article in the top 50 was published in 1988 and the most recent in 2009. The majority of the articles came from Plastic and Reconstructive Surgery with 28 of the 50. The majority of the articles, originated from the United States (56%). Reconstruction of acquired defects was the most commonly examined topic at 46.2%; followed by articles discussing reconstruction of congenital defects (23.1%). The most common level of evidence was level 3. This extensive examination of the craniofacial literature highlights the important part that craniofacial surgery takes in the field of plastic surgery. PMID:26541748

  4. A One-Session Human Immunodeficiency Virus Risk-Reduction Intervention in Adolescents with Psychiatric and Substance Use Disorders

    ERIC Educational Resources Information Center

    Thurstone, Christian; Riggs, Paula D.; Klein, Constance; Mikulich-Gilbertson, Susan K.

    2007-01-01

    Objective: To explore change in human immunodeficiency virus (HIV) risk among teens in outpatient treatment for substance use disorders (SUDs). Method: From December 2002 to August 2004, 50 adolescents (13-19 years) with major depressive disorder, conduct disorder, and one or more non-nicotine SUD completed the Teen Health Survey (THS) at the…

  5. Searching human brain for mechanisms of psychiatric disorders. Implications for studies on schizophrenia.

    PubMed

    Berretta, Sabina; Heckers, Stephan; Benes, Francine M

    2015-09-01

    In the past 25years, research on the human brain has been providing a clear path toward understanding the pathophysiology of psychiatric illnesses. The successes that have been accrued are matched by significant difficulties identifying and controlling a large number of potential confounding variables. By systematically and effectively accounting for unwanted variance in data from imaging and postmortem human brain studies, meaningful and reliable information regarding the pathophysiology of human brain disorders can be obtained. This perspective paper focuses on postmortem investigations to discuss some of the most challenging sources of variance, including diagnosis, comorbidity, substance abuse and pharmacological treatment, which confound investigations of the human brain. PMID:25458567

  6. Contrasting features of urea cycle disorders in human patients and knockout mouse models.

    PubMed

    Deignan, Joshua L; Cederbaum, Stephen D; Grody, Wayne W

    2008-01-01

    The urea cycle exists for the removal of excess nitrogen from the body. Six separate enzymes comprise the urea cycle, and a deficiency in any one of them causes a urea cycle disorder (UCD) in humans. Arginase is the only urea cycle enzyme with an alternate isoform, though no known human disorder currently exists due to a deficiency in the second isoform. While all of the UCDs usually present with hyperammonemia in the first few days to months of life, most disorders are distinguished by a characteristic profile of plasma amino acid alterations that can be utilized for diagnosis. While enzyme assay is possible, an analysis of the underlying mutation is preferable for an accurate diagnosis. Mouse models for each of the urea cycle disorders exist (with the exception of NAGS deficiency), and for almost all of them, their clinical and biochemical phenotypes rather closely resemble the phenotypes seen in human patients. Consequently, all of the current mouse models are highly useful for future research into novel pharmacological and dietary treatments and gene therapy protocols for the management of urea cycle disorders. PMID:17933574

  7. Mutation of the proteolipid protein gene PLP in a human X chromosome-linked myelin disorder.

    PubMed

    Hudson, L D; Puckett, C; Berndt, J; Chan, J; Gencic, S

    1989-10-01

    Myelin is a highly specialized membrane unique to the nervous system that ensheaths axons to permit the rapid saltatory conduction of impulses. The elaboration of a compact myelin sheath is disrupted in a diverse spectrum of human disorders, many of which are of unknown etiology. The X chromosome-linked human disorder Pelizaeus-Merzbacher disease is a clinically and pathologically heterogeneous group of disorders that demonstrate a striking failure of oligodendrocyte differentiation. This disease appears pathologically and genetically to be similar to the disorder seen in the dysmyelinating mouse mutant jimpy, which has a point mutation in the gene encoding an abundant myelin protein, proteolipid protein (PLP). We report that the molecular defect in one Pelizaeus-Merzbacher family is likewise a point mutation in the PLP gene. A single T----C transition results in the substitution of a charged amino acid residue, arginine, for tryptophan in one of the four extremely hydrophobic domains of the PLP protein. The identification of a mutation in this Pelizaeus-Merzbacher family should facilitate the molecular classification and diagnosis of these X chromosome-linked human dysmyelinating disorders. PMID:2479017

  8. Rethinking dependent personality disorder: comparing different human relatedness in cultural contexts.

    PubMed

    Chen, YuJu; Nettles, Margaret E; Chen, Shun-Wen

    2009-11-01

    We argue that the Diagnostic and Statistical Manual of Mental Disorders dependent personality disorder is a culturally related concept reflecting deeply rooted values, beliefs, and assumptions of American individualistic convictions about self and interpersonal relationship. This article integrates social psychology concepts into the exploration of psychopathology. Beginning with the construct of individualism and collectivism, we demonstrate the limitations of this commonly used framework. The indigenous Chinese concept of Confucianism and Chinese Relationalism is introduced to highlight that a well-differentiated self is not a universal premise of human beings, healthy existence. In East Asian Confucianism the manifestation of dependence and submission may be considered individuals' proper behavior and required for their social obligation, rather than a direct display of individuals' personality. Thus, the complexity of dependent personality disorder is beyond the neo-Kraepelinian approach assumed by the Diagnostic and Statistical Manual of Mental Disorders system. PMID:19996716

  9. Widespread Macromolecular Interaction Perturbations in Human Genetic Disorders

    PubMed Central

    Sahni, Nidhi; Yi, Song; Taipale, Mikko; Fuxman Bass, Juan I.; Coulombe-Huntington, Jasmin; Yang, Fan; Peng, Jian; Weile, Jochen; Karras, Georgios I.; Wang, Yang; Kovács, István A.; Kamburov, Atanas; Krykbaeva, Irina; Lam, Mandy H.; Tucker, George; Khurana, Vikram; Sharma, Amitabh; Liu, Yang-Yu; Yachie, Nozomu; Zhong, Quan; Shen, Yun; Palagi, Alexandre; San-Miguel, Adriana; Fan, Changyu; Balcha, Dawit; Dricot, Amelie; Jordan, Daniel M.; Walsh, Jennifer M.; Shah, Akash A.; Yang, Xinping; Stoyanova, Ani; Leighton, Alex; Calderwood, Michael A.; Jacob, Yves; Cusick, Michael E.; Salehi-Ashtiani, Kourosh; Whitesell, Luke J.; Sunyaev, Shamil; Berger, Bonnie; Barabási, Albert-László; Charloteaux, Benoit; Hill, David E.; Hao, Tong; Roth, Frederick P.; Xia, Yu; Walhout, Albertha J.M.; Lindquist, Susan; Vidal, Marc

    2015-01-01

    SUMMARY How disease-associated mutations impair protein activities in the context of biological networks remains mostly undetermined. Although a few renowned alleles are well characterized, functional information is missing for over 100,000 disease-associated variants. Here we functionally profile several thousand missense mutations across a spectrum of Mendelian disorders using various interaction assays. The majority of disease-associated alleles exhibit wild-type chaperone binding profiles, suggesting they preserve protein folding or stability. While common variants from healthy individuals rarely affect interactions, two-thirds of disease-associated alleles perturb protein-protein interactions, with half corresponding to “edgetic” alleles affecting only a subset of interactions while leaving most other interactions unperturbed. With transcription factors, many alleles that leave protein-protein interactions intact affect DNA binding. Different mutations in the same gene leading to different interaction profiles often result in distinct disease phenotypes. Thus disease-associated alleles that perturb distinct protein activities rather than grossly affecting folding and stability are relatively widespread. PMID:25910212

  10. Mutations in NLRP5 are associated with reproductive wastage and multilocus imprinting disorders in humans.

    PubMed

    Docherty, Louise E; Rezwan, Faisal I; Poole, Rebecca L; Turner, Claire L S; Kivuva, Emma; Maher, Eamonn R; Smithson, Sarah F; Hamilton-Shield, Julian P; Patalan, Michal; Gizewska, Maria; Peregud-Pogorzelski, Jaroslaw; Beygo, Jasmin; Buiting, Karin; Horsthemke, Bernhard; Soellner, Lukas; Begemann, Matthias; Eggermann, Thomas; Baple, Emma; Mansour, Sahar; Temple, I Karen; Mackay, Deborah J G

    2015-01-01

    Human-imprinting disorders are congenital disorders of growth, development and metabolism, associated with disturbance of parent of origin-specific DNA methylation at imprinted loci across the genome. Some imprinting disorders have higher than expected prevalence of monozygotic twinning, of assisted reproductive technology among parents, and of disturbance of multiple imprinted loci, for which few causative trans-acting mutations have been found. Here we report mutations in NLRP5 in five mothers of individuals affected by multilocus imprinting disturbance. Maternal-effect mutations of other human NLRP genes, NLRP7 and NLRP2, cause familial biparental hydatidiform mole and multilocus imprinting disturbance, respectively. Offspring of mothers with NLRP5 mutations have heterogenous clinical and epigenetic features, but cases include a discordant monozygotic twin pair, individuals with idiopathic developmental delay and autism, and families affected by infertility and reproductive wastage. NLRP5 mutations suggest connections between maternal reproductive fitness, early zygotic development and genomic imprinting. PMID:26323243

  11. From neural to genetic substrates of panic disorder: Insights from human and mouse studies.

    PubMed

    Santos, Mónica; D'Amico, Davide; Dierssen, Mara

    2015-07-15

    Fear is an ancestral emotion, an intrinsic defensive response present in every organism. Although fear is an evolutionarily advantageous emotion, under certain pathologies such as panic disorder it might become exaggerated and non-adaptive. Clinical and preclinical work pinpoints that changes in cognitive processes, such as perception and interpretation of environmental stimuli that rely on brain regions responsible for high-level function, are essential for the development of fear-related disorders. This review focuses on the involvement of cognitive function to fear circuitry disorders. Moreover, we address how animal models are contributing to understand the involvement of human candidate genes to pathological fear and helping achieve progress in this field. Multidisciplinary approaches that integrate human genetic findings with state of the art genetic mouse models will allow to elucidate the mechanisms underlying pathology and to develop new strategies for therapeutic targeting. PMID:25818748

  12. Mutations in NLRP5 are associated with reproductive wastage and multilocus imprinting disorders in humans

    PubMed Central

    Docherty, Louise E.; Rezwan, Faisal I.; Poole, Rebecca L.; Turner, Claire L. S.; Kivuva, Emma; Maher, Eamonn R.; Smithson, Sarah F.; Hamilton-Shield, Julian P.; Patalan, Michal; Gizewska, Maria; Peregud-Pogorzelski, Jaroslaw; Beygo, Jasmin; Buiting, Karin; Horsthemke, Bernhard; Soellner, Lukas; Begemann, Matthias; Eggermann, Thomas; Baple, Emma; Mansour, Sahar; Temple, I. Karen; Mackay, Deborah J. G.

    2015-01-01

    Human-imprinting disorders are congenital disorders of growth, development and metabolism, associated with disturbance of parent of origin-specific DNA methylation at imprinted loci across the genome. Some imprinting disorders have higher than expected prevalence of monozygotic twinning, of assisted reproductive technology among parents, and of disturbance of multiple imprinted loci, for which few causative trans-acting mutations have been found. Here we report mutations in NLRP5 in five mothers of individuals affected by multilocus imprinting disturbance. Maternal-effect mutations of other human NLRP genes, NLRP7 and NLRP2, cause familial biparental hydatidiform mole and multilocus imprinting disturbance, respectively. Offspring of mothers with NLRP5 mutations have heterogenous clinical and epigenetic features, but cases include a discordant monozygotic twin pair, individuals with idiopathic developmental delay and autism, and families affected by infertility and reproductive wastage. NLRP5 mutations suggest connections between maternal reproductive fitness, early zygotic development and genomic imprinting. PMID:26323243

  13. Reorganization of craniofacial/cleft care delivery: the Massachusetts experience.

    PubMed

    Borah, G L; Hagberg, N; Jakubiak, C; Temple, J

    1993-05-01

    Until 1989, the Commonwealth of Massachusetts operated a mandated care program known as Services for Handicapped Children (SHC) for children with cleft lip/palate or craniofacial anomalies. During the mid 1980s, the federal government reduced its block grant funds and encouraged the Commonwealth of Massachusetts to develop Project SERVE to address this changing fiscal reality. The principal outcome of Project SERVE was the recommendation that the SHC direct care programs, including all craniofacial and cleft palate clinics, should be dismantled over a number of years. However, due to the economic recession, all government funding was suddenly withdrawn from cleft palate teams and the state-run SHC clinics were abruptly dissolved. To treat patients left without coordinated care, former team members reassembled and began a new craniofacial team based at the University of Massachusetts Medical Center. Difficulties with the transition of the clinic included recruiting and retaining team members; remuneration procedures for team members; maintenance of patient records previously kept by the state; coordination of clinical/clerical responsibilities; identifying a physical locale to hold the clinics; and solicitation of referring health care provider referrals and follow-up. All these issues required specific interventions that are presented in this paper. Project SERVE, begun under federal auspices, in the Commonwealth of Massachusetts, has recently been promoted as a model for a new and improved approach to the management of cleft palate and craniofacial care delivery nationwide. Awareness of the potential for abrupt, radical change in funding for federally mandated cleft/craniofacial care is essential, and a successful transition to a medical center-based model is possible using the procedures established at our center. PMID:8338866

  14. Imaging of matrix-disorder in normal and pathological human dermis using nonlinear optical microscopy

    NASA Astrophysics Data System (ADS)

    Zhuo, Shuangmu; Chen, Jianxin; Xie, Shusen; Zheng, Liqin; Jiang, Xingshan

    2009-11-01

    In dermis, collagen and elastin are important structural proteins of extracellular maxtrix. The matrix-disorder is associated with various physiologic processes, such as localized scleroderma, anetoderma, photoaging. In this work, we demonstrate the capability of nonlinear optical microscopy in imaging structural proteins in normal and pathological human dermis.

  15. The role of diet in triggering human inflammatory disorders in the modern age.

    PubMed

    Huang, Edmond Y; Devkota, Suzanne; Moscoso, Dagmara; Chang, Eugene B; Leone, Vanessa A

    2013-11-01

    Previously uncommon human inflammatory disorders are emerging with alarming frequency, possibly triggered by environmental factors introduced through Westernization. This review highlights how Western diets heighten the inflammatory state promoting development of disease. Evidence that this can occur directly or indirectly through perturbations of host-microbe interactions are reviewed. PMID:23876436

  16. Lentiviral vectors for treating and modeling human CNS disorders.

    PubMed

    Azzouz, Mimoun; Kingsman, Susan M; Mazarakis, Nicholas D

    2004-09-01

    Vectors based on lentiviruses efficiently deliver genes into many different types of primary neurons from a broad range of species including man and the resulting gene expression is long term. These vectors are opening up new approaches for the treatment of neurological diseases such as Parkinson's disease (PD), Huntington's disease (HD), and motor neuron diseases (MNDs). Numerous animal studies have now been undertaken with these vectors and correction of disease models has been obtained. Lentiviral vectors also provide a new strategy for in vivo modeling of human diseases; for example, the lentiviral-mediated overexpression of mutated human alpha-synuclein or huntingtin genes in basal ganglia induces neuronal pathology in animals resembling PD and HD in man. These vectors have been refined to a very high level and can be produced safely for the clinic. This review will describe the general features of lentiviral vectors with particular emphasis on vectors derived from the non-primate lentivirus, equine infectious anemia virus (EIAV). It will then describe some key examples of genetic correction and generation of genetic animal models of neurological diseases. The prospects for clinical application of lentiviral vectors for the treatment of PD and MNDs will also be outlined. PMID:15352068

  17. Long-term craniofacial osteoblast culture on a sodium phosphate and a calcium/sodium phosphate glass.

    PubMed

    Gough, J E; Christian, P; Scotchford, C A; Jones, I A

    2003-08-01

    The aim of this study was to determine the characteristics of human craniofacial osteoblasts cultured on sodium phosphate glass and calcium-sodium phosphate glass in a long-term culture of up to 28 days. The characteristics studied were attachment, proliferation, alkaline phosphatase activity, collagen-1 production, and mineralization. A comparison of the degradation rate, measured by mass loss of the glasses, which are intended for use as a component of a novel degradable composite for craniofacial bone repair, was also performed. It was our hypothesis that the glass would be degradable with a change in degradation rate observed by calcium addition and support osteoblast proliferation and expression of the above characteristics. The inclusion of calcium into the reaction mixture significantly decreased the degradation rate, and it is suggested that the slower degradation is the result of pseudo crosslinking (ionic crosslinks rather than covalent bonding) of the polyphosphate chains by the calcium ions. Therefore, twice as many P-O bonds will need to be hydrolyzed for dissolution of the metal phosphate to occur, therefore greatly reducing the rate of hydrolysis. Osteoblasts were able to attach, spread, and proliferate in a manner comparable with the positive control, as shown by analysis of variance. Formation of a collagen-rich mineralized matrix was also observed. The results presented here suggest that a biocompatible soluble glass has been produced, which has potential to be included in a novel biodegradable craniofacial implant. PMID:12888992

  18. Craniofacial variability and morphological integration in mice susceptible to cleft lip and palate

    PubMed Central

    Hallgrímsson, Benedikt; Dorval, Curtis J; Zelditch, Miriam Leah; German, Rebecca Z

    2004-01-01

    A/WySnJ mice are an inbred strain that develops cleft lip with or without cleft palate (CL/P) with a frequency of 25–30% and a predominantly unilateral expression pattern. As in humans, the pattern of incomplete penetrance, and variable and frequent unilateral expression suggests a role for altered regulation of variability (developmental stability, canalization and developmental integration) during growth. We compared both mean and variability parameters for craniofacial shape and size among A/WySnJ mice, a strain that does not develop CL/P (C57BL/6J) and their F1 cross. We show that adult A/WySnJ mice that do not express cleft lip exhibit decreased morphological integration of the cranium and that the co-ordination of overall shape and size variation is disrupted compared with both C57BL/6J mice and the F1 cross. The decrease in integration is most pronounced in the palate and face. The absence of this pattern in the F1 cross suggests that it is determined by recessive genetic factors. By contrast, the shape differences between the strains, which are thought to predispose A/WySnJ mice to CL/P, show a range of dominance which suggests a polygenic basis. We suggest that decreased integration of craniofacial growth may be an aetiological factor for CL/P in A/WySnJ mice. PMID:15610397

  19. Craniofacial and Dental Defects in the Col1a1Jrt/+ Mouse Model of Osteogenesis Imperfecta.

    PubMed

    Eimar, H; Tamimi, F; Retrouvey, J-M; Rauch, F; Aubin, J E; McKee, M D

    2016-07-01

    Certain mutations in the COL1A1 and COL1A2 genes produce clinical symptoms of both osteogenesis imperfecta (OI) and Ehlers-Danlos syndrome (EDS) that include abnormal craniofacial growth, dental malocclusion, and dentinogenesis imperfecta. A mouse model (Col1a1(Jrt)/+) was recently developed that had a skeletal phenotype and other features consistent with moderate-to-severe OI and also with EDS. The craniofacial phenotype of 4- and 20-wk-old Col1a1(Jrt)/+ mice and wild-type littermates was assessed by micro-computed tomography (µCT) and morphometry. Teeth and the periodontal ligament compartment were analyzed by µCT, light microscopy/histomorphometry, and electron microscopy. Over time, at 20 wk, Col1a1(Jrt)/+ mice developed smaller heads, a shortened anterior cranial base, class III occlusion, and a mandibular side shift with shorter morphology in the masticatory region (maxilla and mandible). Col1a1(Jrt)/+ mice also had changes in the periodontal compartment and abnormalities in the dentin matrix and mineralization. These findings validate Col1a1(Jrt)/+ mice as a model for OI and EDS in humans. PMID:26951553

  20. Using skin to assess iron accumulation in human metabolic disorders

    NASA Astrophysics Data System (ADS)

    Guinote, I.; Fleming, R.; Silva, R.; Filipe, P.; Silva, J. N.; Veríssimo, A.; Napoleão, P.; Alves, L. C.; Pinheiro, T.

    2006-08-01

    The distribution of Fe in skin was assessed to monitor body Fe status in human hereditary hemochromatosis. The paper reports on data from nine patients with hemochromatosis that were studied along the therapeutic programme. Systemic evaluation of Fe metabolism was carried out by measuring with PIXE technique the Fe concentration in plasma and blood cells, and by determining with biochemical methods the indicators of Fe transport in serum (ferritin and transferrin). The Fe distribution and concentration in skin was assessed by nuclear microscopy and Fe deposits in liver estimated through nuclear magnetic resonance. Elevated Fe concentrations in skin were related to increased plasma Fe (p < 0.004), serum ferritin content (p < 0.01) and Fe deposits in liver (p < 0.004). The relationship of Fe deposits in organs and metabolism markers may help to better understand Fe pools mobilisation and to establish the quality of skin as a marker for the disease progression and therapy efficacy.

  1. Nasal septal and craniofacial form in European- and African-derived populations.

    PubMed

    Holton, Nathan E; Yokley, Todd R; Figueroa, Aaron

    2012-09-01

    As a component of the chondrocranium, the nasal septum influences the anteroposterior dimensions of the facial skeleton. The role of the septum as a facial growth center, however, has been studied primarily in long-snouted mammals, and its precise influence on human facial growth is not as well understood. Whereas the nasal septum may be important in the anterior growth of the human facial skeleton early in ontogeny, the high incidence of nasal septal deviation in humans suggests the septum's influence on human facial length is limited to the early phases of facial growth. Nevertheless, the nasal septum follows a growth trajectory similar to the facial skeleton and, as such, its prolonged period of growth may influence other aspects of facial development. Using computed tomography scans of living human subjects (n = 70), the goal of the present study is to assess the morphological relationship between the nasal septum and facial skeleton in European- and African-derived populations, which have been shown to exhibit early developmental differences in the nasal septal-premaxillary complex. First we assessed whether there is population variation in the size of the nasal septum in European- and African-derived samples. This included an evaluation of septal deviation and the spatial constraints that influence variation in this condition. Next, we assessed the relationship between nasal septal size and craniofacial shape using multivariate regression techniques. Our results indicate that there is significant population variation in septal size and magnitude of septal deviation, both of which are greater in the European-derived sample. While septal deviation suggests a disjunction between the nasal septum and other components of the facial skeleton, we nevertheless found a significant relationship between the size of the nasal septum and craniofacial shape, which appears to largely be a response to the need to accommodate variation in nasal septal size. PMID:22747629

  2. Nasal septal and craniofacial form in European- and African-derived populations

    PubMed Central

    Holton, Nathan E; Yokley, Todd R; Figueroa, Aaron

    2012-01-01

    As a component of the chondrocranium, the nasal septum influences the anteroposterior dimensions of the facial skeleton. The role of the septum as a facial growth center, however, has been studied primarily in long-snouted mammals, and its precise influence on human facial growth is not as well understood. Whereas the nasal septum may be important in the anterior growth of the human facial skeleton early in ontogeny, the high incidence of nasal septal deviation in humans suggests the septum's influence on human facial length is limited to the early phases of facial growth. Nevertheless, the nasal septum follows a growth trajectory similar to the facial skeleton and, as such, its prolonged period of growth may influence other aspects of facial development. Using computed tomography scans of living human subjects (n = 70), the goal of the present study is to assess the morphological relationship between the nasal septum and facial skeleton in European- and African-derived populations, which have been shown to exhibit early developmental differences in the nasal septal–premaxillary complex. First we assessed whether there is population variation in the size of the nasal septum in European- and African-derived samples. This included an evaluation of septal deviation and the spatial constraints that influence variation in this condition. Next, we assessed the relationship between nasal septal size and craniofacial shape using multivariate regression techniques. Our results indicate that there is significant population variation in septal size and magnitude of septal deviation, both of which are greater in the European-derived sample. While septal deviation suggests a disjunction between the nasal septum and other components of the facial skeleton, we nevertheless found a significant relationship between the size of the nasal septum and craniofacial shape, which appears to largely be a response to the need to accommodate variation in nasal septal size. PMID:22747629

  3. From Pavlov to PTSD: The extinction of conditioned fear in rodents, humans, and in anxiety disorders

    PubMed Central

    VanElzakker, Michael B.; Dahlgren, M. Kathryn; Davis, F. Caroline; Dubois, Stacey; Shin, Lisa M.

    2014-01-01

    Nearly 100 years ago, Ivan Pavlov demonstrated that dogs could learn to use a neutral cue to predict a biologically relevant event: after repeated predictive pairings, Pavlov's dogs were conditioned to anticipate food at the sound of a bell, which caused them to salivate. Like sustenance, danger is biologically relevant, and neutral cues can take on great salience when they predict a threat to survival. In anxiety disorders such as posttraumatic stress disorder (PTSD), this type of conditioned fear fails to extinguish, and reminders of traumatic events can cause pathological conditioned fear responses for decades after danger has passed. In this review, we use fear conditioning and extinction studies to draw a direct line from Pavlov to PTSD and other anxiety disorders. We explain how rodent studies have informed neuroimaging studies of healthy humans and humans with PTSD. We describe several genes that have been linked to both PTSD and fear conditioning and extinction and explain how abnormalities in fear conditioning or extinction may reflect a general biomarker of anxiety disorders. Finally, we explore drug and neuromodulation treatments that may enhance therapeutic extinction in anxiety disorders. PMID:24321650

  4. From Pavlov to PTSD: the extinction of conditioned fear in rodents, humans, and anxiety disorders.

    PubMed

    VanElzakker, Michael B; Dahlgren, M Kathryn; Davis, F Caroline; Dubois, Stacey; Shin, Lisa M

    2014-09-01

    Nearly 100 years ago, Ivan Pavlov demonstrated that dogs could learn to use a neutral cue to predict a biologically relevant event: after repeated predictive pairings, Pavlov's dogs were conditioned to anticipate food at the sound of a bell, which caused them to salivate. Like sustenance, danger is biologically relevant, and neutral cues can take on great salience when they predict a threat to survival. In anxiety disorders such as posttraumatic stress disorder (PTSD), this type of conditioned fear fails to extinguish, and reminders of traumatic events can cause pathological conditioned fear responses for decades after danger has passed. In this review, we use fear conditioning and extinction studies to draw a direct line from Pavlov to PTSD and other anxiety disorders. We explain how rodent studies have informed neuroimaging studies of healthy humans and humans with PTSD. We describe several genes that have been linked to both PTSD and fear conditioning and extinction and explain how abnormalities in fear conditioning or extinction may reflect a general biomarker of anxiety disorders. Finally, we explore drug and neuromodulation treatments that may enhance therapeutic extinction in anxiety disorders. PMID:24321650

  5. Immunohistochemical study of DNA topoisomerase II in human gastric disorders.

    PubMed Central

    Yabuki, N.; Sasano, H.; Kato, K.; Ohara, S.; Toyota, T.; Nagura, H.; Miyaike, M.; Nozaki, N.; Kikuchi, A.

    1996-01-01

    Topoisomerase II (topo II) separates chromosomes at the end of mitosis and is also the target for various chemotherapeutic agents. Expression of this enzyme has been demonstrated to increase rapidly at the end of the S to G2/M phase and decrease after the completion of mitosis. We immunolocalized topo II in specimens of both normal and neoplastic human gastric mucosas to evaluate expression of this enzyme. Three different antibodies were used for the immunostaining of topo II (anti-topo II alpha isoform, anti-topo II beta isoform and anti-topo II alpha and -beta isoforms). There were no significant differences in topo II labeling index (LI) between frozen and paraffin-embedded tissue sections obtained from the same cases. Topo II LI was significantly correlated with Ki67 LI in all of the specimens examined. The area of cells positive for Topo II was much narrower than that of Ki67 in the normal gastric glands, and the pattern of Topo II immunolocalization in both adenomas and adenocarcinomas was also essentially the same as that of Ki67. The topo II LI values (positive cells/1000 cells) for normal gastric gland, adenoma, intestinal-type adenocarcinoma, and diffuse-type adenocarcinoma were 114.7 +/- 2.2, 266.7 +/- 18.8, 277.6 +/- 19.2, and 324.5 +/- 5.3, respectively. Significant differences in topo II LI and topo II/Ki67 index were observed between normal and neoplastic mucosas (P < 0.0001) and between adenomas or intestinal-type adenocarcinoma and diffuse-type adenocarcinoma (P < 0.001 and P < 0.01, respectively). Simultaneous measurement of topo II alpha and nuclear DNA content by two-parameter flow cytometry revealed that the Jurkat cell line established from acute lymphocytic leukemia cells expressed the enzyme in cells at other than S and G2/M phases of the cell cycle whereas topo-II alpha-positive cells were predominantly observed in S and G2/M phases of the cell cycle in the cells from normal lymph nodes. These findings suggest that dys-regulation or

  6. A New Mouse Model for Mania Shares Genetic Correlates with Human Bipolar Disorder

    PubMed Central

    Saul, Michael C.; Gessay, Griffin M.; Gammie, Stephen C.

    2012-01-01

    Bipolar disorder (BPD) is a debilitating heritable psychiatric disorder. Contemporary rodent models for the manic pole of BPD have primarily utilized either single locus transgenics or treatment with psychostimulants. Our lab recently characterized a mouse strain termed Madison (MSN) that naturally displays a manic phenotype, exhibiting elevated locomotor activity, increased sexual behavior, and higher forced swimming relative to control strains. Lithium chloride and olanzapine treatments attenuate this phenotype. In this study, we replicated our locomotor activity experiment, showing that MSN mice display generationally-stable mania relative to their outbred ancestral strain, hsd:ICR (ICR). We then performed a gene expression microarray experiment to compare hippocampus of MSN and ICR mice. We found dysregulation of multiple transcripts whose human orthologs are associated with BPD and other psychiatric disorders including schizophrenia and ADHD, including: Epor, Smarca4, Cmklr1, Cat, Tac1, Npsr1, Fhit, and P2rx7. RT-qPCR confirmed dysregulation for all of seven transcripts tested. Using a novel genome enrichment algorithm, we found enrichment in genome regions homologous to human loci implicated in BPD in replicated linkage studies including homologs of human cytobands 1p36, 3p14, 3q29, 6p21–22, 12q24, 16q24, and 17q25. Using a functional network analysis, we found dysregulation of a gene system related to chromatin packaging, a result convergent with recent human findings on BPD. Our findings suggest that MSN mice represent a polygenic model for the manic pole of BPD showing much of the genetic systems complexity of the corresponding human disorder. Further, the high degree of convergence between our findings and the human literature on BPD brings up novel questions about evolution by analogy in mammalian genomes. PMID:22675514

  7. [Cytoskeletal disorders in human keratinocytes--epidermolysis bullosa simplex].

    PubMed

    Kitajima, Y; Jokura, Y; Yaoita, H

    1991-06-01

    The cytoskeletons possibly related to pathogenesis in skin disease may be limited to keratin intermediate filaments (KIF) in epidermal keratinocytes. Keratins are divided into two subclasses; 11 acidic (type I) keratins and 8 basic (type II) keratins. Combination of equimolar amounts of type I and type II can form KIF. KIFs in human epidermal basal cells consist of a pair of type I and type II keratins specifically synthesized in the basal cells, and those in spinous cells contain two pairs of keratin; a pair of basal cell keratin and another pair of keratin specific for suprabasal cells. In the first section, molecular biology and differentiation of keratins are reviewed. In the second section, epidermolysis bullosa simplex (EBS) was introduced from the view point of abnormal organization of KIFs. In the epidermis of EBS, clefts are induced in the basal cells by minor trauma or frictions consequently to produce bullae. Electron microscopy reveals small spherical aggregations of tonofilaments (KIFs) in the basal cells. In biopsies, these KIF aggregations might be caused by artifacts during procedures for biopsies, so that, in order to avoid these artifacts, we studied the KIF organization in cultured keratinocytes from a patient by immunofluorescence using anti-keratin antibodies and electron microscopy. Anti-keratin antibodies revealed a formation of small droplet-like aggregations of KIFs in many cultured cells adhering to the culture bottles, which were also suggested by electron microscopy. From these observations, it is suggested that the abnormal organization (droplets) of KIFs might be one of intrinsic factors for the pathogenesis of EBS.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1720328

  8. Does D-cycloserine enhance exposure therapy for anxiety disorders in humans? A meta-analysis.

    PubMed

    Rodrigues, Helga; Figueira, Ivan; Lopes, Alessandra; Gonçalves, Raquel; Mendlowicz, Mauro Vitor; Coutinho, Evandro Silva Freire; Ventura, Paula

    2014-01-01

    The treatment of anxiety is on the edge of a new era of combinations of pharmacologic and psychosocial interventions. A new wave of translational research has focused on the use of pharmacological agents as psychotherapy adjuvants using neurobiological insights into the mechanism of the action of certain psychological treatments such as exposure therapy. Recently, d-cycloserine (DCS) an antibiotic used to treat tuberculosis has been applied to enhance exposure-based treatment for anxiety and has proved to be a promising, but as yet unproven intervention. The present study aimed to evaluate the efficacy of DCS in the enhancement of exposure therapy in anxiety disorders. A systematic review/meta-analysis was conducted. Electronic searches were conducted in the databases ISI-Web of Science, Pubmed and PsycINFO. We included only randomized, double-blind, placebo-controlled trials with humans, focusing on the role of DCS in enhancing the action of exposure therapy for anxiety disorders. We identified 328 references, 13 studies were included in our final sample: 4 on obsessive-compulsive disorder, 2 on panic disorder, 2 on social anxiety disorder, 2 on posttraumatic stress disorder, one on acrophobia, and 2 on snake phobia. The results of the present meta-analysis show that DCS enhances exposure therapy in the treatment of anxiety disorders (Cohen d =  -0.34; CI: -0.54 to -0.14), facilitating the specific process of extinction of fear. DCS seems to be effective when administered at a time close to the exposure therapy, at low doses and a limited number of times. DCS emerges as a potential new therapeutic approach for patients with refractory anxiety disorders that are unresponsive to the conventional treatments available. When administered correctly, DCS is a promising strategy for augmentation of CBT and could reduce health care costs, drop-out rates and bring faster relief to patients. PMID:24991926

  9. Does D-Cycloserine Enhance Exposure Therapy for Anxiety Disorders in Humans? A Meta-Analysis

    PubMed Central

    Rodrigues, Helga; Figueira, Ivan; Lopes, Alessandra; Gonçalves, Raquel; Mendlowicz, Mauro Vitor; Coutinho, Evandro Silva Freire; Ventura, Paula

    2014-01-01

    The treatment of anxiety is on the edge of a new era of combinations of pharmacologic and psychosocial interventions. A new wave of translational research has focused on the use of pharmacological agents as psychotherapy adjuvants using neurobiological insights into the mechanism of the action of certain psychological treatments such as exposure therapy. Recently, d-cycloserine (DCS) an antibiotic used to treat tuberculosis has been applied to enhance exposure-based treatment for anxiety and has proved to be a promising, but as yet unproven intervention. The present study aimed to evaluate the efficacy of DCS in the enhancement of exposure therapy in anxiety disorders. A systematic review/meta-analysis was conducted. Electronic searches were conducted in the databases ISI-Web of Science, Pubmed and PsycINFO. We included only randomized, double-blind, placebo-controlled trials with humans, focusing on the role of DCS in enhancing the action of exposure therapy for anxiety disorders. We identified 328 references, 13 studies were included in our final sample: 4 on obsessive-compulsive disorder, 2 on panic disorder, 2 on social anxiety disorder, 2 on posttraumatic stress disorder, one on acrophobia, and 2 on snake phobia. The results of the present meta-analysis show that DCS enhances exposure therapy in the treatment of anxiety disorders (Cohen d =  −0.34; CI: −0.54 to −0.14), facilitating the specific process of extinction of fear. DCS seems to be effective when administered at a time close to the exposure therapy, at low doses and a limited number of times. DCS emerges as a potential new therapeutic approach for patients with refractory anxiety disorders that are unresponsive to the conventional treatments available. When administered correctly, DCS is a promising strategy for augmentation of CBT and could reduce health care costs, drop-out rates and bring faster relief to patients. PMID:24991926

  10. Neuroanatomic Connectivity of the Human Ascending Arousal System Critical to Consciousness and Its Disorders

    PubMed Central

    Edlow, Brian L.; Takahashi, Emi; Wu, Ona; Benner, Thomas; Dai, Guangping; Bu, Lihong; Grant, P. Ellen; Greer, David M.; Greenberg, Steven M.; Kinney, Hannah C.; Folkerth, Rebecca D.

    2012-01-01

    The ascending reticular activating system (ARAS) mediates arousal, an essential component of human consciousness. Lesions of the ARAS cause coma, the most severe disorder of consciousness. Because of current methodological limitations, including of postmortem tissue analysis, the neuroanatomic connectivity of the human ARAS is poorly understood. We applied the advanced imaging technique of high angular resolution diffusion imaging (HARDI) to elucidate the structural connectivity of the ARAS in 3 adult human brains, 2 of which were imaged postmortem. HARDI tractography identified the ARAS connectivity previously described in animals and also revealed novel human pathways connecting the brainstem to the thalamus, hypothalamus, and basal forebrain. Each pathway contained different distributions of fiber tracts from known neurotransmitter-specific ARAS nuclei in the brainstem. The histologically guided tractography findings reported here provide initial evidence for human-specific pathways of the ARAS. The unique composition of neurotransmitter-specific fiber tracts within each ARAS pathway suggests structural specializations that subserve the different functional characteristics of human arousal. This ARAS connectivity analysis provides proof of principle that HARDI tractography may impact the study of human consciousness and its disorders, including in neuropathologic studies of patients dying in coma and the persistent vegetative state. PMID:22592840

  11. Human transcription factors contain a high fraction of intrinsically disordered regions essential for transcriptional regulation.

    PubMed

    Minezaki, Yoshiaki; Homma, Keiichi; Kinjo, Akira R; Nishikawa, Ken

    2006-06-16

    Human transcriptional regulation factors, such as activators, repressors, and enhancer-binding factors are quite different from their prokaryotic counterparts in two respects: the average sequence in human is more than twice as long as that in prokaryotes, while the fraction of sequence aligned to domains of known structure is 31% in human transcription factors (TFs), less than half of that in bacterial TFs (72%). Intrinsically disordered (ID) regions were identified by a disorder-prediction program, and were found to be in good agreement with available experimental data. Analysis of 401 human TFs with experimental evidence from the Swiss-Prot database showed that as high as 49% of the entire sequence of human TFs is occupied by ID regions. More than half of the human TFs consist of a small DNA binding domain (DBD) and long ID regions frequently sandwiching unassigned regions. The remaining TFs have structural domains in addition to DBDs and ID regions. Experimental studies, particularly those with NMR, revealed that the transactivation domains in unbound TFs are usually unstructured, but become structured upon binding to their partners. The sequences of human and mouse TF orthologues are 90.5% identical despite a high incidence of ID regions, probably reflecting important functional roles played by ID regions. In general ID regions occupy a high fraction in TFs of eukaryotes, but not in prokaryotes. Implications of this dichotomy are discussed in connection with their functional roles in transcriptional regulation and evolution. PMID:16697407

  12. Long-Term Expandable SOX9+ Chondrogenic Ectomesenchymal Cells from Human Pluripotent Stem Cells

    PubMed Central

    Umeda, Katsutsugu; Oda, Hirotsugu; Yan, Qing; Matthias, Nadine; Zhao, Jiangang; Davis, Brian R.; Nakayama, Naoki

    2015-01-01

    Summary Here we report the successful generation and long-term expansion of SOX9-expressing CD271+PDGFRα+CD73+ chondrogenic ectomesenchymal cells from the PAX3/SOX10/FOXD3-expressing MIXL1−CD271hiPDGFRαloCD73− neural crest-like progeny of human pluripotent stem cells in a chemically defined medium supplemented with Nodal/Activin/transforming growth factorβ (TGFβ) inhibitor and fibroblast growth factor (FGF). When “primed” with TGFβ, such cells efficiently formed translucent cartilage particles, which were completely mineralized in 12 weeks in immunocompromized mice. The ectomesenchymal cells were expandable without loss of chondrogenic potential for at least 16 passages. They maintained normal karyotype for at least 10 passages and expressed genes representing embryonic progenitors (SOX4/12, LIN28A/B), cranial mesenchyme (ALX1/3/4), and chondroprogenitors (SOX9, COL2A1) of neural crest origin (SOX8/9, NGFR, NES). Ectomesenchyme is a source of many craniofacial bone and cartilage structures. The method we describe for obtaining a large quantity of human ectomesenchymal cells will help to model craniofacial disorders in vitro and potentially provide cells for the repair of craniofacial damage. PMID:25818812

  13. Long-term expandable SOX9+ chondrogenic ectomesenchymal cells from human pluripotent stem cells.

    PubMed

    Umeda, Katsutsugu; Oda, Hirotsugu; Yan, Qing; Matthias, Nadine; Zhao, Jiangang; Davis, Brian R; Nakayama, Naoki

    2015-04-14

    Here we report the successful generation and long-term expansion of SOX9-expressing CD271(+)PDGFRα(+)CD73(+) chondrogenic ectomesenchymal cells from the PAX3/SOX10/FOXD3-expressing MIXL1(-)CD271(hi)PDGFRα(lo)CD73(-) neural crest-like progeny of human pluripotent stem cells in a chemically defined medium supplemented with Nodal/Activin/transforming growth factorβ (TGFβ) inhibitor and fibroblast growth factor (FGF). When "primed" with TGFβ, such cells efficiently formed translucent cartilage particles, which were completely mineralized in 12 weeks in immunocompromized mice. The ectomesenchymal cells were expandable without loss of chondrogenic potential for at least 16 passages. They maintained normal karyotype for at least 10 passages and expressed genes representing embryonic progenitors (SOX4/12, LIN28A/B), cranial mesenchyme (ALX1/3/4), and chondroprogenitors (SOX9, COL2A1) of neural crest origin (SOX8/9, NGFR, NES). Ectomesenchyme is a source of many craniofacial bone and cartilage structures. The method we describe for obtaining a large quantity of human ectomesenchymal cells will help to model craniofacial disorders in vitro and potentially provide cells for the repair of craniofacial damage. PMID:25818812

  14. The suture provides a niche for mesenchymal stem cells of craniofacial bones

    PubMed Central

    Zhao, Hu; Feng, Jifan; Ho, Thach-Vu; Grimes, Weston; Urata, Mark; Chai, Yang

    2015-01-01

    Bone tissue undergoes constant turnover supported by stem cells. Recent studies showed that perivascular mesenchymal stem cells (MSCs) contribute to the turnover of long bones. Craniofacial bones are flat bones derived from a different embryonic origin than the long bones. The identity and regulating niche for craniofacial bone MSCs remain unknown. Here, we identify Gli1+ cells within the suture mesenchyme as the major MSC population for craniofacial bones. They are not associated with vasculature, give rise to all craniofacial bones in the adult and are activated during injury repair. Gli1+ cells are typical MSCs in vitro. Ablation of Gli1+ cells leads to craniosynostosis and arrest of skull growth, indicating these cells are an indispensible stem cell population. Twist1+/− mice with craniosynostosis show reduced Gli1+ MSCs in sutures, suggesting that craniosynostosis may result from diminished suture stem cells. Our study indicates that craniofacial sutures provide a unique niche for MSCs for craniofacial bone homeostasis and repair. PMID:25799059

  15. Overlap of food addiction and substance use disorders definitions: analysis of animal and human studies.

    PubMed

    Hone-Blanchet, Antoine; Fecteau, Shirley

    2014-10-01

    Food has both homeostatic and hedonic components, which makes it a potent natural reward. Food related reward could therefore promote an escalation of intake and trigger symptoms associated to withdrawal, suggesting a behavioral parallel with substance abuse. Animal and human theoretical models of food reward and addiction have emerged, raising further interrogations on the validity of a bond between Substance Use Disorders, as clinically categorized in the DSM 5, and food reward. These models propose that highly palatable food items, rich in sugar and/or fat, are overly stimulating to the brain's reward pathways. Moreover, studies have also investigated the possibility of causal link between food reward and the contemporary obesity epidemic, with obesity being potentiated and maintained due to this overwhelming food reward. Although natural rewards are a hot topic in the definition and categorization of Substance Use Disorders, proofs of concept and definite evidence are still inconclusive. This review focuses on available results from experimental studies in animal and human models exploring the concept of food addiction, in an effort to determine if it depicts a specific phenotype and if there is truly a neurobiological similarity between food addiction and Substance Use Disorders. It describes results from sugar, fat and sweet-fat bingeing in rodent models, and behavioral and neurobiological assessments in different human populations. Although pieces of behavioral and neurobiological evidence supporting a food addiction phenotype in animals and humans are interesting, it seems premature to conclude on its validity. PMID:24863044

  16. The society for craniofacial genetics and developmental biology 38th annual meeting.

    PubMed

    Taneyhill, Lisa A; Hoover-Fong, Julie; Lozanoff, Scott; Marcucio, Ralph; Richtsmeier, Joan T; Trainor, Paul A

    2016-07-01

    The mission of the Society for Craniofacial Genetics and Developmental Biology (SCGDB) is to promote education, research, and communication about normal and abnormal development of the tissues and organs of the head. The SCGDB welcomes as members undergraduate students, graduate students, post doctoral researchers, clinicians, orthodontists, scientists, and academicians who share an interest in craniofacial biology. Each year our members come together to share their novel findings, build upon, and challenge current knowledge of craniofacial biology. © 2016 Wiley Periodicals, Inc. PMID:27102868

  17. Generation algorithm of craniofacial structure contour in cephalometric images

    NASA Astrophysics Data System (ADS)

    Mondal, Tanmoy; Jain, Ashish; Sardana, H. K.

    2010-02-01

    Anatomical structure tracing on cephalograms is a significant way to obtain cephalometric analysis. Computerized cephalometric analysis involves both manual and automatic approaches. The manual approach is limited in accuracy and repeatability. In this paper we have attempted to develop and test a novel method for automatic localization of craniofacial structure based on the detected edges on the region of interest. According to the grey scale feature at the different region of the cephalometric images, an algorithm for obtaining tissue contour is put forward. Using edge detection with specific threshold an improved bidirectional contour tracing approach is proposed by an interactive selection of the starting edge pixels, the tracking process searches repetitively for an edge pixel at the neighborhood of previously searched edge pixel to segment images, and then craniofacial structures are obtained. The effectiveness of the algorithm is demonstrated by the preliminary experimental results obtained with the proposed method.

  18. Expression in the human brain of retinoic acid induced 1, a protein associated with neurobehavioural disorders.

    PubMed

    Fragoso, Yara Dadalti; Stoney, Patrick N; Shearer, Kirsty D; Sementilli, Angelo; Nanescu, Sonia E; Sementilli, Pietro; McCaffery, Peter

    2015-03-01

    Retinoic acid induced 1 (RAI1) is a protein of uncertain mechanism of action which nevertheless has been the focus of attention because it is a major contributing factor in several human developmental disorders including Smith-Magenis and Potocki-Lupski syndromes. Further, RAI1 may be linked to adult neural disorders with developmental origins such as schizophrenia and autism. The protein has been extensively examined in the rodent but very little is known about its distribution in the human central nervous system. This study demonstrated the presence of RAI1 transcript in multiple regions of the human brain. The cellular expression of RAI1 protein in the human brain was found to be similar to that described in the mouse, with high levels in neurons, but not glia, of the dentate gyrus and cornus ammonis of the hippocampus. In the cerebellum, a second region of high expression, RAI1 was present in Purkinje cells, but not granule cells. RAI1 was also found in neurons of the occipital cortex. The expression of this retinoic acid-induced protein matched well in the hippocampus with expression of the retinoic acid receptors. The subcellular distribution of human neuronal RAI1 indicated its presence in both cytoplasm and nucleus. Overall, human RAI1 protein was found to be a highly expressed neuronal protein whose distribution matches well with its role in cognitive and motor skills. PMID:24519454

  19. Human skeletal muscle xenograft as a new preclinical model for muscle disorders.

    PubMed

    Zhang, Yuanfan; King, Oliver D; Rahimov, Fedik; Jones, Takako I; Ward, Christopher W; Kerr, Jaclyn P; Liu, Naili; Emerson, Charles P; Kunkel, Louis M; Partridge, Terence A; Wagner, Kathryn R

    2014-06-15

    Development of novel therapeutics requires good animal models of disease. Disorders for which good animal models do not exist have very few drugs in development or clinical trial. Even where there are accepted, albeit imperfect models, the leap from promising preclinical drug results to positive clinical trials commonly fails, including in disorders of skeletal muscle. The main alternative model for early drug development, tissue culture, lacks both the architecture and, usually, the metabolic fidelity of the normal tissue in vivo. Herein, we demonstrate the feasibility and validity of human to mouse xenografts as a preclinical model of myopathy. Human skeletal muscle biopsies transplanted into the anterior tibial compartment of the hindlimbs of NOD-Rag1(null) IL2rγ(null) immunodeficient host mice regenerate new vascularized and innervated myofibers from human myogenic precursor cells. The grafts exhibit contractile and calcium release behavior, characteristic of functional muscle tissue. The validity of the human graft as a model of facioscapulohumeral muscular dystrophy is demonstrated in disease biomarker studies, showing that gene expression profiles of xenografts mirror those of the fresh donor biopsies. These findings illustrate the value of a new experimental model of muscle disease, the human muscle xenograft in mice, as a feasible and valid preclinical tool to better investigate the pathogenesis of human genetic myopathies and to more accurately predict their response to novel therapeutics. PMID:24452336

  20. Functional genomics of human brain development and implications for autism spectrum disorders

    PubMed Central

    Ziats, M N; Grosvenor, L P; Rennert, O M

    2015-01-01

    Transcription of the inherited DNA sequence into copies of messenger RNA is the most fundamental process by which the genome functions to guide development. Encoded sequence information, inherited epigenetic marks and environmental influences all converge at the level of mRNA gene expression to allow for cell-type-specific, tissue-specific, spatial and temporal patterns of expression. Thus, the transcriptome represents a complex interplay between inherited genomic structure, dynamic experiential demands and external signals. This property makes transcriptome studies uniquely positioned to provide insight into complex genetic–epigenetic–environmental processes such as human brain development, and disorders with non-Mendelian genetic etiologies such as autism spectrum disorders. In this review, we describe recent studies exploring the unique functional genomics profile of the human brain during neurodevelopment. We then highlight two emerging areas of research with great potential to increase our understanding of functional neurogenomics—non-coding RNA expression and gene interaction networks. Finally, we review previous functional genomics studies of autism spectrum disorder in this context, and discuss how investigations at the level of functional genomics are beginning to identify convergent molecular mechanisms underlying this genetically heterogeneous disorder. PMID:26506051

  1. Identification and Evolutionary Analysis of Potential Candidate Genes in a Human Eating Disorder

    PubMed Central

    Mullegama, Saman; Wyckoff, Gerald J.

    2016-01-01

    The purpose of this study was to find genes linked with eating disorders and associated with both metabolic and neural systems. Our operating hypothesis was that there are genetic factors underlying some eating disorders resting in both those pathways. Specifically, we are interested in disorders that may rest in both sleep and metabolic function, generally called Night Eating Syndrome (NES). A meta-analysis of the Gene Expression Omnibus targeting the mammalian nervous system, sleep, and obesity studies was performed, yielding numerous genes of interest. Through a text-based analysis of the results, a number of potential candidate genes were identified. VGF, in particular, appeared to be relevant both to obesity and, broadly, to brain or neural development. VGF is a highly connected protein that interacts with numerous targets via proteolytically digested peptides. We examined VGF from an evolutionary perspective to determine whether other available evidence supported a role for the gene in human disease. We conclude that some of the already identified variants in VGF from human polymorphism studies may contribute to eating disorders and obesity. Our data suggest that there is enough evidence to warrant eGWAS and GWAS analysis of these genes in NES patients in a case-control study. PMID:27088090

  2. Versatility of Distraction Osteogenesis for the Craniofacial Skeleton.

    PubMed

    Klement, Kristen A; Black, Jonathan S; Denny, Arlen D

    2016-05-01

    Malformations of the craniofacial skeleton are common. Restoration of anatomic shape, size, and position has been traditionally accomplished using autologous bone grafting to fill gaps created by surgery and segmental movement. The authors present their practice using distraction in many different ages and settings over 20 years. A retrospective review was performed of all craniofacial patients treated using distraction osteogenesis for mandible, midface, and calvarium. The authors identified 205 patient. Mandible: 112 patients were treated at an average age of 3.4 years. 18.8% of patients required repeat distraction. There was no difference in the neonatal versus older group (P = 0.71). There were significantly higher reoperation rates in syndromic children (P < 0.01). Midface: 58 patients underwent Lefort III distraction at an average age of 13.6 years. One (1.7%) required repeat distraction (Miller syndrome). Five (8.6%) patients underwent subsequent Lefort I advancement for occlusal changes. Calvarium: 33 patients were treated at an average age of 4.7 years. No repeat distractions were performed. One patient required an additional advancement procedure. Distraction demonstrates successful long-term correction of defects in the craniofacial skeleton with the versatility and control needed to treat the wide spectrum of deformity. PMID:26999694

  3. Study on the performance of different craniofacial superimposition approaches (I).

    PubMed

    Ibáñez, O; Vicente, R; Navega, D S; Wilkinson, C; Jayaprakash, P T; Huete, M I; Briers, T; Hardiman, R; Navarro, F; Ruiz, E; Cavalli, F; Imaizumi, K; Jankauskas, R; Veselovskaya, E; Abramov, A; Lestón, P; Molinero, F; Cardoso, J; Çağdır, A S; Humpire, D; Nakanishi, Y; Zeuner, A; Ross, A H; Gaudio, D; Damas, S

    2015-12-01

    As part of the scientific tasks coordinated throughout The 'New Methodologies and Protocols of Forensic Identification by Craniofacial Superimposition (MEPROCS)' project, the current study aims to analyse the performance of a diverse set of CFS methodologies and the corresponding technical approaches when dealing with a common dataset of real-world cases. Thus, a multiple-lab study on craniofacial superimposition has been carried out for the first time. In particular, 26 participants from 17 different institutions in 13 countries were asked to deal with 14 identification scenarios, some of them involving the comparison of multiple candidates and unknown skulls. In total, 60 craniofacial superimposition problems divided in two set of females and males. Each participant follow her/his own methodology and employed her/his particular technological means. For each single case they were asked to report the final identification decision (either positive or negative) along with the rationale supporting the decision and at least one image illustrating the overlay/superimposition outcome. This study is expected to provide important insights to better understand the most convenient characteristics of every method included in this study. PMID:26060056

  4. Web-based cephalometric procedure for craniofacial and dentition analyses

    NASA Astrophysics Data System (ADS)

    Arun Kumar, N. S.; Kamath, Srijit R.; Ram, S.; Muthukumaran, B.; Venkatachalapathy, A.; Nandakumar, A.; Jayakumar, P.

    2000-05-01

    Craniofacial analysis is a very important and widely used procedure in orthodontic caphalometry, which plays a key role in diagnosis and treatment planning. This involves establishing reference standards and specification of landmarks and variables. The manual approach takes up a tremendous amount of the orthodontist's time. In this paper, we developed a web-based approach for the craniofacial and dentition analyses. A digital computed radiography (CR) system is utilized for obtaining the craniofacial image, which is stored as a bitmap file. The system comprises of two components - a server and a client. The server component is a program that runs on a remote machine. To use the system, the user has to connect to the website. The client component is now activated, which uploads the image from the PC and displays it on the canvas area. The landmarks are identified using a mouse interface. The reference lines are generated. The resulting image is then sent to the server which performs all measurement and calculates the mean, standard deviation, etc. of the variables. The results generated are sent immediately to the client where it is displayed on a separate frame along with the standard values for comparison. This system eliminates the need for every user to load other expensive programs on his machine.

  5. Pumpkin Seed Oil Extracted From Cucurbita maxima Improves Urinary Disorder in Human Overactive Bladder.

    PubMed

    Nishimura, Mie; Ohkawara, Tatsuya; Sato, Hiroji; Takeda, Hiroshi; Nishihira, Jun

    2014-01-01

    The pumpkin seed oil obtained from Cucurbita pepo has been shown to be useful for the treatment of nocturia in patients with urinal disorders in several western countries. In this study, we evaluated the effect of the pumpkin seed oil from Cucurbita maxima on urinary dysfunction in human overactive bladder (OAB). Forty-five subjects were enrolled in this study. An extract of pumpkin seed oil from C. maxima (10 g of oil/day) was orally administrated for 12 weeks. After 6 and 12 weeks, urinary function was evaluated using Overactive Bladder Symptom Score (OABSS). Pumpkin seed oil from C. maxima significantly reduced the degree of OABSS in the subjects. The results from our study suggest that pumpkin seed oil extracts from C. maxima as well as from C. pepo are effective for urinary disorders such as OAB in humans. PMID:24872936

  6. Epigenetic Regulation of UBE3A and Roles in Human Neurodevelopmental Disorders

    PubMed Central

    LaSalle, Janine M.; Reiter, Lawrence T.; Chamberlain, Stormy J.

    2016-01-01

    Summary The E3 ubiquitin ligase protein UBE3A, also known as E6-AP, has a multitude of ascribed functions and targets relevant to human health and disease. Epigenetic regulation of the UBE3A gene by parentally imprinted noncoding transcription within human chromosome 15q11.2-q13.3 is responsible for the maternal-specific effects of 15q11.2-q13.3 deletion or duplication disorders. Here, we review the evidence for diverse and emerging roles for UBE3A in the proteasome, synapse, and nucleus in regulating protein stability and transcription as well as the current mechanistic understanding of UBE3A imprinting in neurons. Angelman and Dup15q syndromes as well as experimental models of these neurodevelopmental disorders are highlighted as improving understanding of UBE3A and its complex regulation for improving therapeutic strategies. PMID:26585570

  7. Pumpkin Seed Oil Extracted From Cucurbita maxima Improves Urinary Disorder in Human Overactive Bladder

    PubMed Central

    Nishimura, Mie; Ohkawara, Tatsuya; Sato, Hiroji; Takeda, Hiroshi; Nishihira, Jun

    2014-01-01

    The pumpkin seed oil obtained from Cucurbita pepo has been shown to be useful for the treatment of nocturia in patients with urinal disorders in several western countries. In this study, we evaluated the effect of the pumpkin seed oil from Cucurbita maxima on urinary dysfunction in human overactive bladder (OAB). Forty-five subjects were enrolled in this study. An extract of pumpkin seed oil from C. maxima (10 g of oil/day) was orally administrated for 12 weeks. After 6 and 12 weeks, urinary function was evaluated using Overactive Bladder Symptom Score (OABSS). Pumpkin seed oil from C. maxima significantly reduced the degree of OABSS in the subjects. The results from our study suggest that pumpkin seed oil extracts from C. maxima as well as from C. pepo are effective for urinary disorders such as OAB in humans. PMID:24872936

  8. McCune–Albright syndrome with craniofacial dysplasia: Clinical review and surgical management

    PubMed Central

    Belsuzarri, Telmo Augusto Barba; Araujo, João Flavio Mattos; Melro, Carlos Alberto Morassi; Neves, Maick Willen Fernandes; Navarro, Juliano Nery; Brito, Leandro Gomes; Pontelli, Luis Otavio Carneiro; de Abreu Mattos, Luis Gustavo; Gonçales, Tiago Fernandes; Zeviani, Wolnei Marques

    2016-01-01

    Background: Fibrous dysplasia (FD) is a benign fibro-osseous lesion related to an abnormal bone development and replacement by fibrous tissue. FD has three clinical patterns namely monostotic, polyostotic, and the McCune–Albright syndrome (MAS). MAS is a rare genetic disorder (about 3% of all FD's) that comprises a triad of polyostotic FD, café-au-lait skin macules, and precocious puberty. MAS can involve the orbit region and cause stenosis in the optic canal, leading the patient to a progressive visual loss. Methods: We reported a case of craniofacial FD in MAS in a 9-year-old male with progressive visual loss, submitted to optic nerve decompression by fronto-orbito-zygomatic approach, with total recovery. A research was made at Bireme, PubMed, Cochrane, LILACS, and MEDLINE with the keywords: FD/craniofacial/McCune–Albright/Optic compression for the clinical review. Results: A clinical review of the disease was made, the multiple, clinical, and surgical management options were presented, and the case report was reported. Conclusion: MAS is a rare disease with a progressive polyostotic FD. Whenever it affects the orbit region, the optic canal, and it is associated with a progressive visual loss, the urgent optic nerve decompression is mandatory, either manually or with a rapid drill. It is known that aggressive approach is associated with less recurrence; it is also associated with worsening of the visual loss in optic nerve decompression. In MAS cases, multiple and less aggressive surgeries seem to be more suitable. PMID:27057395

  9. To grow or not to grow: Hair morphogenesis and human genetic hair disorders

    PubMed Central

    Duverger, Olivier; Morasso, Maria I.

    2014-01-01

    Mouse models have greatly helped in elucidating the molecular mechanisms involved in hair formation and regeneration. Recent publications have reviewed the genes involved in mouse hair development based on the phenotype of transgenic, knockout and mutant animal models. While much of this information has been instrumental in determining molecular aspects of human hair development and cycling, mice exhibit a specific pattern of hair morphogenesis and hair distribution throughout the body that cannot be directly correlated to human hair. In this mini-review, we discuss specific aspects of human hair follicle development and present an up-to-date summary of human genetic disorders associated with abnormalities in hair follicle morphogenesis, structure or regeneration. PMID:24361867

  10. To grow or not to grow: hair morphogenesis and human genetic hair disorders.

    PubMed

    Duverger, Olivier; Morasso, Maria I

    2014-01-01

    Mouse models have greatly helped in elucidating the molecular mechanisms involved in hair formation and regeneration. Recent publications have reviewed the genes involved in mouse hair development based on the phenotype of transgenic, knockout and mutant animal models. While much of this information has been instrumental in determining molecular aspects of human hair development and cycling, mice exhibit a specific pattern of hair morphogenesis and hair distribution throughout the body that cannot be directly correlated to human hair. In this mini-review, we discuss specific aspects of human hair follicle development and present an up-to-date summary of human genetic disorders associated with abnormalities in hair follicle morphogenesis, structure or regeneration. PMID:24361867

  11. BCL11B regulates sutural patency in the mouse craniofacial skeleton.

    PubMed

    Kyrylkova, Kateryna; Iwaniec, Urszula T; Philbrick, Kenneth A; Leid, Mark

    2016-07-15

    The transcription factor BCL11B plays essential roles during development of the immune, nervous, and cutaneous systems. Here we show that BCL11B is expressed in both osteogenic and sutural mesenchyme of the developing craniofacial complex. Bcl11b(-/-) mice exhibit increased proliferation of osteoprogenitors, premature osteoblast differentiation, and enhanced skull mineralization leading to synostoses of facial and calvarial sutures. Ectopic expression of Fgfr2c, a gene implicated in craniosynostosis in mice and humans, and that of Runx2 was detected within the affected sutures of Bcl11b(-/-) mice. These data suggest that ectopic expression of Fgfr2c in the sutural mesenchyme, without concomitant changes in the expression of FGF ligands, appears to induce the RUNX2-dependent osteogenic program and craniosynostosis in Bcl11b(-/-) mice. PMID:26453795

  12. Past, present, and future of craniofacial superimposition: Literature and international surveys.

    PubMed

    Huete, Maria Isabel; Ibáñez, Oscar; Wilkinson, Caroline; Kahana, Tzipi

    2015-07-01

    In this manuscript, the past, present and future of the identification of human remains based on craniofacial superimposition is reviewed. An analysis of the different technological approaches developed over time is offered in conjunction with a new classification based on the technology implemented throughout the diverse phases of the process. The state of the art of the technique, in the academic and forensic realms, is reflected in an extensive international survey that includes over one hundred experts worldwide. The results of the survey indicate the current relative importance of the technique, despite of its controversial nature within the scientific community. Finally, the future challenges to be faced to justify the use of this technique for either profiling, exclusion or identification purposes are discussed. PMID:25725530

  13. Human Urine-Derived Renal Progenitors for Personalized Modeling of Genetic Kidney Disorders

    PubMed Central

    Ronconi, Elisa; Angelotti, Maria Lucia; Peired, Anna; Mazzinghi, Benedetta; Becherucci, Francesca; Conti, Sara; Sansavini, Giulia; Sisti, Alessandro; Ravaglia, Fiammetta; Lombardi, Duccio; Provenzano, Aldesia; Manonelles, Anna; Cruzado, Josep M.; Giglio, Sabrina; Roperto, Rosa Maria; Materassi, Marco; Lasagni, Laura

    2015-01-01

    The critical role of genetic and epigenetic factors in the pathogenesis of kidney disorders is gradually becoming clear, and the need for disease models that recapitulate human kidney disorders in a personalized manner is paramount. In this study, we describe a method to select and amplify renal progenitor cultures from the urine of patients with kidney disorders. Urine-derived human renal progenitors exhibited phenotype and functional properties identical to those purified from kidney tissue, including the capacity to differentiate into tubular cells and podocytes, as demonstrated by confocal microscopy, Western blot analysis of podocyte-specific proteins, and scanning electron microscopy. Lineage tracing studies performed with conditional transgenic mice, in which podocytes are irreversibly tagged upon tamoxifen treatment (NPHS2.iCreER;mT/mG), that were subjected to doxorubicin nephropathy demonstrated that renal progenitors are the only urinary cell population that can be amplified in long-term culture. To validate the use of these cells for personalized modeling of kidney disorders, renal progenitors were obtained from (1) the urine of children with nephrotic syndrome and carrying potentially pathogenic mutations in genes encoding for podocyte proteins and (2) the urine of children without genetic alterations, as validated by next-generation sequencing. Renal progenitors obtained from patients carrying pathogenic mutations generated podocytes that exhibited an abnormal cytoskeleton structure and functional abnormalities compared with those obtained from patients with proteinuria but without genetic mutations. The results of this study demonstrate that urine-derived patient-specific renal progenitor cultures may be an innovative research tool for modeling of genetic kidney disorders. PMID:25568173

  14. Human Urine-Derived Renal Progenitors for Personalized Modeling of Genetic Kidney Disorders.

    PubMed

    Lazzeri, Elena; Ronconi, Elisa; Angelotti, Maria Lucia; Peired, Anna; Mazzinghi, Benedetta; Becherucci, Francesca; Conti, Sara; Sansavini, Giulia; Sisti, Alessandro; Ravaglia, Fiammetta; Lombardi, Duccio; Provenzano, Aldesia; Manonelles, Anna; Cruzado, Josep M; Giglio, Sabrina; Roperto, Rosa Maria; Materassi, Marco; Lasagni, Laura; Romagnani, Paola

    2015-08-01

    The critical role of genetic and epigenetic factors in the pathogenesis of kidney disorders is gradually becoming clear, and the need for disease models that recapitulate human kidney disorders in a personalized manner is paramount. In this study, we describe a method to select and amplify renal progenitor cultures from the urine of patients with kidney disorders. Urine-derived human renal progenitors exhibited phenotype and functional properties identical to those purified from kidney tissue, including the capacity to differentiate into tubular cells and podocytes, as demonstrated by confocal microscopy, Western blot analysis of podocyte-specific proteins, and scanning electron microscopy. Lineage tracing studies performed with conditional transgenic mice, in which podocytes are irreversibly tagged upon tamoxifen treatment (NPHS2.iCreER;mT/mG), that were subjected to doxorubicin nephropathy demonstrated that renal progenitors are the only urinary cell population that can be amplified in long-term culture. To validate the use of these cells for personalized modeling of kidney disorders, renal progenitors were obtained from (1) the urine of children with nephrotic syndrome and carrying potentially pathogenic mutations in genes encoding for podocyte proteins and (2) the urine of children without genetic alterations, as validated by next-generation sequencing. Renal progenitors obtained from patients carrying pathogenic mutations generated podocytes that exhibited an abnormal cytoskeleton structure and functional abnormalities compared with those obtained from patients with proteinuria but without genetic mutations. The results of this study demonstrate that urine-derived patient-specific renal progenitor cultures may be an innovative research tool for modeling of genetic kidney disorders. PMID:25568173

  15. Mannose 6-phosphate-dependent targeting of lysosomal enzymes is required for normal craniofacial and dental development.

    PubMed

    Koehne, Till; Markmann, Sandra; Schweizer, Michaela; Muschol, Nicole; Friedrich, Reinhard E; Hagel, Christian; Glatzel, Markus; Kahl-Nieke, Bärbel; Amling, Michael; Schinke, Thorsten; Braulke, Thomas

    2016-09-01

    Mucolipidosis II (MLII) is a severe systemic genetic disorder caused by defects in mannose 6-phosphate-dependent targeting of multiple lysosomal hydrolases and subsequent lysosomal accumulation of non-degraded material. MLII patients exhibit marked facial coarseness and gingival overgrowth soon after birth, accompanied with delayed tooth eruption and dental infections. To examine the pathomechanisms of early craniofacial and dental abnormalities, we analyzed mice with an MLII patient mutation that mimic the clinical and biochemical symptoms of MLII patients. The mouse data were compared with clinical and histological data of gingiva and teeth from MLII patients. Here, we report that progressive thickening and porosity of calvarial and mandibular bones, accompanied by elevated bone loss due to 2-fold higher number of osteoclasts cause the characteristic craniofacial phenotype in MLII. The analysis of postnatal tooth development by microcomputed tomography imaging and histology revealed normal dentin and enamel formation, and increased cementum thickness accompanied with accumulation of storage material in cementoblasts of MLII mice. Massive accumulation of storage material in subepithelial cells as well as disorganization of collagen fibrils led to gingival hypertrophy. Electron and immunofluorescence microscopy, together with (35)S-sulfate incorporation experiments revealed the accumulation of non-degraded material, non-esterified cholesterol and glycosaminoglycans in gingival fibroblasts, which was accompanied by missorting of various lysosomal proteins (α-fucosidase 1, cathepsin L and Z, Npc2, α-l-iduronidase). Our study shows that MLII mice closely mimic the craniofacial and dental phenotype of MLII patients and reveals the critical role of mannose 6-phosphate-dependent targeting of lysosomal proteins for alveolar bone, cementum and gingiva homeostasis. PMID:27239697

  16. Computed tomography assessment of peripubertal craniofacial morphology in a sheep model of binge alcohol drinking in the first trimester.

    PubMed

    Birch, Sharla M; Lenox, Mark W; Kornegay, Joe N; Shen, Li; Ai, Huisi; Ren, Xiaowei; Goodlett, Charles R; Cudd, Tim A; Washburn, Shannon E

    2015-11-01

    Identification of facial dysmorphology is essential for the diagnosis of fetal alcohol syndrome (FAS); however, most children with fetal alcohol spectrum disorders (FASD) do not meet the dysmorphology criterion. Additional objective indicators are needed to help identify the broader spectrum of children affected by prenatal alcohol exposure. Computed tomography (CT) was used in a sheep model of prenatal binge alcohol exposure to test the hypothesis that quantitative measures of craniofacial bone volumes and linear distances could identify alcohol-exposed lambs. Pregnant sheep were randomly assigned to four groups: heavy binge alcohol, 2.5 g/kg/day (HBA); binge alcohol, 1.75 g/kg/day (BA); saline control (SC); and normal control (NC). Intravenous alcohol (BA; HBA) or saline (SC) infusions were given three consecutive days per week from gestation day 4-41, and a CT scan was performed on postnatal day 182. The volumes of eight skull bones, cranial circumference, and 19 linear measures of the face and skull were compared among treatment groups. Lambs from both alcohol groups showed significant reduction in seven of the eight skull bones and total skull bone volume, as well as cranial circumference. Alcohol exposure also decreased four of the 19 craniofacial measures. Discriminant analysis showed that alcohol-exposed and control lambs could be classified with high accuracy based on total skull bone volume, frontal, parietal, or mandibular bone volumes, cranial circumference, or interorbital distance. Total skull volume was significantly more sensitive than cranial circumference in identifying the alcohol-exposed lambs when alcohol-exposed lambs were classified using the typical FAS diagnostic cutoff of ≤10th percentile. This first demonstration of the usefulness of CT-derived craniofacial measures in a sheep model of FASD following binge-like alcohol exposure during the first trimester suggests that volumetric measurement of cranial bones may be a novel biomarker

  17. Latest Research from NIH's National Institute of Dental and Craniofacial Research | NIH MedlinePlus the Magazine

    MedlinePlus

    ... Health Latest Research from NIH's National Institute of Dental and Craniofacial Research Past Issues / Summer 2012 Table ... D., is director of NIH's National Institute of Dental and Craniofacial Research (NIDCR). The NIH's National Institute ...

  18. Prevascularization of biofunctional calcium phosphate cement for dental and craniofacial repairs

    PubMed Central

    Chen, Wenchuan; Thein-Han, WahWah; Weir, Michael D.; Chen, Qianming; Xu, Hockin H.K.

    2014-01-01

    Objectives Calcium phosphate cement (CPC) is promising for dental and craniofacial repairs. Vascularization in bone tissue engineering constructs is currently a major challenge. The objectives of this study were to investigate the prevascularization of macroporous CPC via coculturing human umbilical vein endothelial cells (HUVEC) and human osteoblasts (HOB), and determine the effect of RGD in CPC on microcapillary formation for the first time. Methods Macroporous CPC scaffold was prepared using CPC powder, chitosan liquid and gas-foaming porogen. Chitosan was grafted with Arg-Gly-Asp (RGD) to biofunctionalize the CPC. HUVEC and HOB were cocultured on macroporous CPC-RGD and CPC control without RGD for up to 42 d. The osteogenic and angiogenic differentiation, bone matrix mineral synthesis, and formation of microcapillary-like structures were measured. Results RGD-grafting in CPC increased the genes expressions of osteogenic and angiogenic differentiation markers than those of CPC control without RGD. Cell-synthesized bone mineral content also increased on CPC-RGD, compared to CPC control (p < 0.05). Immunostaining with endothelial marker showed that the amount of microcapillary-like structures on CPC scaffolds increased with time. At 42 d, the cumulative vessel length for CPC-RGD scaffold was 1.69-fold that of CPC control. SEM examination confirmed the morphology of self-assembled microcapillary-like structures on CPC scaffolds. Significance HUVEC+HOB coculture on macroporous CPC scaffold successfully achieved prevascularization. RGD incorporation in CPC enhanced osteogenic differentiation, bone mineral synthesis, and microcapillary-like structure formation. The novel prevascularized CPC-RGD constructs are promising for dental, craniofacial and orthopedic applications. PMID:24731858

  19. A cross-species genetic analysis identifies candidate genes for mouse anxiety and human bipolar disorder.

    PubMed

    Ashbrook, David G; Williams, Robert W; Lu, Lu; Hager, Reinmar

    2015-01-01

    Bipolar disorder (BD) is a significant neuropsychiatric disorder with a lifetime prevalence of ~1%. To identify genetic variants underlying BD genome-wide association studies (GWAS) have been carried out. While many variants of small effect associated with BD have been identified few have yet been confirmed, partly because of the low power of GWAS due to multiple comparisons being made. Complementary mapping studies using murine models have identified genetic variants for behavioral traits linked to BD, often with high power, but these identified regions often contain too many genes for clear identification of candidate genes. In the current study we have aligned human BD GWAS results and mouse linkage studies to help define and evaluate candidate genes linked to BD, seeking to use the power of the mouse mapping with the precision of GWAS. We use quantitative trait mapping for open field test and elevated zero maze data in the largest mammalian model system, the BXD recombinant inbred mouse population, to identify genomic regions associated with these BD-like phenotypes. We then investigate these regions in whole genome data from the Psychiatric Genomics Consortium's bipolar disorder GWAS to identify candidate genes associated with BD. Finally we establish the biological relevance and pathways of these genes in a comprehensive systems genetics analysis. We identify four genes associated with both mouse anxiety and human BD. While TNR is a novel candidate for BD, we can confirm previously suggested associations with CMYA5, MCTP1, and RXRG. A cross-species, systems genetics analysis shows that MCTP1, RXRG, and TNR coexpress with genes linked to psychiatric disorders and identify the striatum as a potential site of action. CMYA5, MCTP1, RXRG, and TNR are associated with mouse anxiety and human BD. We hypothesize that MCTP1, RXRG, and TNR influence intercellular signaling in the striatum. PMID:26190982

  20. A cross-species genetic analysis identifies candidate genes for mouse anxiety and human bipolar disorder

    PubMed Central

    Ashbrook, David G.; Williams, Robert W.; Lu, Lu; Hager, Reinmar

    2015-01-01

    Bipolar disorder (BD) is a significant neuropsychiatric disorder with a lifetime prevalence of ~1%. To identify genetic variants underlying BD genome-wide association studies (GWAS) have been carried out. While many variants of small effect associated with BD have been identified few have yet been confirmed, partly because of the low power of GWAS due to multiple comparisons being made. Complementary mapping studies using murine models have identified genetic variants for behavioral traits linked to BD, often with high power, but these identified regions often contain too many genes for clear identification of candidate genes. In the current study we have aligned human BD GWAS results and mouse linkage studies to help define and evaluate candidate genes linked to BD, seeking to use the power of the mouse mapping with the precision of GWAS. We use quantitative trait mapping for open field test and elevated zero maze data in the largest mammalian model system, the BXD recombinant inbred mouse population, to identify genomic regions associated with these BD-like phenotypes. We then investigate these regions in whole genome data from the Psychiatric Genomics Consortium's bipolar disorder GWAS to identify candidate genes associated with BD. Finally we establish the biological relevance and pathways of these genes in a comprehensive systems genetics analysis. We identify four genes associated with both mouse anxiety and human BD. While TNR is a novel candidate for BD, we can confirm previously suggested associations with CMYA5, MCTP1, and RXRG. A cross-species, systems genetics analysis shows that MCTP1, RXRG, and TNR coexpress with genes linked to psychiatric disorders and identify the striatum as a potential site of action. CMYA5, MCTP1, RXRG, and TNR are associated with mouse anxiety and human BD. We hypothesize that MCTP1, RXRG, and TNR influence intercellular signaling in the striatum. PMID:26190982

  1. The Serotonergic Anatomy of the Developing Human Medulla Oblongata: Implications for Pediatric Disorders of Homeostasis

    PubMed Central

    Kinney, Hannah C.; Broadbelt, Kevin G.; Haynes, Robin L.; Rognum, Ingvar J.; Paterson, David S.

    2011-01-01

    The caudal serotonergic (5-HT) system is a critical component of a medullary “homeostatic network” that regulates protective responses to metabolic stressors such as hypoxia, hypercapnia, and hyperthermia. We define anatomically the caudal 5-HT system in the human medulla as 5-HT neuronal cell bodies located in the raphé (raphé obscurus, raphé magnus, and raphé pallidus), extra-raphé (gigantocellularis, paragigantocellularis lateralis, intermediate reticular zone, lateral reticular nucleus, and nucleus subtrigeminalis), and ventral surface (arcuate nucleus). These 5-HT neurons are adjacent to all of the respiratory- and autonomic-related nuclei in the medulla where they are positioned to modulate directly the responses of these effector nuclei. In the following review, we highlight the topography and development of the caudal 5-HT system in the human fetus and infant, and its inter-relationships with nicotinic, GABAergic, and cytokine receptors. We also summarize pediatric disorders in early life which we term “developmental serotonopathies” of the caudal (as well as rostral) 5-HT domain and which are associated with homeostatic imbalances. The delineation of the development and organization of the human caudal 5-HT system provides the critical foundation for the neuropathologic elucidation of its disorders directly in the human brain. PMID:21640183

  2. Translational Meta-analytical Methods to Localize the Regulatory Patterns of Neurological Disorders in the Human Brain

    PubMed Central

    Sochat, Vanessa; David, Maude; Wall, Dennis P

    2015-01-01

    The task of mapping neurological disorders in the human brain must be informed by multiple measurements of an individual’s phenotype - neuroimaging, genomics, and behavior. We developed a novel meta-analytical approach to integrate disparate resources and generated transcriptional maps of neurological disorders in the human brain yielding a purely computational procedure to pinpoint the brain location of transcribed genes likely to be involved in either onset or maintenance of the neurological condition. PMID:26958307

  3. Structural Disorder in the Complex of Human Pregnane X Receptor and the Macrolide Antibiotic Rifampicin

    SciTech Connect

    Chrencik, Jill E.; Orans, Jillian; Moore, Linda B.; Xue, Yu; Peng, Li; Collins, Jon L.; Wisely, G. Bruce; Lambert, Millard H.; Kliewer, Steven A.; Redinbo, Matthew R.

    2010-07-13

    The human nuclear xenobiotic receptor, pregnane X receptor (PXR), detects a variety of structurally distinct endogenous and xenobiotic compounds and controls expression of genes central to drug and cholesterol metabolism. The macrolide antibiotic rifampicin, a front-line treatment for tuberculosis, is an established PXR agonist and, at 823 Da, is one of the largest known ligands for the receptor. We present the 2.8 {angstrom} crystal structure of the ligand-binding domain of human PXR in complex with rifampicin. We also use structural and mutagenesis data to examine the origins of the directed promiscuity exhibited by the PXRs across species. Three structurally flexible loops adjacent to the ligand-binding pocket of PXR are disordered in this crystal structure, including the 200-210 region that is part of a sequence insert novel to the promiscuous PXRs relative to other members of the nuclear receptor superfamily. The 4-methyl-1-piperazinyl ring of rifampicin, which would lie adjacent to the disordered protein regions, is also disordered and not observed in the structure. Taken together, our results indicate that one wall of the PXR ligand-binding cavity can remain flexible even when the receptor is in complex with an activating ligand. These observations highlight the key role that structural flexibility plays in PXR's promiscuous response to xenobiotics.

  4. Comparing ESC and iPSC—Based Models for Human Genetic Disorders

    PubMed Central

    Halevy, Tomer; Urbach, Achia

    2014-01-01

    Traditionally, human disorders were studied using animal models or somatic cells taken from patients. Such studies enabled the analysis of the molecular mechanisms of numerous disorders, and led to the discovery of new treatments. Yet, these systems are limited or even irrelevant in modeling multiple genetic diseases. The isolation of human embryonic stem cells (ESCs) from diseased blastocysts, the derivation of induced pluripotent stem cells (iPSCs) from patients’ somatic cells, and the new technologies for genome editing of pluripotent stem cells have opened a new window of opportunities in the field of disease modeling, and enabled studying diseases that couldn’t be modeled in the past. Importantly, despite the high similarity between ESCs and iPSCs, there are several fundamental differences between these cells, which have important implications regarding disease modeling. In this review we compare ESC-based models to iPSC-based models, and highlight the advantages and disadvantages of each system. We further suggest a roadmap for how to choose the optimal strategy to model each specific disorder. PMID:26237596

  5. Insight into GATA1 transcriptional activity through interrogation of cis elements disrupted in human erythroid disorders.

    PubMed

    Wakabayashi, Aoi; Ulirsch, Jacob C; Ludwig, Leif S; Fiorini, Claudia; Yasuda, Makiko; Choudhuri, Avik; McDonel, Patrick; Zon, Leonard I; Sankaran, Vijay G

    2016-04-19

    Whole-exome sequencing has been incredibly successful in identifying causal genetic variants and has revealed a number of novel genes associated with blood and other diseases. One limitation of this approach is that it overlooks mutations in noncoding regulatory elements. Furthermore, the mechanisms by which mutations in transcriptionalcis-regulatory elements result in disease remain poorly understood. Here we used CRISPR/Cas9 genome editing to interrogate three such elements harboring mutations in human erythroid disorders, which in all cases are predicted to disrupt a canonical binding motif for the hematopoietic transcription factor GATA1. Deletions of as few as two to four nucleotides resulted in a substantial decrease (>80%) in target gene expression. Isolated deletions of the canonical GATA1 binding motif completely abrogated binding of the cofactor TAL1, which binds to a separate motif. Having verified the functionality of these three GATA1 motifs, we demonstrate strong evolutionary conservation of GATA1 motifs in regulatory elements proximal to other genes implicated in erythroid disorders, and show that targeted disruption of such elements results in altered gene expression. By modeling transcription factor binding patterns, we show that multiple transcription factors are associated with erythroid gene expression, and have created predictive maps modeling putative disruptions of their binding sites at key regulatory elements. Our study provides insight into GATA1 transcriptional activity and may prove a useful resource for investigating the pathogenicity of noncoding variants in human erythroid disorders. PMID:27044088

  6. Insight into GATA1 transcriptional activity through interrogation of cis elements disrupted in human erythroid disorders

    PubMed Central

    Wakabayashi, Aoi; Ulirsch, Jacob C.; Ludwig, Leif S.; Fiorini, Claudia; Yasuda, Makiko; Choudhuri, Avik; McDonel, Patrick; Zon, Leonard I.; Sankaran, Vijay G.

    2016-01-01

    Whole-exome sequencing has been incredibly successful in identifying causal genetic variants and has revealed a number of novel genes associated with blood and other diseases. One limitation of this approach is that it overlooks mutations in noncoding regulatory elements. Furthermore, the mechanisms by which mutations in transcriptional cis-regulatory elements result in disease remain poorly understood. Here we used CRISPR/Cas9 genome editing to interrogate three such elements harboring mutations in human erythroid disorders, which in all cases are predicted to disrupt a canonical binding motif for the hematopoietic transcription factor GATA1. Deletions of as few as two to four nucleotides resulted in a substantial decrease (>80%) in target gene expression. Isolated deletions of the canonical GATA1 binding motif completely abrogated binding of the cofactor TAL1, which binds to a separate motif. Having verified the functionality of these three GATA1 motifs, we demonstrate strong evolutionary conservation of GATA1 motifs in regulatory elements proximal to other genes implicated in erythroid disorders, and show that targeted disruption of such elements results in altered gene expression. By modeling transcription factor binding patterns, we show that multiple transcription factors are associated with erythroid gene expression, and have created predictive maps modeling putative disruptions of their binding sites at key regulatory elements. Our study provides insight into GATA1 transcriptional activity and may prove a useful resource for investigating the pathogenicity of noncoding variants in human erythroid disorders. PMID:27044088

  7. The Developmental Transcriptome of the Human Brain: Implications for Neurodevelopmental Disorders

    PubMed Central

    Tebbenkamp, Andrew T. N.; Willsey, A. Jeremy; State, Matthew W.; Šestan, Nenad

    2014-01-01

    Purpose of review Recent characterizations of the transcriptome of the developing human brain by several groups have generated comprehensive datasets on coding and noncoding RNAs that will be instrumental for illuminating the underlying biology of complex neurodevelopmental disorders. This review summarizes recent studies successfully utilizing these data to increase our understanding of the molecular mechanisms of pathogenesis. Recent findings Several approaches have successfully integrated developmental transcriptome data with gene discovery to generate testable hypotheses about when and where in the developing human brain disease-associated genes converge. Specifically, these include the projection neurons in the prefrontal and primary motor-somatosensory cortex during mid-fetal development in autism spectrum disorder and the frontal cortex during fetal development in schizophrenia. Summary Developmental transcriptome data is a key to interpreting disease-associated mutations and transcriptional changes. Novel approaches integrating the spatial and temporal dimensions of these data have increased our understanding of when and where pathology occurs. Refinement of spatial and temporal properties and expanding these findings to other neurodevelopmental disorders will provide critical insights for understanding disease biology. PMID:24565942

  8. Emotion recognition in animated compared to human stimuli in adolescents with autism spectrum disorder.

    PubMed

    Brosnan, Mark; Johnson, Hilary; Grawmeyer, Beate; Chapman, Emma; Benton, Laura

    2015-06-01

    There is equivocal evidence as to whether there is a deficit in recognising emotional expressions in Autism spectrum disorder (ASD). This study compared emotion recognition in ASD in three types of emotion expression media (still image, dynamic image, auditory) across human stimuli (e.g. photo of a human face) and animated stimuli (e.g. cartoon face). Participants were 37 adolescents (age 11-16) with a diagnosis of ASD (33 male, 4 female). 42 males and 39 females served as typically developing, age-matched controls. Overall there was significant advantage for control groups over the ASD group for emotion recognition in human stimuli but not animated stimuli, across modalities. For static animated images specifically, those with ASD significantly outperformed controls. The findings are consistent with the ASD group using atypical explicit strategies. PMID:25567528

  9. Astrocytes As the Main Players in Primary Degenerative Disorders of the Human Central Nervous System

    PubMed Central

    Capani, Francisco; Quarracino, Cecilia; Caccuri, Roberto; Sica, Roberto E. P.

    2016-01-01

    Along the last years it has been demonstrated that non-neural cells play a major role in the pathogenesis of the primary degenerative disorders (PDDs) of the human central nervous system. Among them, astrocytes coordinate and participate in many different and complex metabolic processes, in close interaction with neurons. Moreover, increasing experimental evidence hints an early astrocytic dysfunction in these diseases. In this mini review we summarize the astrocytic behavior in PDDs, with special consideration to the experimental observations where astrocytic pathology precedes the development of neuronal dysfunction. We also suggest a different approach that could be consider in human investigations in Alzheimer’s and Parkinson’s disease. We believe that the study of PDDs with human brain samples may hold the key of a paradigmatic physiopathological process in which astrocytes might be the main players. PMID:26973519

  10. Astrocytes As the Main Players in Primary Degenerative Disorders of the Human Central Nervous System.

    PubMed

    Capani, Francisco; Quarracino, Cecilia; Caccuri, Roberto; Sica, Roberto E P

    2016-01-01

    Along the last years it has been demonstrated that non-neural cells play a major role in the pathogenesis of the primary degenerative disorders (PDDs) of the human central nervous system. Among them, astrocytes coordinate and participate in many different and complex metabolic processes, in close interaction with neurons. Moreover, increasing experimental evidence hints an early astrocytic dysfunction in these diseases. In this mini review we summarize the astrocytic behavior in PDDs, with special consideration to the experimental observations where astrocytic pathology precedes the development of neuronal dysfunction. We also suggest a different approach that could be consider in human investigations in Alzheimer's and Parkinson's disease. We believe that the study of PDDs with human brain samples may hold the key of a paradigmatic physiopathological process in which astrocytes might be the main players. PMID:26973519

  11. Insights from exome sequencing in common and rare human endocrine disorders

    PubMed Central

    Dauber, Andrew; de Bruin, Christiaan

    2016-01-01

    Exome sequencing has emerged in recent years as a rapid and effective tool for the elucidation of genetic defects underlying both rare and common human disease. Increased availability and decreased costs of next generation sequencing has enabled researchers worldwide to use this approach not only in individual patients with rare diseases, but also to screen larger cohorts or populations for genetic determinants of disease. Within the field of endocrinology, exome sequencing has led to significant advancements in our understanding of numerous disorders including adrenal disease, growth and pubertal disorders, type 2 diabetes, as well as a multitude of rare genetic syndromes with prominent endocrine involvement. In this review, we aim to provide an overview of these recent new insights and discuss the role that exome sequencing is expected to play in endocrine research and clinical practice in the coming years. PMID:25963271

  12. GAD2 Alternative Transcripts in the Human Prefrontal Cortex, and in Schizophrenia and Affective Disorders

    PubMed Central

    Li, Chao; Gao, Yuan; Gondré-Lewis, Marjorie C.; Lipska, Barbara K.; Shin, Joo Heon; Xie, Bin; Ye, Tianzhang; Weinberger, Daniel R.; Kleinman, Joel E.; Hyde, Thomas M.

    2016-01-01

    Genetic variation and early adverse environmental events work together to increase risk for schizophrenia. γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in adult mammalian brain, plays a major role in normal brain development, and has been strongly implicated in the pathobiology of schizophrenia. GABA synthesis is controlled by two glutamic acid decarboxylase (GAD) genes, GAD1 and GAD2, both of which produce a number of alternative transcripts. Genetic variants in the GAD1 gene are associated with increased risk for schizophrenia, and reduced expression of its major transcript in the human dorsolateral prefrontal cortex (DLPFC). No consistent changes in GAD2 expression have been found in brains from patients with schizophrenia. In this work, with the use of RNA sequencing and PCR technologies, we confirmed and tracked the expression of an alternative truncated transcript of GAD2 (ENST00000428517) in human control DLPFC homogenates across lifespan besides the well-known full length transcript of GAD2. In addition, using quantitative RT-PCR, expression of GAD2 full length and truncated transcripts were measured in the DLPFC of patients with schizophrenia, bipolar disorder and major depression. The expression of GAD2 full length transcript is decreased in the DLPFC of schizophrenia and bipolar disorder patients, while GAD2 truncated transcript is increased in bipolar disorder patients but decreased in schizophrenia patients. Moreover, the patients with schizophrenia with completed suicide or positive nicotine exposure showed significantly higher expression of GAD2 full length transcript. Alternative transcripts of GAD2 may be important in the growth and development of GABA-synthesizing neurons as well as abnormal GABA signaling in the DLPFC of patients with schizophrenia and affective disorders. PMID:26848839

  13. Effect of zinc-deficient nutrition on craniofacial bone growth in rats

    PubMed Central

    Seyedmajidi, Seyed Ali; Seyedmajidi, Maryam; Moghadamnia, Aliakbar; Haghanifar, Sina; Ziaei, Reihaneh; Zahedpasha, Samir; Arash, Valioallah; Jorsaraei, Gholamali; Halalkhor, Sohrab

    2014-01-01

    Background: Zinc (Zn) is an essential nutrient that is required in humans and animals for the growth, development, and maintenance of healthy bones. The aim of this study is to investigate the effects of zinc-deficient nutrition on the dental, mandibular, maxillary, and cranial dimensions of rats. Materials and Methods: This experimental study was carried out on 14 male Wistar rats. The rats were randomly divided into two groups. Group I rats were fed with a Zn-deficient (ZD) diet, and Group II rats with a Zn-containing (ZC) diet. All the rats on the experimental diet were killed at the end of the fourth week and their blood samples were taken. The serum Zn levels were measured by an atomic absorption spectrophotometer. Radiographic assessment of the jaw bone density was done at the end of the study. Subsequently, the final measurements were made on the dry skulls, the mandibles, and teeth in both the groups. Statistical evaluation was performed by the student's t-test and repeated measures analysis. The difference between the groups was considered statistically significant if P < 0.05. Results: The ZD group showed a significantly lower value in body weight (P < 0.05), serum level of zinc (P < 0.0001), and radiographic bone density of the mandible (P = 0.02). With regard to the craniofacial parameters, a significant difference was observed only in the length of the clinical crowns of the teeth (L13), which were longer in group II as compared to group I (P = 0.03). Conclusion: This study confirmed that changes in zinc intake could not affect the growth of craniofacial structures. Also, it might change the radiographic bone density of the mandible. PMID:25225561

  14. Magnesium Alloys as a Biomaterial for Degradable Craniofacial Screws

    PubMed Central

    Henderson, Sarah E.; Verdelis, Konstantinos; Maiti, Spandan; Pal, Siladitya; Chung, William L.; Chou, Da-Tren; Kumta, Prashant N.; Almarza, Alejandro J.

    2014-01-01

    Recently, magnesium (Mg) alloys have received significant attention as a potential biomaterial for degradable implants, and this study was directed at evaluating the suitability of Mg for craniofacial bone screws. The objective was to implant screws fabricated from commercially available Mg-alloys (pure Mg and AZ31) in-vivo in a rabbit mandible. First, Mg-alloy screws were compared to stainless steel screws in an in-vitro pull-out test and determined to have a similar holding strength (~40N). A finite element model of the screw was created using the pull-out test data, and the model can be used for future Mg-alloy screw design. Then, Mg-alloy screws were implanted for 4, 8, and 12 weeks, with two controls of an osteotomy site (hole) with no implant and a stainless steel screw implanted for 12 weeks. MicroCT (computed tomography) was used to assess bone remodeling and Mg-alloy degradation, both visually and qualitatively through volume fraction measurements for all time points. Histologic analysis was also completed for the Mg-alloys at 12 weeks. The results showed that craniofacial bone remodeling occurred around both Mg-alloy screw types. Pure Mg had a different degradation profile than AZ31, however bone growth occurred around both screw types. The degradation rate of both Mg-alloy screw types in the bone marrow space and the muscle were faster than in the cortical bone space at 12 weeks. Furthermore, it was shown that by alloying Mg, the degradation profile could be changed. These results indicate the promise of using Mg-alloys for craniofacial applications. PMID:24384125

  15. SP8 regulates signaling centers during craniofacial development.

    PubMed

    Kasberg, Abigail D; Brunskill, Eric W; Steven Potter, S

    2013-09-15

    Much of the bone, cartilage and smooth muscle of the vertebrate face is derived from neural crest (NC) cells. During craniofacial development, the anterior neural ridge (ANR) and olfactory pit (OP) signaling centers are responsible for driving the outgrowth, survival, and differentiation of NC populated facial prominences, primarily via FGF. While much is known about the functional importance of signaling centers, relatively little is understood of how these signaling centers are made and maintained. In this report we describe a dramatic craniofacial malformation in mice mutant for the zinc finger transcription factor gene Sp8. At E14.5 they show facial prominences that are reduced in size and underdeveloped, giving an almost faceless phenotype. At later times they show severe midline defects, excencephaly, hyperterlorism, cleft palate, and a striking loss of many NC and paraxial mesoderm derived cranial bones. Sp8 expression was primarily restricted to the ANR and OP regions during craniofacial development. Analysis of an extensive series of conditional Sp8 mutants confirmed the critical role of Sp8 in signaling centers, and not directly in the NC and paraxial mesoderm cells. The NC cells of the Sp8 mutants showed increased levels of apoptosis and decreased cell proliferation, thereby explaining the reduced sizes of the facial prominences. Perturbed gene expression in the Sp8 mutants was examined by laser capture microdissection coupled with microarrays, as well as in situ hybridization and immunostaining. The most dramatic differences included striking reductions in Fgf8 and Fgf17 expression in the ANR and OP signaling centers. We were also able to achieve genetic and pharmaceutical partial rescue of the Sp8 mutant phenotype by reducing Sonic Hedgehog (SHH) signaling. These results show that Sp8 primarily functions to promote Fgf expression in the ANR and OP signaling centers that drive the survival, proliferation, and differentiation of the NC and paraxial

  16. SP8 regulates signaling centers during craniofacial development

    PubMed Central

    Kasberg, Abigail D.; Brunskill, Eric W.; Potter, S. Steven

    2014-01-01

    Much of the bone, cartilage and smooth muscle of the vertebrate face is derived from neural crest (NC) cells. During craniofacial development, the anterior neural ridge (ANR) and olfactory pit (OP) signaling centers are responsible for driving the outgrowth, survival, and differentiation of NC populated facial prominences, primarily via FGF. While much is known about the functional importance of signaling centers, relatively little is understood of how these signaling centers are made and maintained. In this report we describe a dramatic craniofacial malformation in mice mutant for the zinc finger transcription factor gene Sp8. At E14.5 they show facial prominences that are reduced in size and underdeveloped, giving an almost faceless phenotype. At later times they show severe midline defects, excencephaly, hyperterlorism, cleft palate, and a striking loss of many NC and paraxial mesoderm derived cranial bones. Sp8 expression was primarily restricted to the ANR and OP regions during craniofacial development. Analysis of an extensive series of conditional Sp8 mutants confirmed the critical role of Sp8 in signaling centers, and not directly in the NC and paraxial mesoderm cells. The NC cells of the Sp8 mutants showed increased levels of apoptosis and decreased cell proliferation, thereby explaining the reduced sizes of the facial prominences. Perturbed gene expression in the Sp8 mutants was examined by laser capture microdissection coupled with microarrays, as well as in situ hybridization and immunostaining. The most dramatic differences included striking reductions in Fgf8 and Fgf17 expression in the ANR and OP signaling centers. We were also able to achieve genetic and pharmaceutical partial rescue of the Sp8 mutant phenotype by reducing Sonic Hedgehog (SHH) signaling. These results show that Sp8 primarily functions to promote Fgf expression in the ANR and OP signaling centers that drive the survival, proliferation, and differentiation of the NC and paraxial

  17. Antibacterial coating on biocomposites for cranio-facial reconstruction

    PubMed Central

    LAZAR, MADALINA ANCA; VODNAR, DAN; PRODAN, DOINA; ROTARU, HORATIU; ROMAN, CALIN RARES; SORCOI, LIDIA ADRIANA; BACIUT, GRIGORE; CAMPIAN, RADU SEPTIMIU

    2016-01-01

    Background and aims Despite the fact that implants are sterilized, antiseptic techniques are applied and systemic antibiotics are routinely administered prior to and after craniofacial surgery, infection rates between 3% and 40% are still reported for alloplastic implants, urging for implant removal. The present study focuses on the development of a fiber-reinforced composite (FRC) implant for craniofacial reconstruction with antimicrobial properties. Methods A new fiber-reinforced composite coated with gentamicin was developed and tested for bacterial adherence and antibacterial efficiency, using two of the most involved bacterial strains in the postoperative infections: Staphylococcus aureus and Pseudomonas aeruginosa. Results Bacteria were efficiently inactivated in direct contact with gentamicin coatings (p<0.05). The inhibition zone for Staphylococcus aureus ranged from 17.21 mm to 20.13 mm and for Pseudomonas aeruginosa ranged from 12.93 mm to 15.33 mm. Although no significant statistical results were found for bacterial adhesion and gentamicin concentration, (Staphylococcus aureus: β= −0.974; p=0.144>0.05 and Pseudomonas aeruginosa: β = −0.921; p=0.255>0.05), a negative relation was observed, indicating the reversed relation between the antibiotic dosage and the bacterial adherence. Conclusion The results of the two applied microbiological protocols used in the study suggested that gentamicin eluting coating inhibited not only the bacterial growth, but also led to a lower initial bacterial adhesion to the surface of the implant. Thus, antibiotic coating of craniofacial implants may reduce the infection rate related to reconstructive surgery. PMID:27547065

  18. First molar health status in different craniofacial relationships

    PubMed Central

    Linjawi, Amal I

    2016-01-01

    Objective To investigate the association between the health status of permanent first molars and different craniofacial relationships among adolescents. Study design This is a retrospective study on patients’ records aged 11–15 years. Sex, skeletal relationship, vertical growth pattern, malocclusion, overjet, and overbite were assessed. The health status of permanent first molars was recorded from the orthopantomograms and intraoral photographs as “sound” and “not sound”. Chi-square, Mann–Whitney U and Kruskal–Wallis tests, and Pearson’s correlation coefficient were used to analyze and correlate the assessed variables. Significance level was set at P<0.05. Results A total of 210 records were evaluated; 81 were male, 68 had Class I and 91 had Class II skeletal relationships. More than half of the subjects had normal (n=67) to moderate deep bite (n=72); normal (n=91), moderately increased (n=54), to severely increased (n=50) overjet; and Class I (n=106) and Class II division 1 (n=75) malocclusion. Significant differences were found in the health status of the permanent first molars with respect to sex (P=0.034), vertical growth pattern (P=0.01), and overbite (P=0.047). Strong correlations were only found between the health status of the permanent first molars and the following variables: sex (P=0.036) and vertical growth pattern (P=0.004). Significant correlation was further found between the upper left first molar health status and sex (P=0.019) and the lower right first molar health status and the vertical growth pattern (P=0.001). No significant association was found with the anteroposterior craniofacial relationships (P>0.05). Conclusion Sex difference and vertical growth patterns were found to be potential predictors of the health status of the permanent first molars. No significant association was found with the anteroposterior craniofacial relationships. PMID:27462176

  19. A Dual Comparative Approach: Integrating Lines of Evidence from Human Evolutionary Neuroanatomy and Neurodevelopmental Disorders

    PubMed Central

    Hanson, Kari L.; Hrvoj-Mihic, Branka; Semendeferi, Katerina

    2014-01-01

    The evolution of the human brain has been marked by a nearly three-fold increase in size since our divergence from the last common ancestor shared with chimpanzees and bonobos. Despite increased interest in comparative neuroanatomy and phylogenetic methods, relatively little is known regarding the effects that this enlargement has had on its internal organization, and how certain areas of the brain have differentially expanded over evolutionary time. Analyses of the microstructure of several regions of the human cortex and subcortical structures have demonstrated subtle changes at the cellular and molecular level, suggesting that the human brain is more than simply a ‘scaled-up’ primate brain. Ongoing research in comparative neuroanatomy has much to offer our understanding of human brain evolution. Through analysis of the neuroanatomical phenotype at the level of reorganization in cytoarchitecture and cellular morphology, new data continue to highlight changes in cell density and organization associated with volumetric changes in discrete regions. An understanding of the functional significance of variation in neural circuitry can further be approached through studies of atypical human development. Many neurodevelopmental disorders cause disruption in systems associated with uniquely human features of cognition, including language and social cognition. Understanding the genetic and developmental mechanisms that underlie variation in the human cognitive phenotype can help to clarify the functional significance of interspecific variation. By uniting approaches from comparative neuroanatomy and neuropathology, insights can be gained that clarify trends in human evolution. Here, we explore these lines of evidence, and their significance for understanding functional variation between species, and within neuropathological variation in the human brain. PMID:25247986

  20. Drosophila and Caenorhabditis elegans as Discovery Platforms for Genes Involved in Human Alcohol Use Disorder

    PubMed Central

    Grotewiel, Mike; Bettinger, Jill C.

    2015-01-01

    Background Despite the profound clinical significance and strong heritability of alcohol use disorder (AUD), we do not yet have a comprehensive understanding of the naturally occurring genetic variance within the human genome that drives its development. This lack of understanding is likely to be due in part to the large phenotypic and genetic heterogeneities that underlie human AUD. As a complement to genetic studies in humans, many laboratories are using the invertebrate model organisms (iMOs) Drosophila melanogaster (fruit fly) and Caenorhabditis elegans (nematode worm) to identify genetic mechanisms that influence the effects of alcohol (ethanol) on behavior. While these extremely powerful models have identified many genes that influence the behavioral responses to alcohol, in most cases it has remained unclear whether results from behavioral–genetic studies in iMOs are directly applicable to understanding the genetic basis of human AUD. Methods In this review, we critically evaluate the utility of the fly and worm models for identifying genes that influence AUD in humans. Results Based on results published through early 2015, studies in flies and worms have identified 91 and 50 genes, respectively, that influence 1 or more aspects of behavioral responses to alcohol. Collectively, these fly and worm genes correspond to 293 orthologous genes in humans. Intriguingly, 51 of these 293 human genes have been implicated in AUD by at least 1 study in human populations. Conclusions Our analyses strongly suggest that the Drosophila and C. elegans models have considerable utility for identifying orthologs of genes that influence human AUD. PMID:26173477

  1. An image processing system for locating craniofacial landmarks

    SciTech Connect

    Cardillo, J.; Sid-Ahmed, M.A. . Dept. of Electrical Engineering)

    1994-06-01

    A new automatic target recognition algorithm has been developed to extract craniofacial landmarks from lateral skull x-rays (cephalograms). The locations of these landmarks are used by orthodontists in what is referred to as a cephalometric evaluation. The evaluation assists in the diagnosis of anomalies and in the monitoring of treatments. The algorithm is based on gray-scale mathematical morphology. A statistical approach to training was used to overcome subtle differences in skeletal topographies. Decomposition was used to desensitize the algorithm to size differences. A system was trained to locate 20 landmarks. Tests on 40 x-rays showed an 85% recognition rate on average.

  2. Measuring outcomes in craniofacial and pediatric plastic surgery.

    PubMed

    Wong, Karen W Y; Forrest, Christopher R; Goodacre, Tim E E; Klassen, Anne F

    2013-04-01

    This article discusses the measurement of outcomes in craniofacial and pediatric plastic surgery, using examples of craniosynostosis and cleft lip and/or palate (CLP). The challenges in measuring the standard outcomes of function, aesthetics, and health-related quality of life are discussed, along with the importance of developing evidence and studying quality improvement in this specialty. The need to define specific and comprehensive goals is discussed with a focus on patient-reported outcomes (PROs). Examples from the development of the CLEFT-Q, a PRO instrument for patients with CLP, are provided to support the need to seek the patient perspective. PMID:23506771

  3. Crystal structure of human CRMP-4: correction of intensities for lattice-translocation disorder

    SciTech Connect

    Ponnusamy, Rajesh; Lebedev, Andrey A.; Pahlow, Steffen; Lohkamp, Bernhard

    2014-06-01

    Crystals of human CRMP-4 showed severe lattice-translocation disorder. Intensities were demodulated using the so-called lattice-alignment method and a new more general method with simplified parameterization, and the structure is presented. Collapsin response mediator proteins (CRMPs) are cytosolic phosphoproteins that are mainly involved in neuronal cell development. In humans, the CRMP family comprises five members. Here, crystal structures of human CRMP-4 in a truncated and a full-length version are presented. The latter was determined from two types of crystals, which were either twinned or partially disordered. The crystal disorder was coupled with translational NCS in ordered domains and manifested itself with a rather sophisticated modulation of intensities. The data were demodulated using either the two-lattice treatment of lattice-translocation effects or a novel method in which demodulation was achieved by independent scaling of several groups of intensities. This iterative protocol does not rely on any particular parameterization of the modulation coefficients, but uses the current refined structure as a reference. The best results in terms of R factors and map correlation coefficients were obtained using this new method. The determined structures of CRMP-4 are similar to those of other CRMPs. Structural comparison allowed the confirmation of known residues, as well as the identification of new residues, that are important for the homo- and hetero-oligomerization of these proteins, which are critical to nerve-cell development. The structures provide further insight into the effects of medically relevant mutations of the DPYSL-3 gene encoding CRMP-4 and the putative enzymatic activities of CRMPs.

  4. Effects of Pax3 modifier genes on craniofacial morphology, pigmentation, and viability: A murine model of Waardenburg syndrome variation

    SciTech Connect

    Asher, J.H. Jr.; Harrison, R.W.; Morell, R.; Carey, M.L.

    1996-06-15

    Waardenburg syndrome type 1 is caused by mutations in PAX3. Over 50 human PAX3 mutations that lead to hearing, craniofacial, limb, and pigmentation anomalies have been identified. A PAX3 mutant allele, segregating in a family, can show reduced penetrance and variable expressivity that cannot be explained by the nature of the mutation alone. The Mus musculus Pax3 mutation Sp{sup d} (Splotch-delayed, Pax3{sup Sd}p), coisogenic on the C57BL/6J (B{sub 6}) genetic background, produces in heterozygotes a white belly spot with 100% penetrance and very few other anomalies. By contrast, many Sp{sup d}/+ BC{sub 1} progeny [F{sub 1} {female} Sp{sup d}/+ ({female} Sp{sup d}/+ B{sub 6} x {male} +/+ Mus spretus) x {male} +/+ B{sub 6}] exhibit highly variable craniofacial and pigmentary anomalies. Of the BC{sub 1} Sp{sup d}/+ progeny, 23.9% are estimated to be nonviable, and 32.1% are nonpenetrant for the white belly spot. The penetrance and expressivity of the Sp{sup d}/+ genotype are controlled in part by the genetic background and the sex of the individual. A minimum of two genes interact with Sp{sup d} to influence the craniofacial features of these mice. One of these genes may be either X-linked or sex-influenced, while the other is autosomal. The A-locus (Agouti) or a gene closely linked to A also plays a role in determining craniofacial features. At least one additional gene, possibly the A-locus or a gene linked to A, interacts with Sp{sup d} and determines the presence and size of the white belly spot. The viability of BC{sub 1} mice is influenced by at least three factors: Sp{sup d}, A-locus alleles or a gene closely linked to the A-locus, and the sex of the mouse. The BC{sub 1} mice provide an opportunity to identify genes that interact with and modify the expression of Pax3 and serve as a model to identify the genes that modify the expression of human PAX3 mutations. 65 refs., 3 figs., 6 tabs.

  5. Human PEX1 is mutated in complementation group 1 of the peroxisome biogenesis disorders.

    PubMed

    Portsteffen, H; Beyer, A; Becker, E; Epplen, C; Pawlak, A; Kunau, W H; Dodt, G

    1997-12-01

    Human peroxisome biogenesis disorders (PBDs) are a group of genetically heterogeneous autosomal-recessive disease caused by mutations in PEX genes that encode peroxins, proteins required for peroxisome biogenesis. These lethal diseases include Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD) and infantile Refsum's disease (IRD), three phenotypes now thought to represent a continuum of clinical features that are most severe in ZS, milder in NALD and least severe in IRD2. At least eleven PBD complementation groups have been identified by somatic-cell hybridization analysis compared to the eighteen PEX complementation groups that have been found in yeast. We have cloned the human PEX1 gene encoding a 147-kD member of the AAA protein family (ATPases associated with diverse cellular activities), which is the putative orthologue of Saccharomyces cerevisiae Pex1p (ScPex1p). Human PEX1 has been identified by computer-based 'homology probing' using the ScPex1p sequence to screen databases of expressed sequence tags (dbEST) for human cDNA clones. Expression of PEX1 rescued the cells from the biogenesis defect in human fibroblasts of complementation group 1 (CG1), the largest PBD complementation group. We show that PEX1 is mutated in CG1 patients. PMID:9398848

  6. Light treatment for sleep disorders: consensus report. I. Chronology of seminal studies in humans.

    PubMed

    Campbell, S S; Eastman, C I; Terman, M; Lewy, A J; Boulos, Z; Dijk, D J

    1995-06-01

    Examination of the influence of the light-dark cycle on circadian rhythmicity has been a fundamental aspect of chronobiology since its inception as a scientific discipline. Beginning with Bünning's hypothetical phase response curve in 1936, the impact of timed light exposure on circadian rhythms of literally hundreds of species has been described. The view that the light-dark cycle was an important zeitgeber for the human circadian system, as well, seemed to be supported by early studies of blind and sighted subjects. Yet, by the early 1970s, based primarily on a series of studies conducted at Erling-Andechs, Germany, the notion became widely accepted that the light-dark cycle had only a weak influence on the human circadian system and that social cues played a more important role in entrainment. In 1980, investigators at the National Institute of Mental Health reported that bright light could suppress melatonin production in humans, thereby demonstrating unequivocally the powerful effects of light on the human central nervous system. This finding led directly to the use of timed bright light exposure as a tool for the study and treatment of human circadian rhythms disorders. PMID:7632984

  7. Grainyhead-like 3 regulation of endothelin-1 in the pharyngeal endoderm is critical for growth and development of the craniofacial skeleton.

    PubMed

    Dworkin, Sebastian; Simkin, Johanna; Darido, Charbel; Partridge, Darren D; Georgy, Smitha R; Caddy, Jacinta; Wilanowski, Tomasz; Lieschke, Graham J; Doggett, Karen; Heath, Joan K; Jane, Stephen M

    2014-08-01

    Craniofacial development is a highly conserved process that requires complex interactions between neural crest cells (NCCs) and pharyngeal tissues derived from all three germ layers. Signals emanating from the pharyngeal endoderm drive differentiation of NCCs into craniofacial cartilage, and disruption of this process underpins several human craniofacial defects (CFD). Here, we demonstrate that morpholino (MO)-mediated knockdown in zebrafish of the highly conserved transcription factor grainyhead-like 3 (grhl3), which is selectively expressed in the pharyngeal endoderm, leads to severe hypoplasia of the lower jaw cartilages. Phylogenetic analysis of conserved grhl-binding sites in gene regulatory regions identified endothelin-1 (edn1) as a putative direct grhl3 target gene, and this was confirmed by chromatin precipitation (ChIP) assays in zebrafish embryos. Injection of sub-phenotypic concentrations of MOs targeting both grhl3 and edn1 induced jaw abnormalities, and injection of edn1 mRNA into grhl3-morphants rescued both pharyngeal expression of the downstream effectors of edn1, and jaw cartilage formation. This study sheds new light on the role of endodermal endothelin-1 in vertebrate jaw development, and highlights potential new genetic defects that could underpin human CFD. PMID:24915580

  8. Craniofacial resection: decreased complication rate with a modified subcranial approach.

    PubMed

    Ross, D A; Marentette, L J; Moore, C E; Switz, K L

    1999-01-01

    The authors have successfully utilized a modified subcranial approach to the anterior skull base, based upon the procedure first described by Joram Raveh, as an alternative to standard craniofacial resection. The complication rate of this procedure in 31 consecutive cases (28 tumors, 2 congenital malformations, and 1 mucocele) has been 19.4% with no permanent complications, no deaths, no new neurological deficits, no brain injuries, no infections, and no seizures. Minor complications without permanent sequelae included two cases of tension pnenmocephalus, a subdural hygroma, two transient cerebrospinal fluid leaks, and a case of bacterial meningitis secondary to fecal contamination of a lumbar drain in a child. Average length of hospitalization was 7.1 days (range 2 to 16 days). The overall complication rate is considerably below the complication rate for other reported craniofacial procedures. We describe the technique we have used and the results. The subcranial approach as described herein provides wide exposure of the anterior cranial base without brain retraction, does not require prolonged operating times or hospitalization, and has a potentially lower complication rate than reported for other transfrontal transbasal approaches. PMID:17171124

  9. IFT46 plays crucial roles in craniofacial and cilia development.

    PubMed

    Park, Inji; Lee, Hyun-Kyung; Kim, Chowon; Ismail, Tayaba; Kim, Yoo-Kyung; Park, Jeen-Woo; Kwon, Oh-Shin; Kang, Beom Sik; Lee, Dong-Seok; Park, Tae-Joo; Park, Mae-Ja; Choi, Sun-Cheol; Lee, Hyun-Shik

    2016-08-26

    The intraflagellar transport (IFT) system is essential for bidirectional movement of ciliary components from the basal body to the tip beneath the ciliary sheath and is conserved for cilia and flagella formation in most vertebrates. IFT complex A is involved in anterograde trafficking, whereas complex B is involved in retrograde trafficking. IFT46 is well known as a crucial component of IFT complex B, however, its developmental functions are poorly understood. In this study, we investigated the novel functions of IFT46 during vertebrate development, especially, ciliogenesis and neurogenesis, because IFT46 is strongly expressed in both multiciliated cells of epithelial and neural tissues. Knockdown of IFT46 using morpholino microinjections caused shortening of the body axis as well as the formation of fewer and shorter cilia. Furthermore, loss of IFT46 down-regulated the expression of the neural plate and neural tube markers, thus may influence Wnt/planar cell polarity and the sonic hedgehog signaling pathway during neurogenesis. In addition, loss of IFT46 caused craniofacial defects by interfering with cartilage formation. In conclusion, our results depict that IFT46 plays important roles in cilia as well as in neural and craniofacial development. PMID:27320864

  10. Thermal shell fragment craniofacial injury: biophysics, pathophysiology, and management.

    PubMed

    Shuker, Sabri T

    2015-01-01

    This article aims to bring attention to unique risks and burns by thermal shell fragment craniofacial soft tissue injury. Hot shrapnel may inflict burns to major vessel walls and lead to life-threatening hemorrhaging or death, which adds a new challenge for craniofacial surgeons. Morbidity of thermal deep tissue may lead to deep tissue necrosis and infection.Thermal energy (TE) physics, biophysics, and pathophysiological effects relate directly to the amount of heat generated from shell casing detonation, which transfers to skin, deep tissue, as well as brain and leads to life-threatening burning of organs; this is different from shrapnel kinetic energy injury.The unprecedented increase in using a large range of explosives and high-heat thermobaric weapons contributes to the superfluous and unnecessary suffering caused by thermal injury wounds.Surgeons and medics should recognize that a surprising amount of TE can be found in an explosion or detonation of a steel-encased explosive, resulting in TEs ranging from 400 F up to 1000 F. PMID:25534053

  11. Developmental mechanisms underlying variation in craniofacial disease and evolution.

    PubMed

    Fish, Jennifer L

    2016-07-15

    Craniofacial disease phenotypes exhibit significant variation in penetrance and severity. Although many genetic contributions to phenotypic variation have been identified, genotype-phenotype correlations remain imprecise. Recent work in evolutionary developmental biology has exposed intriguing developmental mechanisms that potentially explain incongruities in genotype-phenotype relationships. This review focuses on two observations from work in comparative and experimental animal model systems that highlight how development structures variation. First, multiple genetic inputs converge on relatively few developmental processes. Investigation of when and how variation in developmental processes occurs may therefore help predict potential genetic interactions and phenotypic outcomes. Second, genetic mutation is typically associated with an increase in phenotypic variance. Several models outlining developmental mechanisms underlying mutational increases in phenotypic variance are discussed using Satb2-mediated variation in jaw size as an example. These data highlight development as a critical mediator of genotype-phenotype correlations. Future research in evolutionary developmental biology focusing on tissue-level processes may help elucidate the "black box" between genotype and phenotype, potentially leading to novel treatment, earlier diagnoses, and better clinical consultations for individuals affected by craniofacial anomalies. PMID:26724698

  12. Stem cells, growth factors and scaffolds in craniofacial regenerative medicine

    PubMed Central

    Tollemar, Viktor; Collier, Zach J.; Mohammed, Maryam K.; Lee, Michael J.; Ameer, Guillermo A.; Reid, Russell R.

    2015-01-01

    Current reconstructive approaches to large craniofacial skeletal defects are often complicated and challenging. Critical-sized defects are unable to heal via natural regenerative processes and require surgical intervention, traditionally involving autologous bone (mainly in the form of nonvascularized grafts) or alloplasts. Autologous bone grafts remain the gold standard of care in spite of the associated risk of donor site morbidity. Tissue engineering approaches represent a promising alternative that would serve to facilitate bone regeneration even in large craniofacial skeletal defects. This strategy has been tested in a myriad of iterations by utilizing a variety of osteoconductive scaffold materials, osteoblastic stem cells, as well as osteoinductive growth factors and small molecules. One of the major challenges facing tissue engineers is creating a scaffold fulfilling the properties necessary for controlled bone regeneration. These properties include osteoconduction, osetoinduction, biocompatibility, biodegradability, vascularization, and progenitor cell retention. This review will provide an overview of how optimization of the aforementioned scaffold parameters facilitates bone regenerative capabilities as well as a discussion of common osteoconductive scaffold materials. PMID:27239485

  13. A gene expression atlas of early craniofacial development.

    PubMed

    Brunskill, Eric W; Potter, Andrew S; Distasio, Andrew; Dexheimer, Phillip; Plassard, Andrew; Aronow, Bruce J; Potter, S Steven

    2014-07-15

    We present a gene expression atlas of early mouse craniofacial development. Laser capture microdissection (LCM) was used to isolate cells from the principal critical microregions, whose development, differentiation and signaling interactions are responsible for the construction of the mammalian face. At E8.5, as migrating neural crest cells begin to exit the neural fold/epidermal ectoderm boundary, we examined the cranial mesenchyme, composed of mixed neural crest and paraxial mesoderm cells, as well as cells from adjacent neuroepithelium. At E9.5 cells from the cranial mesenchyme, overlying olfactory placode/epidermal ectoderm, and underlying neuroepithelium, as well as the emerging mandibular and maxillary arches were sampled. At E10.5, as the facial prominences form, cells from the medial and lateral prominences, the olfactory pit, multiple discrete regions of underlying neuroepithelium, the mandibular and maxillary arches, including both their mesenchymal and ectodermal components, as well as Rathke's pouch, were similarly sampled and profiled using both microarray and RNA-seq technologies. Further, we performed single cell studies to better define the gene expression states of the early E8.5 pioneer neural crest cells and paraxial mesoderm. Taken together, and analyzable by a variety of biological network approaches, these data provide a complementing and cross validating resource capable of fueling discovery of novel compartment specific markers and signatures whose combinatorial interactions of transcription factors and growth factors/receptors are responsible for providing the master genetic blueprint for craniofacial development. PMID:24780627

  14. A Gene Expression Atlas of Early Craniofacial Development

    PubMed Central

    Brunskill, Eric W.; Potter, Andrew S.; Distasio, Andrew; Dexheimer, Phillip; Plassard, Andrew; Aronow, Bruce J.; Potter, S. Steven

    2014-01-01

    We present a gene expression atlas of early mouse craniofacial development. Laser capture microdissection (LCM) was used to isolate cells from the principal critical micro-regions, whose development, differentiation and signaling interactions are responsible for the construction of the mammalian face. At E8.5, as migrating neural crest cells begin to exit the neural fold/epidermal ectoderm boundary, we examined the cranial mesenchyme, composed of mixed neural crest and paraxial mesoderm cells, as well as cells from adjacent neuroepithelium. At E9.5 cells from the cranial mesenchyme, overlying olfactory placode/epidermal ectoderm, and underlying neuroepithelium, as well as the emerging mandibular and maxillary arches were sampled. At E10.5, as the facial prominences form, cells from the medial and lateral prominences, the olfactory pit, multiple discrete regions of underlying neuroepithelium, the mandibular and maxillary arches, including both their mesenchymal and ectodermal components, as well as Rathke’s pouch, were similarly sampled and profiled using both microarray and RNA-seq technologies. Further, we performed single cell studies to better define the gene expression states of the early E8.5 pioneer neural crest cells and paraxial mesoderm. Taken together, and analyzable by a variety of biological network approaches, these data provide a complementing and cross-validating resource capable of fueling discovery of novel compartment specific markers and signatures whose combinatorial interactions of transcription factors and growth factors/receptors are responsible for providing the master genetic blueprint for craniofacial development. PMID:24780627

  15. Creation of three-dimensional craniofacial standards from CBCT images

    NASA Astrophysics Data System (ADS)

    Subramanyan, Krishna; Palomo, Martin; Hans, Mark

    2006-03-01

    Low-dose three-dimensional Cone Beam Computed Tomography (CBCT) is becoming increasingly popular in the clinical practice of dental medicine. Two-dimensional Bolton Standards of dentofacial development are routinely used to identify deviations from normal craniofacial anatomy. With the advent of CBCT three dimensional imaging, we propose a set of methods to extend these 2D Bolton Standards to anatomically correct surface based 3D standards to allow analysis of morphometric changes seen in craniofacial complex. To create 3D surface standards, we have implemented series of steps. 1) Converting bi-plane 2D tracings into set of splines 2) Converting the 2D splines curves from bi-plane projection into 3D space curves 3) Creating labeled template of facial and skeletal shapes and 4) Creating 3D average surface Bolton standards. We have used datasets from patients scanned with Hitachi MercuRay CBCT scanner providing high resolution and isotropic CT volume images, digitized Bolton Standards from age 3 to 18 years of lateral and frontal male, female and average tracings and converted them into facial and skeletal 3D space curves. This new 3D standard will help in assessing shape variations due to aging in young population and provide reference to correct facial anomalies in dental medicine.

  16. Bioinformatics analysis identifies several intrinsically disordered human E3 ubiquitin-protein ligases

    PubMed Central

    Nielsen, Sofie V.; Lindorff-Larsen, Kresten; Hartmann-Petersen, Rasmus

    2016-01-01

    The ubiquitin-proteasome system targets misfolded proteins for degradation. Since the accumulation of such proteins is potentially harmful for the cell, their prompt removal is important. E3 ubiquitin-protein ligases mediate substrate ubiquitination by bringing together the substrate with an E2 ubiquitin-conjugating enzyme, which transfers ubiquitin to the substrate. For misfolded proteins, substrate recognition is generally delegated to molecular chaperones that subsequently interact with specific E3 ligases. An important exception is San1, a yeast E3 ligase. San1 harbors extensive regions of intrinsic disorder, which provide both conformational flexibility and sites for direct recognition of misfolded targets of vastly different conformations. So far, no mammalian ortholog of San1 is known, nor is it clear whether other E3 ligases utilize disordered regions for substrate recognition. Here, we conduct a bioinformatics analysis to examine >600 human and S. cerevisiae E3 ligases to identify enzymes that are similar to San1 in terms of function and/or mechanism of substrate recognition. An initial sequence-based database search was found to detect candidates primarily based on the homology of their ordered regions, and did not capture the unique disorder patterns that encode the functional mechanism of San1. However, by searching specifically for key features of the San1 sequence, such as long regions of intrinsic disorder embedded with short stretches predicted to be suitable for substrate interaction, we identified several E3 ligases with these characteristics. Our initial analysis revealed that another remarkable trait of San1 is shared with several candidate E3 ligases: long stretches of complete lysine suppression, which in San1 limits auto-ubiquitination. We encode these characteristic features into a San1 similarity-score, and present a set of proteins that are plausible candidates as San1 counterparts in humans. In conclusion, our work indicates that San1 is

  17. Dystonia and Paroxysmal Dyskinesias: Under-Recognized Movement Disorders in Domestic Animals? A Comparison with Human Dystonia/Paroxysmal Dyskinesias

    PubMed Central

    Richter, Angelika; Hamann, Melanie; Wissel, Jörg; Volk, Holger A.

    2015-01-01

    Dystonia is defined as a neurological syndrome characterized by involuntary sustained or intermittent muscle contractions causing twisting, often repetitive movements, and postures. Paroxysmal dyskinesias are episodic movement disorders encompassing dystonia, chorea, athetosis, and ballism in conscious individuals. Several decades of research have enhanced the understanding of the etiology of human dystonia and dyskinesias that are associated with dystonia, but the pathophysiology remains largely unknown. The spontaneous occurrence of hereditary dystonia and paroxysmal dyskinesia is well documented in rodents used as animal models in basic dystonia research. Several hyperkinetic movement disorders, described in dogs, horses and cattle, show similarities to these human movement disorders. Although dystonia is regarded as the third most common movement disorder in humans, it is often misdiagnosed because of the heterogeneity of etiology and clinical presentation. Since these conditions are poorly known in veterinary practice, their prevalence may be underestimated in veterinary medicine. In order to attract attention to these movement disorders, i.e., dystonia and paroxysmal dyskinesias associated with dystonia, and to enhance interest in translational research, this review gives a brief overview of the current literature regarding dystonia/paroxysmal dyskinesia in humans and summarizes similar hereditary movement disorders reported in domestic animals. PMID:26664992

  18. Structural basis for early-onset neurological disorders caused by mutations in human selenocysteine synthase

    PubMed Central

    Puppala, Anupama K.; French, Rachel L.; Matthies, Doreen; Baxa, Ulrich; Subramaniam, Sriram; Simonović, Miljan

    2016-01-01

    Selenocysteine synthase (SepSecS) catalyzes the terminal reaction of selenocysteine, and is vital for human selenoproteome integrity. Autosomal recessive inheritance of mutations in SepSecS–Ala239Thr, Thr325Ser, Tyr334Cys and Tyr429*–induced severe, early-onset, neurological disorders in distinct human populations. Although harboring different mutant alleles, patients presented remarkably similar phenotypes typified by cerebellar and cerebral atrophy, seizures, irritability, ataxia, and extreme spasticity. However, it has remained unclear how these genetic alterations affected the structure of SepSecS and subsequently elicited the development of a neurological pathology. Herein, our biophysical and structural characterization demonstrates that, with the exception of Tyr429*, pathogenic mutations decrease protein stability and trigger protein misfolding. We propose that the reduced stability and increased propensity towards misfolding are the main causes for the loss of SepSecS activity in afflicted patients, and that these factors contribute to disease progression. We also suggest that misfolding of enzymes regulating protein synthesis should be considered in the diagnosis and study of childhood neurological disorders. PMID:27576344

  19. Salt handling in the distal nephron: lessons learned from inherited human disorders.

    PubMed

    Jeck, Nikola; Schlingmann, Karl P; Reinalter, Stephan C; Kömhoff, Martin; Peters, Melanie; Waldegger, Siegfried; Seyberth, Hannsjörg W

    2005-04-01

    The molecular basis of inherited salt-losing tubular disorders with secondary hypokalemia has become much clearer in the past two decades. Two distinct segments along the nephron turned out to be affected, the thick ascending limb of Henle's loop and the distal convoluted tubule, accounting for two major clinical phenotypes, hyperprostaglandin E syndrome and Bartter-Gitelman syndrome. To date, inactivating mutations have been detected in six different genes encoding for proteins involved in renal transepithelial salt transport. Careful examination of genetically defined patients ("human knockouts") allowed us to determine the individual role of a specific protein and its contribution to the overall process of renal salt reabsorption. The recent generation of several genetically engineered mouse models that are deficient in orthologous genes further enabled us to compare the human phenotype with the animal models, revealing some unexpected interspecies differences. As the first line treatment in hyperprostaglandin E syndrome includes cyclooxygenase inhibitors, we propose some hypotheses about the mysterious role of PGE(2) in the etiology of renal salt-losing disorders. PMID:15793031

  20. Crystal structure of human CRMP-4: correction of intensities for lattice-translocation disorder

    PubMed Central

    Ponnusamy, Rajesh; Lebedev, Andrey A.; Pahlow, Steffen; Lohkamp, Bernhard

    2014-01-01

    Collapsin response mediator proteins (CRMPs) are cytosolic phosphoproteins that are mainly involved in neuronal cell development. In humans, the CRMP family comprises five members. Here, crystal structures of human CRMP-4 in a truncated and a full-length version are presented. The latter was determined from two types of crystals, which were either twinned or partially disordered. The crystal disorder was coupled with translational NCS in ordered domains and manifested itself with a rather sophisticated modulation of intensities. The data were demodulated using either the two-lattice treatment of lattice-translocation effects or a novel method in which demodulation was achieved by independent scaling of several groups of intensities. This iterative protocol does not rely on any particular parameterization of the modulation coefficients, but uses the current refined structure as a reference. The best results in terms of R factors and map correlation coefficients were obtained using this new method. The determined structures of CRMP-4 are similar to those of other CRMPs. Structural comparison allowed the confirmation of known residues, as well as the identification of new residues, that are important for the homo- and hetero-oligomerization of these proteins, which are critical to nerve-cell development. The structures provide further insight into the effects of medically relevant mutations of the DPYSL-3 gene encoding CRMP-4 and the putative enzymatic activities of CRMPs. PMID:24914979

  1. Structural basis for early-onset neurological disorders caused by mutations in human selenocysteine synthase.

    PubMed

    Puppala, Anupama K; French, Rachel L; Matthies, Doreen; Baxa, Ulrich; Subramaniam, Sriram; Simonović, Miljan

    2016-01-01

    Selenocysteine synthase (SepSecS) catalyzes the terminal reaction of selenocysteine, and is vital for human selenoproteome integrity. Autosomal recessive inheritance of mutations in SepSecS-Ala239Thr, Thr325Ser, Tyr334Cys and Tyr429*-induced severe, early-onset, neurological disorders in distinct human populations. Although harboring different mutant alleles, patients presented remarkably similar phenotypes typified by cerebellar and cerebral atrophy, seizures, irritability, ataxia, and extreme spasticity. However, it has remained unclear how these genetic alterations affected the structure of SepSecS and subsequently elicited the development of a neurological pathology. Herein, our biophysical and structural characterization demonstrates that, with the exception of Tyr429*, pathogenic mutations decrease protein stability and trigger protein misfolding. We propose that the reduced stability and increased propensity towards misfolding are the main causes for the loss of SepSecS activity in afflicted patients, and that these factors contribute to disease progression. We also suggest that misfolding of enzymes regulating protein synthesis should be considered in the diagnosis and study of childhood neurological disorders. PMID:27576344

  2. Neural and Synaptic Defects in slytherin a Zebrafish Model for Human Congenital Disorders of Glycosylation

    SciTech Connect

    Y Song; J Willer; P Scherer; J Panzer; A Kugath; E Skordalakes; R Gregg; G Willer; R Balice-Gordon

    2011-12-31

    Congenital disorder of glycosylation type IIc (CDG IIc) is characterized by mental retardation, slowed growth and severe immunodeficiency, attributed to the lack of fucosylated glycoproteins. While impaired Notch signaling has been implicated in some aspects of CDG IIc pathogenesis, the molecular and cellular mechanisms remain poorly understood. We have identified a zebrafish mutant slytherin (srn), which harbors a missense point mutation in GDP-mannose 4,6 dehydratase (GMDS), the rate-limiting enzyme in protein fucosylation, including that of Notch. Here we report that some of the mechanisms underlying the neural phenotypes in srn and in CGD IIc are Notch-dependent, while others are Notch-independent. We show, for the first time in a vertebrate in vivo, that defects in protein fucosylation leads to defects in neuronal differentiation, maintenance, axon branching, and synapse formation. Srn is thus a useful and important vertebrate model for human CDG IIc that has provided new insights into the neural phenotypes that are hallmarks of the human disorder and has also highlighted the role of protein fucosylation in neural development.

  3. The FGF23/KLOTHO Regulatory Network and Its Roles in Human Disorders.

    PubMed

    Kinoshita, S; Kawai, M

    2016-01-01

    The functions of Klotho (KL) are multifaceted and include the regulation of aging and mineral metabolism. It was originally identified as the gene responsible for premature aging-like symptoms in mice and was subsequently shown to function as a coreceptor in the fibroblast growth factor (FGF) 23 signaling pathway. The discovery of KL as a partner for FGF23 led to significant advances in understanding of the molecular mechanisms underlying phosphate and vitamin D metabolism, and simultaneously clarified the pathogenic roles of the FGF23 signaling pathway in human diseases. These novel insights led to the development of new strategies to combat disorders associated with the dysregulated metabolism of phosphate and vitamin D, and clinical trials on the blockade of FGF23 signaling in X-linked hypophosphatemic rickets are ongoing. Molecular and functional insights on KL and FGF23 have been discussed in this review and were extended to how dysregulation of the FGF23/KL axis causes human disorders associated with abnormal mineral metabolism. PMID:27125741

  4. Neural and Synaptic Defects in slytherin, a Zebrafish Model for Human Congenital Disorders of Glycosylation

    PubMed Central

    Song, Yuanquan; Willer, Jason R.; Scherer, Paul C.; Panzer, Jessica A.; Kugath, Amy; Skordalakes, Emmanuel; Gregg, Ronald G.; Willer, Gregory B.; Balice-Gordon, Rita J.

    2010-01-01

    Congenital disorder of glycosylation type IIc (CDG IIc) is characterized by mental retardation, slowed growth and severe immunodeficiency, attributed to the lack of fucosylated glycoproteins. While impaired Notch signaling has been implicated in some aspects of CDG IIc pathogenesis, the molecular and cellular mechanisms remain poorly understood. We have identified a zebrafish mutant slytherin (srn), which harbors a missense point mutation in GDP-mannose 4,6 dehydratase (GMDS), the rate-limiting enzyme in protein fucosylation, including that of Notch. Here we report that some of the mechanisms underlying the neural phenotypes in srn and in CGD IIc are Notch-dependent, while others are Notch-independent. We show, for the first time in a vertebrate in vivo, that defects in protein fucosylation leads to defects in neuronal differentiation, maintenance, axon branching, and synapse formation. Srn is thus a useful and important vertebrate model for human CDG IIc that has provided new insights into the neural phenotypes that are hallmarks of the human disorder and has also highlighted the role of protein fucosylation in neural development. PMID:21060795

  5. BCL11B expression in intramembranous osteogenesis during murine craniofacial suture development

    PubMed Central

    Holmes, Greg; van Bakel, Harm; Zhou, Xueyan; Losic, Bojan; Jabs, Ethylin Wang

    2014-01-01

    Sutures, where neighboring craniofacial bones are separated by undifferentiated mesenchyme, are major growth sites during craniofacial development. Pathologic fusion of bones within sutures occurs in a wide variety of craniosynostosis conditions and can result in dysmorphic craniofacial growth and secondary neurologic deficits. Our knowledge of the genes involved in suture formation is poor. Here we describe the novel expression pattern of the BCL11B transcription factor protein during murine embryonic craniofacial bone formation. We examined BCL11B protein expression at E14.5, E16.5, and E18.5 in 14 major craniofacial sutures of C57BL/6J mice. We found BCL11B expression to be associated with all intramembranous craniofacial bones examined. The most striking aspects of BCL11B expression were its high levels in suture mesenchyme and increasingly complementary expression with RUNX2 in differentiating osteoblasts during development. BCL11B was also expressed in mesenchyme at the non-sutural edges of intramembranous bones. No expression was seen in osteoblasts involved in endochondral ossification of the cartilaginous cranial base. BCL11B is expressed to potentially regulate the transition of mesenchymal differentiation and suture formation within craniofacial intramembranous bone. PMID:25511173

  6. Human-initiated disaster, social disorganization and post-traumatic stress disorder above Nigeria's oil basins.

    PubMed

    Beiser, Morton; Wiwa, Owens; Adebajo, Sylvia

    2010-07-01

    Survivors of human-initiated disaster are at high risk for mental disorder, most notably post-traumatic stress disorder (PTSD). Studies of PTSD have tended to focus on soldiers returning home after combat or on refugees living in resettlement countries under conditions of relative safety. However, most survivors of human-initiated disasters continue to live in or near the places where they initially experienced trauma. Insufficient attention has been paid to social disorganization in situations of continuing unrest and to its role in creating or stabilizing the symptoms of PTSD. The current study took place in the Niger Delta region of Nigeria, the scene of long-standing violence and human rights abuse that reached its apogee in 1995. The investigation, which took place in 2002, focused on two villages, one that was heavily exposed to the conflict (A, the affected village), the other relatively spared (NA, not affected). Probability samples of 45 adult residents from A and 55 from NA were interviewed with a schedule that contained the PTSD module from the WHO Diagnostic Interview Schedule. The schedule also contained a measure of exposure to the violence and abuses during the height of the conflict, as well as measures of structural and social capital that are components of community resilience. These included economic security, a sense of moral order, a sense of safety and perceived social support. The six month period prevalence of PTSD was 60 percent in A, and 14.5 percent in NA. Degree of exposure to stress as well as compromised sense of moral order, not feeling safe, and perceived lack of social support were independent predictors of PTSD. In places like the Niger Delta, where people do not physically escape from past trauma, sociocultural disintegration may interfere with communal functioning, thereby eroding community capacity to promote self-healing. PMID:20471148

  7. Ocular and craniofacial phenotypes in a large Brazilian family with congenital aniridia.

    PubMed

    Fernandes-Lima, Z S; Paixão-Côrtes, V R; Andrade, A K M de; Fernandes, A S; Coronado, B N L; Monte Filho, H P; Santos, M J; Omena Filho, R L de; Biondi, F C; Ruiz-Linares, A; Ramallo, V; Hünemeier, T; Schuler-Faccini, L; Monlleó, I L

    2015-01-01

    Congenital aniridia is a rare genetic disorder characterized by varying degrees of iris hypoplasia that are associated with additional ocular abnormalities. More than 90% of the causal mutations identified are found in the PAX6 gene, a transcription factor of critical importance in the process of neurogenesis and ocular development. Here, we investigate clinical, molecular, and craniofacial features of a large Brazilian family with congenital aniridia. Among the 56 eyes evaluated, phenotype variation encompassed bilateral total aniridia to mild iris defects with extensive variation between eyes of the same individual. PAX6 molecular screening indicated a heterozygous splice mutation (c.141 + 1G>A). Thus, we hypothesize that this splicing event may cause variation in the expression of the wild-type transcript, which may lead to the observed variation in phenotype. Affected individuals were more brachycephalic, even though their face height and cephalic circumference were not significantly different when compared to those of non-affected relatives. From this, we infer that the head shape of affected subjects may also be a result of the PAX6 splice-site mutation. Our data summarize the clinical variability associated with the ocular phenotype in a large family with aniridia, and help shed light on the role of PAX6 in neurocranial development. PMID:24266705

  8. Changing Paradigms in Cranio-Facial Regeneration: Current and New Strategies for the Activation of Endogenous Stem Cells.

    PubMed

    Mele, Luigi; Vitiello, Pietro Paolo; Tirino, Virginia; Paino, Francesca; De Rosa, Alfredo; Liccardo, Davide; Papaccio, Gianpaolo; Desiderio, Vincenzo

    2016-01-01

    Craniofacial area represent a unique district of human body characterized by a very high complexity of tissues, innervation and vascularization, and being deputed to many fundamental function such as eating, speech, expression of emotions, delivery of sensations such as taste, sight, and earing. For this reasons, tissue loss in this area following trauma or for example oncologic resection, have a tremendous impact on patients' quality of life. In the last 20 years regenerative medicine has emerged as one of the most promising approach to solve problem related to trauma, tissue loss, organ failure etc. One of the most powerful tools to be used for tissue regeneration is represented by stem cells, which have been successfully implanted in different tissue/organs with exciting results. Nevertheless, both autologous and allogeneic stem cell transplantation raise many practical and ethical concerns that make this approach very difficult to apply in clinical practice. For this reason different cell free approaches have been developed aiming to the mobilization, recruitment, and activation of endogenous stem cells into the injury site avoiding exogenous cells implant but instead stimulating patients' own stem cells to repair the lesion. To this aim many strategies have been used including functionalized bioscaffold, controlled release of stem cell chemoattractants, growth factors, BMPs, Platelet-Rich-Plasma, and other new strategies such as ultrasound wave and laser are just being proposed. Here we review all the current and new strategies used for activation and mobilization of endogenous stem cells in the regeneration of craniofacial tissue. PMID:26941656

  9. Changing Paradigms in Cranio-Facial Regeneration: Current and New Strategies for the Activation of Endogenous Stem Cells

    PubMed Central

    Mele, Luigi; Vitiello, Pietro Paolo; Tirino, Virginia; Paino, Francesca; De Rosa, Alfredo; Liccardo, Davide; Papaccio, Gianpaolo; Desiderio, Vincenzo

    2016-01-01

    Craniofacial area represent a unique district of human body characterized by a very high complexity of tissues, innervation and vascularization, and being deputed to many fundamental function such as eating, speech, expression of emotions, delivery of sensations such as taste, sight, and earing. For this reasons, tissue loss in this area following trauma or for example oncologic resection, have a tremendous impact on patients' quality of life. In the last 20 years regenerative medicine has emerged as one of the most promising approach to solve problem related to trauma, tissue loss, organ failure etc. One of the most powerful tools to be used for tissue regeneration is represented by stem cells, which have been successfully implanted in different tissue/organs with exciting results. Nevertheless, both autologous and allogeneic stem cell transplantation raise many practical and ethical concerns that make this approach very difficult to apply in clinical practice. For this reason different cell free approaches have been developed aiming to the mobilization, recruitment, and activation of endogenous stem cells into the injury site avoiding exogenous cells implant but instead stimulating patients' own stem cells to repair the lesion. To this aim many strategies have been used including functionalized bioscaffold, controlled release of stem cell chemoattractants, growth factors, BMPs, Platelet–Rich-Plasma, and other new strategies such as ultrasound wave and laser are just being proposed. Here we review all the current and new strategies used for activation and mobilization of endogenous stem cells in the regeneration of craniofacial tissue. PMID:26941656

  10. Psychosocial aspects of craniofacial disfigurement. A "State of the Art" assessment conducted by the Craniofacial Anomalies Program Branch, The National Institute of Dental Research.

    PubMed

    Stricker, G; Clifford, E; Cohen, L K; Giddon, D B; Meskin, L H; Evans, C A

    1979-10-01

    The psychosocial sequelae of craniofacial disfigurement may have as great an impact on the patient as the strictly physical aspects of the problem. Very little systematic work has been focused directly on these effects. The following broad recommendations would constitute initial research steps in this field: Development of satisfactory measures of physical attractiveness and their use in studies to explore the role of craniofacial features in over-all physical attractiveness. The establishment of valid metrics for assessing the severity of craniofacial anomalies through the use of both physiologic and behavioral measures, thus constructing a broader definition of what constitutes a craniofacial handicap. Studies of the relationships among physiologic and behavioral variables using recently developed statistical techniques and computer methods to determine the psychosocial consequences of craniofacial disfigurement. Studies of the process through which persons with various types of malocclusion decide to seek and complete treatment. The studies would include the patients' demographic characteristics, self-perceptions, perceptions of them by others, and the complex patient-clinician interactions during the treatment programs. PMID:386802

  11. Tissue-nonspecific Alkaline Phosphatase Deficiency Causes Abnormal Craniofacial Bone Development in the Alpl−/− Mouse Model of Infantile Hypophosphatasia

    PubMed Central

    Liu, Jin; Nam, Hwa Kyung; Campbell, Cassie; Gasque, Kellen Cristina da Silva; Millán, José Luis; Hatch, Nan E.

    2014-01-01

    Tissue-nonspecific alkaline phosphatase (TNAP) is an enzyme present on the surface of mineralizing cells and their derived matrix vesicles that promotes hydroxyapatite crystal growth. Hypophosphatasia (HPP) is an inborn-error-of-metabolism that, dependent upon age of onset, features rickets or osteomalacia due to loss-of function mutations in the gene (Alpl) encoding TNAP. Craniosynostosis is prevalent in infants with HPP and other forms of rachitic disease but how craniosynostosis develops in these disorders is unknown. Objectives: Because craniosynostosis carries high morbidity, we are investigating craniofacial skeletal abnormalities in Alpl−/− mice to establish these mice as a model of HPP-associated craniosynostosis and determine mechanisms by which TNAP influences craniofacial skeletal development. Methods: Cranial bone, cranial suture and cranial base abnormalities were analyzed by micro-CT and histology. Craniofacial shape abnormalities were quantified using digital calipers. TNAP expression was suppressed in MC3T3E1(C4) calvarial cells by TNAP-specific shRNA. Cells were analyzed for changes in mineralization, gene expression, proliferation, apoptosis, matrix deposition and cell adhesion. Results: Alpl−/− mice feature craniofacial shape abnormalities suggestive of limited anterior-posterior growth. Craniosynostosis in the form of bony coronal suture fusion is present by three weeks after birth. Alpl−/− mice also exhibit marked histologic abnormalities of calvarial bones and the cranial base involving growth plates, cortical and trabecular bone within two weeks of birth. Analysis of calvarial cells in which TNAP expression was suppressed by shRNA indicates that TNAP deficiency promotes aberrant osteoblastic gene expression, diminished matrix deposition, diminished proliferation, increased apoptosis and increased cell adhesion. Conclusions: These findings demonstrate that Alpl−/− mice exhibit a craniofacial skeletal phenotype similar to that

  12. PHD fingers in human diseases: disorders arising from misinterpreting epigenetic marks

    PubMed Central

    Baker, Lindsey A.; Allis, C. David; Wang, Gang G.

    2008-01-01

    Histone covalent modifications regulate many, if not all, DNA-templated processes, including gene expression and DNA damage response. The biological consequences of histone modifications are mediated partially by evolutionarily conserved “reader/effector” modules that bind to histone marks in a modification- and context-specific fashion and subsequently enact chromatin changes or recruit other proteins to do so. Recently, the Plant Homeodomain (PHD) finger has emerged as a class of specialized “reader” modules that, in some instances, recognize the methylation status of histone lysine residues, such as histone H3 lysine 4 (H3K4). While mutations in catalytic enzymes that mediate the addition or removal of histone modifications (i.e., “writers” and “erasers”) are already known to be involved in various human diseases, mutations in the modification-specific “reader” proteins are only beginning to be recognized as contributing to human diseases. For instance, point mutations, deletions or chromosomal translocations that target PHD fingers encoded by many genes (such as RAG2, ING, NSD1 and ATRX) have been associated with a wide range of human pathologies including immunological disorders, cancers, and neurological diseases. In this review, we will discuss the structural features of PHD fingers as well as the diseases for which direct mutation or dysregulation of the PHD finger has been reported. We propose that misinterpretation of the epigenetic marks may serve as a general mechanism for human diseases of this category. Determining the regulatory roles of histone covalent modifications in the context of human disease will allow for a more thorough understanding of normal and pathological development, and may provide innovative therapeutic strategies wherein “chromatin readers” stand as potential drug targets. PMID:18682256

  13. Cortico-basal ganglia circuits involved in different motivation disorders in non-human primates.

    PubMed

    Sgambato-Faure, Véronique; Worbe, Yulia; Epinat, Justine; Féger, Jean; Tremblay, Léon

    2016-01-01

    The ventral striatum (VS) is of particular interest in the study of neuropsychiatric disorders. In this study, performed on non-human primates, we associated local perturbation with monosynaptic axonal tracer injection into medial, central and lateral VS to characterize anatomo-functional circuits underlying the respective expression of sexual manifestations, stereotyped behaviors and hypoactive state associated with loss of food motivation. For the three behavioral effects, we demonstrated the existence of three distinct cortico-basal ganglia (BG) circuits that were topographically organized and overlapping at some cortical (orbitofrontal cortex, anterior cingulate cortex) and subcortical (caudal levels of BG) levels, suggesting interactions between motivation domains. Briefly, erection was associated with a circuit involving the orbitofrontal cortex, medial prefrontal cortex (areas 10, 11) and limbic parts of BG, i.e. medial parts of the pallidal complex and the substantia nigra pars reticulata (SNr). Stereotyped behavior was linked to a circuit involving the lateral orbitofrontal cortex (area 12/47) and limbic parts of the pallidal complex and of the SNr, while the apathetic state was underlined by a circuit involving not only the orbital and medial prefrontal cortex but also the lateral prefrontal cortex (area 8, 45), the anterior insula and the lateral parts of the medial pallidal complex and of the ventro-medial SNr. For the three behavioral effects, the cortico-BG circuits mainly involved limbic regions of the external and internal pallidum, as well as the limbic part of the substantia nigra pars reticulata (SNr), suggesting the involvement of both direct and indirect striatal pathways and both output BG structures. As these motivation disorders could still be induced in dopamine (DA)-depleted monkeys, we suggest that DA issued from the substantia nigra pars compacta (SNc) modulates their expression rather than causes them. Finally, this study may give some

  14. Complicated grief and posttraumatic stress disorder in humans' response to the death of pets/animals.

    PubMed

    Adrian, Julie A Luiz; Deliramich, Aimee N; Frueh, B Christopher

    2009-01-01

    The present exploratory project represents a cross-sectional study designed to determine the percentage of people reporting significant symptoms of complicated grief (CG) and/or posttraumatic stress disorder (PTSD) in response to the death of companion pets/animals. Human participants (N = 106) were sampled from a veterinary clinic. Fifty-two percent of participants had lost one to three pets from natural causes, 60% had never lost a pet to euthanasia, and 37% had lost one to three pets to euthanasia. The study suggests that many people experience significant attachment to their pets/animals and experience significant features of grief reactions (about 20%) after the death of a pet/animal. However, the percentage of people experiencing major pathological disruption is relatively low (<5%-12%). Thus, subclinical levels of grief and sadness are relatively common human responses to the death of companion pets/animals and last 6 months or more for about 30% of those sampled. Severe pathological reactions do occur but are quite rare among human survivors. Implications for mental health clinicians working with affected populations are discussed. PMID:19807222

  15. A novel disorder reveals clathrin heavy chain-22 is essential for human pain and touch development

    PubMed Central

    Al-Gazali, Lihadh; Hertecant, Jozef; Owen, David J.; Borner, Georg H. H.; Chen, Ya-Chun; Benn, Caroline L.; Carvalho, Ofélia P.; Shaikh, Samiha S.; Phelan, Anne; Robinson, Margaret S.; Royle, Stephen J.

    2015-01-01

    Congenital inability to feel pain is very rare but the identification of causative genes has yielded significant insights into pain pathways and also novel targets for pain treatment. We report a novel recessive disorder characterized by congenital insensitivity to pain, inability to feel touch, and cognitive delay. Affected individuals harboured a homozygous missense mutation in CLTCL1 encoding the CHC22 clathrin heavy chain, p.E330K, which we demonstrate to have a functional effect on the protein. We found that CLTCL1 is significantly upregulated in the developing human brain, displaying an expression pattern suggestive of an early neurodevelopmental role. Guided by the disease phenotype, we investigated the role of CHC22 in two human neural crest differentiation systems; human induced pluripotent stem cell-derived nociceptors and TRKB-dependant SH-SY5Y cells. In both there was a significant downregulation of CHC22 upon the onset of neural differentiation. Furthermore, knockdown of CHC22 induced neurite outgrowth in neural precursor cells, which was rescued by stable overexpression of small interfering RNA-resistant CHC22, but not by mutant CHC22. Similarly, overexpression of wild-type, but not mutant, CHC22 blocked neurite outgrowth in cells treated with retinoic acid. These results reveal an essential and non-redundant role for CHC22 in neural crest development and in the genesis of pain and touch sensing neurons. PMID:26068709

  16. Genetics of multifactorial disorders: proceedings of the 6th Pan Arab Human Genetics Conference.

    PubMed

    Nair, Pratibha; Bizzari, Sami; Rajah, Nirmal; Assaf, Nada; Al-Ali, Mahmoud Taleb; Hamzeh, Abdul Rezzak

    2016-01-01

    The 6th Pan Arab Human Genetics Conference (PAHGC), "Genetics of Multifactorial Disorders" was organized by the Center for Arab Genomic Studies (http://www.cags.org.ae) in Dubai, United Arab Emirates from 21 to 23 January, 2016. The PAHGCs are held biennially to provide a common platform to bring together regional and international geneticists to share their knowledge and to discuss common issues. Over 800 delegates attended the first 2 days of the conference and these came from various medical and scientific backgrounds. They consisted of geneticists, molecular biologists, medical practitioners, postdoctoral researchers, technical staff (e.g., nurses and lab technicians) and medical students from 35 countries around the world. On the 3rd day, a one-day workshop on "Genetic Counseling" was delivered to 26 participants. The conference focused on four major topics, namely, diabetes, genetics of neurodevelopmental disorders, congenital anomalies and cancer genetics. Personalized medicine was a recurrent theme in most of the research presented at the conference, as was the application of novel molecular findings in clinical settings. This report discusses a summary of the presentations from the meeting. PMID:27095177

  17. Human movement stochastic variability leads to diagnostic biomarkers In Autism Spectrum Disorders (ASD)

    NASA Astrophysics Data System (ADS)

    Wu, Di; Torres, Elizabeth B.; Jose, Jorge V.

    2015-03-01

    ASD is a spectrum of neurodevelopmental disorders. The high heterogeneity of the symptoms associated with the disorder impedes efficient diagnoses based on human observations. Recent advances with high-resolution MEM wearable sensors enable accurate movement measurements that may escape the naked eye. It calls for objective metrics to extract physiological relevant information from the rapidly accumulating data. In this talk we'll discuss the statistical analysis of movement data continuously collected with high-resolution sensors at 240Hz. We calculated statistical properties of speed fluctuations within the millisecond time range that closely correlate with the subjects' cognitive abilities. We computed the periodicity and synchronicity of the speed fluctuations' from their power spectrum and ensemble averaged two-point cross-correlation function. We built a two-parameter phase space from the temporal statistical analyses of the nearest neighbor fluctuations that provided a quantitative biomarker for ASD and adult normal subjects and further classified ASD severity. We also found age related developmental statistical signatures and potential ASD parental links in our movement dynamical studies. Our results may have direct clinical applications.

  18. Comparative proteomics as a new tool for exploring human mitochondrial tRNA disorders.

    PubMed

    Rabilloud, Thierry; Strub, Jean-Marc; Carte, Nathalie; Luche, Sylvie; Van Dorsselaer, Alain; Lunardi, Joël; Giegé, Richard; Florentz, Catherine

    2002-01-01

    More than 70 different point mutations in human mitochondrial tRNA genes are correlated with severe disorders, including fatal cardiopathies, encephalopathies, myopathies, and others. So far, investigation of the molecular impact(s) of mutations has focused on the affected tRNA itself by seeking structural and/or functional perturbations capable of interfering with synthesis of the 13 mitochondrion-encoded subunits of respiratory chain complexes. Here, a proteomic approach was used to investigate whether such mutations would affect the pattern of mitochondrial proteins at a broader level. Analysis of several hundred mitochondrial proteins from sibling cybrid cell lines by two-dimensional electrophoresis, an approach that takes into account all regulatory steps of mitochondrial and nuclear gene expression, indeed reveals a number of up- and downregulated proteins when healthy and single-point-mutation-carrying mitochondria representative of either MELAS or MERRF syndrome were compared. Assignment by mass spectrometry of the two proteins which exhibit obvious large quantitative decreases in the levels of both pathologic mitochondria identified nuclear-encoded subunits of cytochrome c oxidase, a respiratory chain complex. This clearly shows a linkage between the effects of mutations in mitochondrial tRNA genes and the steady-state level of nuclear-encoded proteins in mitochondria. It opens new routes toward a large-scale exploration of potential proteic partners involved in the genotype-phenotype correlation of mitochondrial disorders. PMID:11772011

  19. Clinical guidelines for the management of craniofacial fibrous dysplasia

    PubMed Central

    2012-01-01

    Fibrous dysplasia (FD) is a non-malignant condition caused by post-zygotic, activating mutations of the GNAS gene that results in inhibition of the differentiation and proliferation of bone-forming stromal cells and leads to the replacement of normal bone and marrow by fibrous tissue and woven bone. The phenotype is variable and may be isolated to a single skeletal site or multiple sites and sometimes is associated with extraskeletal manifestations in the skin and/or endocrine organs (McCune-Albright syndrome). The clinical behavior and progression of FD may also vary, thereby making the management of this condition difficult with few established clinical guidelines. This paper provides a clinically-focused comprehensive description of craniofacial FD, its natural progression, the components of the diagnostic evaluation and the multi-disciplinary management, and considerations for future research. PMID:22640797

  20. Clinical guidelines for the management of craniofacial fibrous dysplasia.

    PubMed

    Lee, J S; FitzGibbon, E J; Chen, Y R; Kim, H J; Lustig, L R; Akintoye, S O; Collins, M T; Kaban, L B

    2012-05-24

    Fibrous dysplasia (FD) is a non-malignant condition caused by post-zygotic, activating mutations of the GNAS gene that results in inhibition of the differentiation and proliferation of bone-forming stromal cells and leads to the replacement of normal bone and marrow by fibrous tissue and woven bone. The phenotype is variable and may be isolated to a single skeletal site or multiple sites and sometimes is associated with extraskeletal manifestations in the skin and/or endocrine organs (McCune-Albright syndrome). The clinical behavior and progression of FD may also vary, thereby making the management of this condition difficult with few established clinical guidelines. This paper provides a clinically-focused comprehensive description of craniofacial FD, its natural progression, the components of the diagnostic evaluation and the multi-disciplinary management, and considerations for future research. PMID:22640797

  1. Implant-retained craniofacial prostheses for facial defects

    PubMed Central

    Federspil, Philipp A.

    2012-01-01

    Craniofacial prostheses, also known as epistheses, are artificial substitutes for facial defects. The breakthrough for rehabilitation of facial defects with implant-retained prostheses came with the development of the modern silicones and bone anchorage. Following the discovery of the osseointegration of titanium in the 1950s, dental implants have been made of titanium in the 1960s. In 1977, the first extraoral titanium implant was inserted in a patient. Later, various solitary extraoral implant systems were developed. Grouped implant systems have also been developed which may be placed more reliably in areas with low bone presentation, as in the nasal and orbital region, or the ideally pneumatised mastoid process. Today, even large facial prostheses may be securely retained. The classical atraumatic surgical technique has remained an unchanged prerequisite for successful implantation of any system. This review outlines the basic principles of osseointegration as well as the main features of extraoral implantology. PMID:22073096

  2. Functional coupling constrains craniofacial diversification in Lake Tanganyika cichlids.

    PubMed

    Tsuboi, Masahito; Gonzalez-Voyer, Alejandro; Kolm, Niclas

    2015-05-01

    Functional coupling, where a single morphological trait performs multiple functions, is a universal feature of organismal design. Theory suggests that functional coupling may constrain the rate of phenotypic evolution, yet empirical tests of this hypothesis are rare. In fish, the evolutionary transition from guarding the eggs on a sandy/rocky substrate (i.e. substrate guarding) to mouthbrooding introduces a novel function to the craniofacial system and offers an ideal opportunity to test the functional coupling hypothesis. Using a combination of geometric morphometrics and a recently developed phylogenetic comparative method, we found that head morphology evolution was 43% faster in substrate guarding species than in mouthbrooding species. Furthermore, for species in which females were solely responsible for mouthbrooding the males had a higher rate of head morphology evolution than in those with bi-parental mouthbrooding. Our results support the hypothesis that adaptations resulting in functional coupling constrain phenotypic evolution. PMID:25948565

  3. Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders

    PubMed Central

    Lim, Elaine T.; Raychaudhuri, Soumya; Sanders, Stephan J.; Stevens, Christine; Sabo, Aniko; MacArthur, Daniel G.; Neale, Benjamin M.; Kirby, Andrew; Ruderfer, Douglas M.; Fromer, Menachem; Lek, Monkol; Liu, Li; Flannick, Jason; Ripke, Stephan; Nagaswamy, Uma; Muzny, Donna; Reid, Jeffrey G.; Hawes, Alicia; Newsham, Irene; Wu, Yuanqing; Lewis, Lora; Dinh, Huyen; Gross, Shannon; Wang, Li-San; Lin, Chiao-Feng; Valladares, Otto; Gabriel, Stacey B.; dePristo, Mark; Altshuler, David M.; Purcell, Shaun M.; State, Matthew W.; Boerwinkle, Eric; Buxbaum, Joseph D.; Cook, Edwin H.; Gibbs, Richard A.; Schellenberg, Gerard D.; Sutcliffe, James S.; Devlin, Bernie; Roeder, Kathryn; Daly, Mark J.

    2013-01-01

    SUMMARY To characterize the role of rare complete human knockouts in autism spectrum disorders (ASD), we identify genes with homozygous or compound heterozygous loss-of-function (LoF) variants (defined as nonsense and essential splice sites) from exome sequencing of 933 cases and 869 controls. We identify a two-fold increase in complete knockouts of autosomal genes with low rates of LoF variation (≤5% frequency) in cases and estimate a 3% contribution to ASD risk by these events, confirming this observation in an independent set of 563 probands and 4,605 controls. Outside the pseudo-autosomal regions on the X-chromosome, we similarly observe a significant 1.5-fold increase in rare hemizygous knockouts in males, contributing to another 2% of ASDs in males. Taken together these results provide compelling evidence that rare autosomal and X-chromosome complete gene knockouts are important inherited risk factors for ASD. PMID:23352160

  4. Transcriptional activity of human endogenous retrovirus in Albanian children with autism spectrum disorders.

    PubMed

    Balestrieri, Emanuela; Cipriani, Chiara; Matteucci, Claudia; Capodicasa, Natale; Pilika, Anita; Korca, Ina; Sorrentino, Roberta; Argaw-Denboba, Ayele; Bucci, Ilaria; Miele, Martino Tony; Coniglio, Antonella; Alessandrelli, Riccardo; Sinibaldi Vallebona, Paola

    2016-09-01

    Recent studies suggest that autism spectrum disorders (ASD) result from interactions between genetic and environmental factors, whose possible links could be represented by epigenetic mechanisms. Here, we investigated the transcriptional activity of three human endogenous retrovirus (HERV) families, in peripheral blood mononuclear cells (PBMCs) from Albanian ASD children, by quantitative real-time PCR. We aimed to confirm the different expression profile already found in Italian ASD children, and to highlight any social and family health condition emerging from information gathered through a questionnaire, to be included among environmental risk factors. The presence of increased HERV-H transcriptional activity in all autistic patients could be understood as a constant epigenetic imprinting of the disease, potentially useful for early diagnosis and for the development of effective novel therapeutic strategies. PMID:27602423

  5. Incentive-Related Human Resource Practices for Substance Use Disorder Counselors: Salaries, Benefits, and Training

    PubMed Central

    Rothrauff, Tanja C.; Abraham, Amanda J.; Bride, Brian E.; Roman, Paul M.

    2011-01-01

    Understanding factors associated with incentive-related human resource practices for substance use disorder counselors can help promote a stable workforce in this occupation. We examined three counselor incentives—salaries, benefits, training—and the link with organizational, counselor, and patient characteristics. Data were collected in 2007/08 via face-to-face interviews with 345 administrators/clinical directors in private treatment centers. Centers paid counselors an average of $38,800 annually and provided a mean of 2.83 benefits and 1.61 training (0-4 scales). Characteristics differed based on the incentive. Centers’ managements need to be aware of different incentives that can help attract and retain counselors. PMID:22039315

  6. Computed tomography of craniofacial trauma at a combat support hospital in Afghanistan.

    PubMed

    Statler, John D; Tempel, Carl G; Harcke, H Theodore

    2005-03-01

    Complex craniofacial injuries are encountered among both soldiers and civilians in combat zones. Computed tomography is a necessary and effective tool for the evaluation and treatment of these injuries in the forward-deployed combat support hospital. PMID:15828695

  7. Effects of sex hormone disturbances on craniofacial growth in newborn mice.

    PubMed

    Fujita, T; Ohtani, J; Shigekawa, M; Kawata, T; Kaku, M; Kohno, S; Tsutsui, K; Tenjo, K; Motokawa, M; Tohma, Y; Tanne, K

    2004-03-01

    It is well-known that sex hormones influence bone metabolism. However, it remains unclear as to how sex hormones affect bone growth in newborn mice. In this study, we performed orchiectomy (ORX) and ovariectomy (OVX) on newborn mice, and examined the effects on craniofacial growth morphometrically. ORX and OVX were performed on five-day-old C57BL/6J mice. Four weeks after surgery, lateral cephalograms were taken of all of the mice, with the use of a rat and mouse cephalometer. Cephalometric analysis of the craniofacial skeleton was performed by means of a personal computer. Inhibition of craniofacial growth was found in the experimental groups but not in the sham-operated groups. In the nasomaxillary bone and mandible, the amount of growth was significantly reduced. These results suggest that craniofacial growth is inhibited by sex hormone disturbances not only in puberty but also immediately after birth. PMID:14981129

  8. Assessing Species-specific Contributions To Craniofacial Development Using Quail-duck Chimeras

    PubMed Central

    Fish, Jennifer L.; Schneider, Richard A.

    2014-01-01

    The generation of chimeric embryos is a widespread and powerful approach to study cell fates, tissue interactions, and species-specific contributions to the histological and morphological development of vertebrate embryos. In particular, the use of chimeric embryos has established the importance of neural crest in directing the species-specific morphology of the craniofacial complex. The method described herein utilizes two avian species, duck and quail, with remarkably different craniofacial morphology. This method greatly facilitates the investigation of molecular and cellular regulation of species-specific pattern in the craniofacial complex. Experiments in quail and duck chimeric embryos have already revealed neural crest-mediated tissue interactions and cell-autonomous behaviors that regulate species-specific pattern in the craniofacial skeleton, musculature, and integument. The great diversity of neural crest derivatives suggests significant potential for future applications of the quail-duck chimeric system to understanding vertebrate development, disease, and evolution. PMID:24962088

  9. 77 FR 2987 - National Institute of Dental & Craniofacial Research; Notice of Closed Meetings

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-20

    ... Emphasis Panel; Review of R34 Clinical Trial Planning Grants. Date: February 21, 2012. Time: 1 p.m. to 2:30...: National Institute of Dental and Craniofacial Research Special Emphasis Panel; Review of R34 Clinical...

  10. PATHOGENESIS OF METHANOL-INDUCED CRANIOFACIAL DEFECTS IN C57BL/6J MICE

    EPA Science Inventory

    BACKGROUND: Methanol administered to C57BL/6J mice during gastrulation causes severe craniofacial dysmorphology. We describe dysmorphogenesis, cell death, cell cycle assessment, and effects on development of cranial ganglia and nerves observed following administration of methanol...

  11. Attention Deficit Disorder--A New Age Yuppie Disorder or an Age Old Human Characteristic Essential for Our Survival?

    ERIC Educational Resources Information Center

    Orgill, Anna A.

    This brief paper suggests that Attention Deficit Disorder (ADD) may result from a specific "novelty seeking" gene which has been associated over the history of man's evolution with a biological advantage in situations where energy, risk taking, and creativity are essentials. It reviews research on the genetics of ADD which suggest that novelty…

  12. Development of a biodegradable bone cement for craniofacial applications.

    PubMed

    Henslee, Allan M; Gwak, Dong-Ho; Mikos, Antonios G; Kasper, F Kurtis

    2012-09-01

    This study investigated the formulation of a two-component biodegradable bone cement comprising the unsaturated linear polyester macromer poly(propylene fumarate) (PPF) and crosslinked PPF microparticles for use in craniofacial bone repair applications. A full factorial design was employed to evaluate the effects of formulation parameters such as particle weight percentage, particle size, and accelerator concentration on the setting and mechanical properties of crosslinked composites. It was found that the addition of crosslinked microparticles to PPF macromer significantly reduced the temperature rise upon crosslinking from 100.3°C ± 21.6°C to 102.7°C ± 49.3°C for formulations without microparticles to 28.0°C ± 2.0°C to 65.3°C ± 17.5°C for formulations with microparticles. The main effects of increasing the particle weight percentage from 25 to 50% were to significantly increase the compressive modulus by 37.7 ± 16.3 MPa, increase the compressive strength by 2.2 ± 0.5 MPa, decrease the maximum temperature by 9.5°C ± 3.7°C, and increase the setting time by 0.7 ± 0.3 min. Additionally, the main effects of increasing the particle size range from 0-150 μm to 150-300 μm were to significantly increase the compressive modulus by 31.2 ± 16.3 MPa and the compressive strength by 1.3 ± 0.5 MPa. However, the particle size range did not have a significant effect on the maximum temperature and setting time. Overall, the composites tested in this study were found to have properties suitable for further consideration in craniofacial bone repair applications. PMID:22499285

  13. Characterization of porous polymethylmethacrylate space maintainers for craniofacial reconstruction.

    PubMed

    Wang, Limin; Yoon, Diana M; Spicer, Patrick P; Henslee, Allan M; Scott, David W; Wong, Mark E; Kasper, F Kurtis; Mikos, Antonios G

    2013-07-01

    Porous polymethylmethacrylate (PMMA) has been used as an alloplastic bone substitute in the craniofacial complex, showing integration with the surrounding soft and hard tissue. This study investigated the physicochemical properties of curing and cured mixtures of a PMMA-based bone cement and a carboxymethylcellulose (CMC) gel porogen. Four formulations yielding porous PMMA of varied porosity were examined; specifically, two groups containing 30% (w/w) CMC gel in the mixture using a 7% (w/v) or 9% (w/v) stock CMC gel (30-7 and 30-9, respectively) and two groups containing 40% (w/w) CMC gel (40-7 and 40-9). An additional group comprising solid PMMA without CMC was investigated. The incorporation of the CMC gel into the PMMA bone cement during polymerization decreased the setting time from 608 ± 12 s for the solid PMMA to 427 ± 10 s for the 40-9 group, and decreased the maximum temperature from 81 ± 4°C for the solid PMMA to 38 ± 2°C for the 40-9 group. The porous PMMA groups exhibited reduced compressive strength and bending modulus and strength relative to the solid PMMA. All the porous PMMA formulations released more unconverted methylmethacrylate (MMA) monomer and N,N-dimethyl-p-toluidine (DMT) from cured specimens and less MMA and DMT from curing specimens than the solid PMMA. The data suggest that the physicochemical properties of the porous PMMA formulations are appropriate for their application in craniofacial space maintenance. PMID:23359449

  14. Evolving toward a human-cell based and multiscale approach to drug discovery for CNS disorders

    PubMed Central

    Schadt, Eric E.; Buchanan, Sean; Brennand, Kristen J.; Merchant, Kalpana M.

    2014-01-01

    A disruptive approach to therapeutic discovery and development is required in order to significantly improve the success rate of drug discovery for central nervous system (CNS) disorders. In this review, we first assess the key factors contributing to the frequent clinical failures for novel drugs. Second, we discuss cancer translational research paradigms that addressed key issues in drug discovery and development and have resulted in delivering drugs with significantly improved outcomes for patients. Finally, we discuss two emerging technologies that could improve the success rate of CNS therapies: human induced pluripotent stem cell (hiPSC)-based studies and multiscale biology models. Coincident with advances in cellular technologies that enable the generation of hiPSCs directly from patient blood or skin cells, together with methods to differentiate these hiPSC lines into specific neural cell types relevant to neurological disease, it is also now possible to combine data from large-scale forward genetics and post-mortem global epigenetic and expression studies in order to generate novel predictive models. The application of systems biology approaches to account for the multiscale nature of different data types, from genetic to molecular and cellular to clinical, can lead to new insights into human diseases that are emergent properties of biological networks, not the result of changes to single genes. Such studies have demonstrated the heterogeneity in etiological pathways and the need for studies on model systems that are patient-derived and thereby recapitulate neurological disease pathways with higher fidelity. In the context of two common and presumably representative neurological diseases, the neurodegenerative disease Alzheimer’s Disease, and the psychiatric disorder schizophrenia, we propose the need for, and exemplify the impact of, a multiscale biology approach that can integrate panomic, clinical, imaging, and literature data in order to construct

  15. Evolving toward a human-cell based and multiscale approach to drug discovery for CNS disorders.

    PubMed

    Schadt, Eric E; Buchanan, Sean; Brennand, Kristen J; Merchant, Kalpana M

    2014-01-01

    A disruptive approach to therapeutic discovery and development is required in order to significantly improve the success rate of drug discovery for central nervous system (CNS) disorders. In this review, we first assess the key factors contributing to the frequent clinical failures for novel drugs. Second, we discuss cancer translational research paradigms that addressed key issues in drug discovery and development and have resulted in delivering drugs with significantly improved outcomes for patients. Finally, we discuss two emerging technologies that could improve the success rate of CNS therapies: human induced pluripotent stem cell (hiPSC)-based studies and multiscale biology models. Coincident with advances in cellular technologies that enable the generation of hiPSCs directly from patient blood or skin cells, together with methods to differentiate these hiPSC lines into specific neural cell types relevant to neurological disease, it is also now possible to combine data from large-scale forward genetics and post-mortem global epigenetic and expression studies in order to generate novel predictive models. The application of systems biology approaches to account for the multiscale nature of different data types, from genetic to molecular and cellular to clinical, can lead to new insights into human diseases that are emergent properties of biological networks, not the result of changes to single genes. Such studies have demonstrated the heterogeneity in etiological pathways and the need for studies on model systems that are patient-derived and thereby recapitulate neurological disease pathways with higher fidelity. In the context of two common and presumably representative neurological diseases, the neurodegenerative disease Alzheimer's Disease, and the psychiatric disorder schizophrenia, we propose the need for, and exemplify the impact of, a multiscale biology approach that can integrate panomic, clinical, imaging, and literature data in order to construct

  16. Intrauterine effect of dam on prenatal development of craniofacial complex of mouse embryo.

    PubMed

    Nonaka, K; Sasaki, Y; Yanagita, K; Matsumoto, T; Watanabe, Y; Nakata, M

    1993-01-01

    Embryo transfer effect and intrauterine effect of the dam on prenatal development of the craniofacial complex of mice embryos were investigated with the use of embryo transfer and cephalostat. DDD strain embryos were transferred to the three strains of recipients (DDD, C57BL, and DBA). The cephalometric observation of newborn offspring developed from transferred embryos was performed just after parturition. Dorso-ventral craniofacial size of newborn offspring was calculated using values of X- and Y-coordinates on a dorsoventral cephalogram. Statistical analysis showed that a significant intergroup difference in craniofacial size between transferred and nontransferred groups as well as a significant inter-strain difference among those of the three strains of recipients were observed. Thus, it was disclosed that embryo transfer technique might retard the prenatal development of craniofacial complex of transferred embryo and that the three strains of recipients contributed unequally to the prenatal development of craniofacial complex of transferred embryo through each of their intrauterine environments as a prenatal maternal effect. These results indicated that the intrauterine environment of the recipient played an important role in the prenatal development of the craniofacial complex of the mice embryo. PMID:8227293

  17. Cdh1 regulates craniofacial development via APC-dependent ubiquitination and activation of Goosecoid.

    PubMed

    Shao, Rui; Liu, Jia; Yan, Guang; Zhang, Jinfang; Han, Yujiao; Guo, Jianfeng; Xu, Zhan; Yuan, Zhu; Liu, Jiankang; Malumbres, Marcos; Wan, Lixin; Wei, Wenyi; Zou, Weiguo

    2016-06-01

    Craniofacial anomalies (CFAs) characterized by birth defects of skull and facial bones are the most frequent congenital disease. Genomic analysis has identified multiple genes responsible for CFAs; however, the underlying genetic mechanisms for the majority of CFAs remain largely unclear. Our previous study revealed that the Wwp2 E3 ubiquitin ligase facilitates craniofacial development in part through inducing monoubiquitination and activation of the paired-like homeobox transcription factor, Goosecoid (Gsc). Here we report that Gsc is also ubiquitinated and activated by the APC(Cdh1) E3 ubiquitin ligase, leading to transcriptional activation of various Gsc target genes crucial for craniofacial development. Consistenly, neural crest-specific Cdh1-knockout mice display similar bone malformation as Wwp2-deficient mice in the craniofacial region, characterized by a domed skull, a short snout and a twisted nasal bone. Mechanistically, like Wwp2-deficient mice, mice with Cdh1 deficiency in neural crest cells exhibit reduced Gsc/Sox6 transcriptional activities. Simultaneous deletion of Cdh1 and Wwp2 results in a more severe craniofacial defect compared with single gene deletion, suggesting a synergistic augmentation of Gsc activity by these two E3 ubiquitin ligases. Hence, our study reveals a novel role for Cdh1 in craniofacial development through promoting APC-dependent non-proteolytic ubiquitination and activation of Gsc. PMID:27126000

  18. A polymorphic genomic duplication on human chromosome 15 is a susceptibility factor for panic and phobic disorders.

    PubMed

    Gratacòs, M; Nadal, M; Martín-Santos, R; Pujana, M A; Gago, J; Peral, B; Armengol, L; Ponsa, I; Miró, R; Bulbena, A; Estivill, X

    2001-08-10

    Anxiety disorders are complex and common psychiatric illnesses associated with considerable morbidity and social cost. We have studied the molecular basis of the cooccurrence of panic and phobic disorders with joint laxity. We have identified an interstitial duplication of human chromosome 15q24-26 (named DUP25), which is significantly associated with panic/agoraphobia/social phobia/joint laxity in families, and with panic disorder in nonfamilial cases. Mosaicism, different forms of DUP25 within the same family, and absence of segregation of 15q24-26 markers with DUP25 and the psychiatric phenotypes suggest a non-Mendelian mechanism of disease-causing mutation. We propose that DUP25, which is present in 7% control subjects, is a susceptibility factor for a clinical phenotype that includes panic and phobic disorders and joint laxity. PMID:11509185

  19. Infection and characterization of Toxoplasma gondii in human induced neurons from patients with brain disorders and healthy controls.

    PubMed

    Passeri, Eleonora; Jones-Brando, Lorraine; Bordón, Claudia; Sengupta, Srona; Wilson, Ashley M; Primerano, Amedeo; Rapoport, Judith L; Ishizuka, Koko; Kano, Shin-ichi; Yolken, Robert H; Sawa, Akira

    2016-02-01

    Toxoplasma gondii is a protozoan parasite capable of establishing persistent infection within the brain. Serological studies in humans have linked exposure to Toxoplasma to neuropsychiatric disorders. However, serological studies have not elucidated the related molecular mechanisms within neuronal cells. To address this question, we used human induced neuronal cells derived from peripheral fibroblasts of healthy individuals and patients with genetically-defined brain disorders (i.e. childhood-onset schizophrenia with disease-associated copy number variations). Parasite infection was characterized by differential detection of tachyzoites and tissue cysts in induced neuronal cells. This approach may aid study of molecular mechanisms underlying individual predisposition to Toxoplasma infection linked to neuropathology of brain disorders. PMID:26432947

  20. Mutations in sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders

    PubMed Central

    Drenth, Joost P.H.; Waxman, Stephen G.

    2007-01-01

    The voltage-gated sodium-channel type IX α subunit, known as Nav1.7 and encoded by the gene SCN9A, is located in peripheral neurons and plays an important role in action potential production in these cells. Recent genetic studies have identified Nav1.7 dysfunction in three different human pain disorders. Gain-of-function missense mutations in Nav1.7 have been shown to cause primary erythermalgia and paroxysmal extreme pain disorder, while nonsense mutations in Nav1.7 result in loss of Nav1.7 function and a condition known as channelopathy-associated insensitivity to pain, a rare disorder in which affected individuals are unable to feel physical pain. This review highlights these recent developments and discusses the critical role of Nav1.7 in pain sensation in humans. PMID:18060017

  1. The Role of Cathepsin D in the Pathogenesis of Human Neurodegenerative Disorders.

    PubMed

    Vidoni, Chiara; Follo, Carlo; Savino, Miriam; Melone, Mariarosa A B; Isidoro, Ciro

    2016-09-01

    In familial neurodegenerative disorders, protein aggregates form continuously because of genetic mutations that drive the synthesis of truncated or unfolded proteins. The oxidative stress imposed by neurotransmitters and environmental neurotoxins constitutes an additional threat to the folding of the proteins and the integrity of organelle membranes in neurons. Failure in degrading such altered materials compromises the function of neurons and eventually leads to neurodegeneration. The lysosomal proteolytic enzyme Cathepsin D is the only aspartic-type protease ubiquitously expressed in all the cells of the human body, and it is expressed at high level in the brain. In general, cathepsin D mediated proteolysis is essential to neuronal cell homeostasis through the degradation of unfolded or oxidized protein aggregates delivered to lysosomes via autophagy or endocytosis. More specifically, many altered neuronal proteins that hallmark neurodegenerative diseases (e.g., the amyloid precursor, α-synuclein, and huntingtin) are physiologic substrates of cathepsin D and would abnormally accumulate if not efficiently degraded by this enzyme. Furthermore, experimental evidence indicates that cathepsin D activity is linked to the metabolism of cholesterol and of glycosaminoglycans, which accounts for its involvement in neuronal plasticity. This review focuses on the unique role of cathepsin D mediated proteolysis in the pathogenesis of human neurodegenerative diseases. PMID:27114232

  2. Brain Insulin Resistance at the Crossroads of Metabolic and Cognitive Disorders in Humans.

    PubMed

    Kullmann, Stephanie; Heni, Martin; Hallschmid, Manfred; Fritsche, Andreas; Preissl, Hubert; Häring, Hans-Ulrich

    2016-10-01

    Ever since the brain was identified as an insulin-sensitive organ, evidence has rapidly accumulated that insulin action in the brain produces multiple behavioral and metabolic effects, influencing eating behavior, peripheral metabolism, and cognition. Disturbances in brain insulin action can be observed in obesity and type 2 diabetes (T2D), as well as in aging and dementia. Decreases in insulin sensitivity of central nervous pathways, i.e., brain insulin resistance, may therefore constitute a joint pathological feature of metabolic and cognitive dysfunctions. Modern neuroimaging methods have provided new means of probing brain insulin action, revealing the influence of insulin on both global and regional brain function. In this review, we highlight recent findings on brain insulin action in humans and its impact on metabolism and cognition. Furthermore, we elaborate on the most prominent factors associated with brain insulin resistance, i.e., obesity, T2D, genes, maternal metabolism, normal aging, inflammation, and dementia, and on their roles regarding causes and consequences of brain insulin resistance. We also describe the beneficial effects of enhanced brain insulin signaling on human eating behavior and cognition and discuss potential applications in the treatment of metabolic and cognitive disorders. PMID:27489306

  3. Human DNA repair disorders in dermatology: A historical perspective, current concepts and new insight.

    PubMed

    Moriwaki, Shinichi

    2016-02-01

    Products of DNA damage, such as cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidone photoproducts (6-4 PPs), are continually formed in genomes after exposure to UV radiation. When these DNA damages remain unrepaired in essential DNA sites for prolonged periods, DNA replication and transcription are hampered or mutation is induced, which may cause cell death, cellular senescence, and carcinogenesis of the skin. To protect against such UV-induced DNA damage, living organisms nicely retain "DNA repair systems", which can efficiently repair "harmful" DNA damage through precise mechanisms by the integrated functions of many proteins. In humans, the failure of DNA repair systems causes a variety of disorders. Dermatological conditions such as hereditary photodermatoses, xeroderma pigmentosum (XP) and Cockayne syndrome (CS) are caused by congenital functional defects in the nucleotide excision repair (NER) system or the translesion synthesis (TLS) system. In this review, we describe the historical progress, recent findings, and future prospects of studies of human diseases associated with DNA-repair defects. PMID:26493104

  4. Intention Perception in High Functioning People with Autism Spectrum Disorders Using Animacy Displays Derived from Human Actions

    ERIC Educational Resources Information Center

    McAleer, Phil; Kay, Jim W.; Pollick, Frank E.; Rutherford, M. D.

    2011-01-01

    The perception of intent in Autism Spectrum Disorders (ASD) often relies on synthetic animacy displays. This study tests intention perception in ASD via animacy stimuli derived from human motion. Using a forced choice task, 28 participants (14 ASDs; 14 age and verbal-I.Q. matched controls) categorized displays of Chasing, Fighting, Flirting,…

  5. Impairments in Monkey and Human Face Recognition in 2-Year-Old Toddlers with Autism Spectrum Disorder and Developmental Delay

    ERIC Educational Resources Information Center

    Chawarska, Katarzyna; Volkmar, Fred

    2007-01-01

    Face recognition impairments are well documented in older children with Autism Spectrum Disorders (ASD); however, the developmental course of the deficit is not clear. This study investigates the progressive specialization of face recognition skills in children with and without ASD. Experiment 1 examines human and monkey face recognition in…

  6. Oral and Craniofacial Manifestations and Two Novel Missense Mutations of the NTRK1 Gene Identified in the Patient with Congenital Insensitivity to Pain with Anhidrosis

    PubMed Central

    Bai, Yudi; Liu, Xin; Yu, Ping; Xue, Yang; Ma, Shufang; Wei, Kewen; Jin, Yan; Wen, Lingying; Xuan, Kun

    2013-01-01

    Congenital insensitivity to pain with anhidrosis (CIPA) is a rare inherited disorder of the peripheral nervous system resulting from mutations in neurotrophic tyrosine kinase receptor 1 gene (NTRK1), which encodes the high-affinity nerve growth factor receptor TRKA. Here, we investigated the oral and craniofacial manifestations of a Chinese patient affected by autosomal-recessive CIPA and identified compound heterozygosity in the NTRK1 gene. The affected boy has multisystemic disorder with lack of reaction to pain stimuli accompanied by self-mutilation behavior, the inability to sweat leading to defective thermoregulation, and mental retardation. Oral and craniofacial manifestations included a large number of missing teeth, nasal malformation, submucous cleft palate, severe soft tissue injuries, dental caries and malocclusion. Histopathological evaluation of the skin sample revealed severe peripheral nerve fiber loss as well as mild loss and absent innervation of sweat glands. Ultrastructural and morphometric studies of a shed tooth revealed dental abnormalities, including hypomineralization, dentin hypoplasia, cementogenesis defects and a dysplastic periodontal ligament. Genetic analysis revealed a compound heterozygosity- c.1561T>C and c.2057G>A in the NTRK1 gene. This report extends the spectrum of NTRK1 mutations observed in patients diagnosed with CIPA and provides additional insight for clinical and molecular diagnosis. PMID:23799134

  7. Insights into the regulation of intrinsically disordered proteins in the human proteome by analyzing sequence and gene expression data

    PubMed Central

    Edwards, Yvonne JK; Lobley, Anna E; Pentony, Melissa M; Jones, David T

    2009-01-01

    Background Disordered proteins need to be expressed to carry out specified functions; however, their accumulation in the cell can potentially cause major problems through protein misfolding and aggregation. Gene expression levels, mRNA decay rates, microRNA (miRNA) targeting and ubiquitination have critical roles in the degradation and disposal of human proteins and transcripts. Here, we describe a study examining these features to gain insights into the regulation of disordered proteins. Results In comparison with ordered proteins, disordered proteins have a greater proportion of predicted ubiquitination sites. The transcripts encoding disordered proteins also have higher proportions of predicted miRNA target sites and higher mRNA decay rates, both of which are indicative of the observed lower gene expression levels. The results suggest that the disordered proteins and their transcripts are present in the cell at low levels and/or for a short time before being targeted for disposal. Surprisingly, we find that for a significant proportion of highly disordered proteins, all four of these trends are reversed. Predicted estimates for miRNA targets, ubiquitination and mRNA decay rate are low in the highly disordered proteins that are constitutively and/or highly expressed. Conclusions Mechanisms are in place to protect the cell from these potentially dangerous proteins. The evidence suggests that the enrichment of signals for miRNA targeting and ubiquitination may help prevent the accumulation of disordered proteins in the cell. Our data also provide evidence for a mechanism by which a significant proportion of highly disordered proteins (with high expression levels) can escape rapid degradation to allow them to successfully carry out their function. PMID:19432952

  8. Astrocyte pathology in major depressive disorder: insights from human postmortem brain tissue.

    PubMed

    Rajkowska, Grazyna; Stockmeier, Craig A

    2013-10-01

    The present paper reviews astrocyte pathology in major depressive disorder (MDD) and proposes that reductions in astrocytes and related markers are key features in the pathology of MDD. Astrocytes are the most numerous and versatile of all types of glial cells. They are crucial to the neuronal microenvironment by regulating glucose metabolism, neurotransmitter uptake (particularly for glutamate), synaptic development and maturation and the blood brain barrier. Pathology of astrocytes has been consistently noted in MDD as well as in rodent models of depressive-like behavior. This review summarizes evidence from human postmortem tissue showing alterations in the expression of protein and mRNA for astrocyte markers such as glial fibrillary acidic protein (GFAP), gap junction proteins (connexin 40 and 43), the water channel aquaporin-4 (AQP4), a calcium-binding protein S100B and glutamatergic markers including the excitatory amino acid transporters 1 and 2 (EAAT1, EAAT2) and glutamine synthetase. Moreover, preclinical studies are presented that demonstrate the involvement of GFAP and astrocytes in animal models of stress and depressive-like behavior and the influence of different classes of antidepressant medications on astrocytes. In light of the various astrocyte deficits noted in MDD, astrocytes may be novel targets for the action of antidepressant medications. Possible functional consequences of altered expression of astrocytic markers in MDD are also discussed. Finally, the unique pattern of cell pathology in MDD, characterized by prominent reductions in the density of astrocytes and in the expression of their markers without obvious neuronal loss, is contrasted with that found in other neuropsychiatric and neurodegenerative disorders. PMID:23469922

  9. 11,000 years of craniofacial and mandibular variation in Lower Nubia.

    PubMed

    Galland, Manon; Van Gerven, Denis P; Von Cramon-Taubadel, Noreen; Pinhasi, Ron

    2016-01-01

    The transition to agriculture was a key event in human history. The extent to which this transition is associated with biological changes in different world regions remains debated. Cultural and osteological records in Lower Nubia throughout the Holocene have been interpreted as a result of in situ differentiation or alternatively as migratory events and possible admixture with surrounding populations. Here we investigated the patterns of craniofacial and mandibular variation from Mesolithic hunting-gathering to late farming, a period spanning 11,000 years. We analyzed 102 adult specimens spanning five cultural horizons: Mesolithic, A-group, C-group, Pharaonic and Meroitic, by means of 3D geometric morphometric methods, in order to assess shape variation and diachronic patterns at the transition to farming and in subsequent periods. Our results highlight a strong morphometric distinction between Mesolithic hunter-gatherers and farmers as well as differences between transitional and intensive farmers in mandibular variation which is consistent with differential impact of selective pressures on different regions of the skull. This study corroborates a major biological change during the transition from hunting to farming, supporting the masticatory-functional hypothesis for the mandible and suggesting population continuity among farming populations throughout the Holocene based on the overall shape of the cranium. PMID:27503560

  10. Fat-Dachsous Signaling Coordinates Cartilage Differentiation and Polarity during Craniofacial Development

    PubMed Central

    Le Pabic, Pierre; Ng, Carrie; Schilling, Thomas F.

    2014-01-01

    Organogenesis requires coordinated regulation of cellular differentiation and morphogenesis. Cartilage cells in the vertebrate skeleton form polarized stacks, which drive the elongation and shaping of skeletal primordia. Here we show that an atypical cadherin, Fat3, and its partner Dachsous-2 (Dchs2), control polarized cell-cell intercalation of cartilage precursors during craniofacial development. In zebrafish embryos deficient in Fat3 or Dchs2, chondrocytes fail to stack and misregulate expression of sox9a. Similar morphogenetic defects occur in rerea/atr2a −/− mutants, and Fat3 binds REREa, consistent with a model in which Fat3, Dchs2 and REREa interact to control polarized cell-cell intercalation and simultaneously control differentiation through Sox9. Chimaeric analyses support such a model, and reveal long-range influences of all three factors, consistent with the activation of a secondary signal that regulates polarized cell-cell intercalation. This coordinates the spatial and temporal morphogenesis of chondrocytes to shape skeletal primordia and defects in these processes underlie human skeletal malformations. Similar links between cell polarity and differentiation mechanisms are also likely to control organ formation in other contexts. PMID:25340762

  11. 11,000 years of craniofacial and mandibular variation in Lower Nubia

    PubMed Central

    Galland, Manon; Van Gerven, Denis P.; Von Cramon-Taubadel, Noreen; Pinhasi, Ron

    2016-01-01

    The transition to agriculture was a key event in human history. The extent to which this transition is associated with biological changes in different world regions remains debated. Cultural and osteological records in Lower Nubia throughout the Holocene have been interpreted as a result of in situ differentiation or alternatively as migratory events and possible admixture with surrounding populations. Here we investigated the patterns of craniofacial and mandibular variation from Mesolithic hunting-gathering to late farming, a period spanning 11,000 years. We analyzed 102 adult specimens spanning five cultural horizons: Mesolithic, A-group, C-group, Pharaonic and Meroitic, by means of 3D geometric morphometric methods, in order to assess shape variation and diachronic patterns at the transition to farming and in subsequent periods. Our results highlight a strong morphometric distinction between Mesolithic hunter-gatherers and farmers as well as differences between transitional and intensive farmers in mandibular variation which is consistent with differential impact of selective pressures on different regions of the skull. This study corroborates a major biological change during the transition from hunting to farming, supporting the masticatory-functional hypothesis for the mandible and suggesting population continuity among farming populations throughout the Holocene based on the overall shape of the cranium. PMID:27503560

  12. Actin capping protein CAPZB regulates cell morphology, differentiation, and neural crest migration in craniofacial morphogenesis†.

    PubMed

    Mukherjee, Kusumika; Ishii, Kana; Pillalamarri, Vamsee; Kammin, Tammy; Atkin, Joan F; Hickey, Scott E; Xi, Qiongchao J; Zepeda, Cinthya J; Gusella, James F; Talkowski, Michael E; Morton, Cynthia C; Maas, Richard L; Liao, Eric C

    2016-04-01

    CAPZB is an actin-capping protein that caps the growing end of F-actin and modulates the cytoskeleton and tethers actin filaments to the Z-line of the sarcomere in muscles. Whole-genome sequencing was performed on a subject with micrognathia, cleft palate and hypotonia that harbored a de novo, balanced chromosomal translocation that disrupts the CAPZB gene. The function of capzb was analyzed in the zebrafish model. capzb(-/-) mutants exhibit both craniofacial and muscle defects that recapitulate the phenotypes observed in the human subject. Loss of capzb affects cell morphology, differentiation and neural crest migration. Differentiation of both myogenic stem cells and neural crest cells requires capzb. During palate morphogenesis, defective cranial neural crest cell migration in capzb(-/-) mutants results in loss of the median cell population, creating a cleft phenotype. capzb is also required for trunk neural crest migration, as evident from melanophores disorganization in capzb(-/-) mutants. In addition, capzb over-expression results in embryonic lethality. Therefore, proper capzb dosage is important during embryogenesis, and regulates both cell behavior and tissue morphogenesis. PMID:26758871

  13. Keratin gene mutations in disorders of human skin and its appendages.

    PubMed

    Chamcheu, Jean Christopher; Siddiqui, Imtiaz A; Syed, Deeba N; Adhami, Vaqar M; Liovic, Mirjana; Mukhtar, Hasan

    2011-04-15

    Keratins, the major structural protein of all epithelia are a diverse group of cytoskeletal scaffolding proteins that form intermediate filament networks, providing structural support to keratinocytes that maintain the integrity of the skin. Expression of keratin genes is usually regulated by differentiation of the epidermal cells within the stratifying squamous epithelium. Amongst the 54 known functional keratin genes in humans, about 22 different genes including, the cornea, hair and hair follicle-specific keratins have been implicated in a wide range of hereditary diseases. The exact phenotype of each disease usually reflects the spatial expression level and the types of mutated keratin genes, the location of the mutations and their consequences at sub-cellular levels as well as other epigenetic and/or environmental factors. The identification of specific pathogenic mutations in keratin disorders formed the basis of our understanding that led to re-classification, improved diagnosis with prognostic implications, prenatal testing and genetic counseling in severe keratin genodermatoses. Molecular defects in cutaneous keratin genes encoding for keratin intermediate filaments (KIFs) causes keratinocytes and tissue-specific fragility, accounting for a large number of genetic disorders in human skin and its appendages. These diseases are characterized by keratinocytes fragility (cytolysis), intra-epidermal blistering, hyperkeratosis, and keratin filament aggregation in severely affected tissues. Examples include epidermolysis bullosa simplex (EBS; K5, K14), keratinopathic ichthyosis (KPI; K1, K2, K10) i.e. epidermolytic ichthyosis (EI; K1, K10) and ichthyosis bullosa of Siemens (IBS; K2), pachyonychia congenita (PC; K6a, K6b, K16, K17), epidermolytic palmo-plantar keratoderma (EPPK; K9, (K1)), monilethrix (K81, K83, K86), ectodermal dysplasia (ED; K85) and steatocystoma multiplex. These keratins also have been identified to have roles in apoptosis, cell proliferation

  14. 30-year International Pediatric Craniofacial Surgery Partnership: Evolution from the “Third World” Forward

    PubMed Central

    Swanson, Jordan W.; Skirpan, Jan; Stanek, Beata; Kowalczyk, Maciej

    2016-01-01

    Background: Craniofacial diseases constitute an important component of the surgical disease burden in low- and middle-income countries. The consideration to introduce craniofacial surgery into such settings poses different questions, risks, and challenges compared with cleft or other forms of plastic surgery. We report the evolution, innovations, and challenges of a 30-year international craniofacial surgery partnership. Methods: We retrospectively report a partnership between surgeons at the Uniwersytecki Szpital Dzieciecy in Krakow, Poland, and a North American craniofacial surgeon. We studied patient conditions, treatment patterns, and associated complications, as well as program advancements and limitations as perceived by surgeons, patient families, and hospital administrators. Results: Since partnership inception in 1986, the complexity of cases performed increased gradually, with the first intracranial case performed in 1995. In the most recent 10-year period (2006–2015), 85 patients have been evaluated, with most common diagnoses of Apert syndrome, Crouzon syndrome, and single-suture craniosynostosis. In the same period, 55 major surgical procedures have been undertaken, with LeFort III midface distraction, posterior vault distraction, and frontoorbital advancement performed most frequently. Key innovations have been the employment of craniofacial distraction osteogenesis, the use of Internet communication and digital photography, and increased understanding of how craniofacial morphology may improve in the absence of surgical intervention. Ongoing challenges include prohibitive training pathways for pediatric plastic surgeons, difficulty in coordinating care with surgeons in other institutions, and limited medical and material resources. Conclusion: Safe craniofacial surgery can be introduced and sustained in a resource-limited setting through an international partnership. PMID:27200233

  15. Transcriptional profiling and biological pathway analysis of human equivalence PCB exposure in vitro: Indicator of Disease and disorder development in humans

    PubMed Central

    Ghosh, Somiranjan; Mitra, Partha S.; Loffredo, Christopher A.; Trnovec, Tomas; Murinova, Lubica; Sovcikova, Eva; Ghimbovschi, Svetlana; Zang, Shizhu; Hoffman, Eric P.; Dutta, Sisir K.

    2015-01-01

    Background and Aims Our earlier gene-expression studies with a Slovak PCBs-exposed population have revealed possible disease and disorder development in accordance with epidemiological studies. The present investigation aimed to develop an in vitro model system that can provide an indication of disrupted biological pathways associated with developing future diseases, well in advance of the clinical manifestations that may take years to appear in the actual human exposure scenario. Methods We used human PBMC (Primary Blood Mononuclear Cells) and exposed them to a mixture of human equivalence levels of PCBs (PCB-118,138,153,170,180) as found in the PCBs-exposed Slovak population. The microarray studies of global gene expression were conducted on the Affymetrix platform using Human Genome U133 Plus 2.0 Array along with Ingenuity Pathway Analysis (IPA) to associate the affected genes with their mechanistic pathways. High-throughput qRT-PCR Taqman Low Density Array (TLDA) was done to further validate the selected 6 differentially expressed genes of our interest, viz., ARNT, CYP2D6, LEPR, LRP12, RRAD, TP53, with a small population validation sample (n=71). Results Overall, we revealed a discreet gene expression profile in the experimental model that resembled the diseases and disorders observed in PCBs-exposed population studies. The disease pathways included Endocrine System disorders, Genetic disorders, Metabolic diseases, Developmental disorders, and Cancers, strongly consistent with the evidence from epidemiological studies. Interpretation These gene finger prints could lead to the identification of populations and subgroups at high risk for disease, and can pose as early disease biomarkers well ahead of time, before the actual disease becomes visible. PMID:25725301

  16. Chromosomal and multifactorial genetic disorders with oral manifestations.

    PubMed

    Patil, Shankargouda; Rao, Roopa S; Majumdar, Barnali

    2014-09-01

    The chromosomal disorders are individually rare, but collectively they are common whereas the multifactorial disorders are the most common form of genetic disorders. The chromosomal anomalies typically arise from alterations in the DNA containing chromosomal regions and can be reliably detected by karyotype analysis, whereas the multifactorial disorders demonstrate multi-gene as well as environmental interactions. Both the chromosomal and multifactorial disorders may manifest signs and symptoms such as a combination of birth defects, physical disabilities, challenging behavior and certain craniofacial defects as well, the knowledge of which can aid in a better patient management in everyday practice of dentistry. PMID:25395808

  17. Chromosomal and Multifactorial Genetic Disorders with Oral Manifestations

    PubMed Central

    Patil, Shankargouda; Rao, Roopa S; Majumdar, Barnali

    2014-01-01

    The chromosomal disorders are individually rare, but collectively they are common whereas the multifactorial disorders are the most common form of genetic disorders. The chromosomal anomalies typically arise from alterations in the DNA containing chromosomal regions and can be reliably detected by karyotype analysis, whereas the multifactorial disorders demonstrate multi-gene as well as environmental interactions. Both the chromosomal and multifactorial disorders may manifest signs and symptoms such as a combination of birth defects, physical disabilities, challenging behavior and certain craniofacial defects as well, the knowledge of which can aid in a better patient management in everyday practice of dentistry. PMID:25395808

  18. The crystal structure of human GlnRS provides basis for the development of neurological disorders

    PubMed Central

    Ognjenović, Jana; Wu, Jiang; Matthies, Doreen; Baxa, Ulrich; Subramaniam, Sriram; Ling, Jiqiang; Simonović, Miljan

    2016-01-01

    Cytosolic glutaminyl-tRNA synthetase (GlnRS) is the singular enzyme responsible for translation of glutamine codons. Compound heterozygous mutations in GlnRS cause severe brain disorders by a poorly understood mechanism. Herein, we present crystal structures of the wild type and two pathological mutants of human GlnRS, which reveal, for the first time, the domain organization of the intact enzyme and the structure of the functionally important N-terminal domain (NTD). Pathological mutations mapping in the NTD alter the domain structure, and decrease catalytic activity and stability of GlnRS, whereas missense mutations in the catalytic domain induce misfolding of the enzyme. Our results suggest that the reduced catalytic efficiency and a propensity of GlnRS mutants to misfold trigger the disease development. This report broadens the spectrum of brain pathologies elicited by protein misfolding and provides a paradigm for understanding the role of mutations in aminoacyl-tRNA synthetases in neurological diseases. PMID:26869582

  19. Gene expression in human brain implicates sexually dimorphic pathways in autism spectrum disorders

    PubMed Central

    Werling, Donna M.; Parikshak, Neelroop N.; Geschwind, Daniel H.

    2016-01-01

    Autism spectrum disorder (ASD) is more prevalent in males, and the mechanisms behind this sex-differential risk are not fully understood. Two competing, but not mutually exclusive, hypotheses are that ASD risk genes are sex-differentially regulated, or alternatively, that they interact with characteristic sexually dimorphic pathways. Here we characterized sexually dimorphic gene expression in multiple data sets from neurotypical adult and prenatal human neocortical tissue, and evaluated ASD risk genes for evidence of sex-biased expression. We find no evidence for systematic sex-differential expression of ASD risk genes. Instead, we observe that genes expressed at higher levels in males are significantly enriched for genes upregulated in post-mortem autistic brain, including astrocyte and microglia markers. This suggests that it is not sex-differential regulation of ASD risk genes, but rather naturally occurring sexually dimorphic processes, potentially including neuron–glial interactions, that modulate the impact of risk variants and contribute to the sex-skewed prevalence of ASD. PMID:26892004

  20. Triallelic and epigenetic-like inheritance in human disorders of telomerase

    PubMed Central

    Collopy, Laura C.; Walne, Amanda J.; Cardoso, Shirleny; de la Fuente, Josu; Mohamed, Mahfuzah; Toriello, Helga; Tamary, Hannah; Ling, Adam J. Y. V.; Lloyd, Timothy; Kassam, Rebecca; Tummala, Hemanth; Dokal, Inderjeet

    2015-01-01

    Dyskeratosis congenita (DC) and related diseases are a heterogeneous group of disorders characterized by impaired telomere maintenance, known collectively as the telomeropathies. Disease-causing variants have been identified in 10 telomere-related genes including the reverse transcriptase (TERT) and the RNA component (TERC) of the telomerase complex. Variants in TERC and TERT can impede telomere elongation causing stem cells to enter premature replicative senescence and/or apoptosis as telomeres become critically short. This explains the major impact of the disease on highly proliferative tissues such as the bone marrow and skin. However, telomerase variants are not always fully penetrant and in some families disease-causing variants are seen in asymptomatic family members. As a result, determining the pathogenic status of newly identified variants in TERC or TERT can be quite challenging. Over a 3-year period, we have identified 26 telomerase variants (16 of which are novel) in 23 families. Additional investigations (including family segregation and functional studies) enabled these to be categorized into 3 groups: (1) disease-causing (n = 15), (2) uncertain status (n = 6), and (3) bystanders (n = 5). Remarkably, this process has also enabled us to identify families with novel mechanisms of inheriting human telomeropathies. These include triallelic mutations, involving 2 different telomerase genes, and an epigenetic-like inheritance of short telomeres in the absence of a telomerase mutation. This study therefore highlights that telomerase variants have highly variable functional and clinical manifestations and require thorough investigation to assess their pathogenic contribution. PMID:26024875

  1. Circulating Human Eosinophils Share a Similar Transcriptional Profile in Asthma and Other Hypereosinophilic Disorders

    PubMed Central

    Barnig, Cindy; Dembélé, Doulaye; Paul, Nicodème; Poirot, Anh; Uring-Lambert, Béatrice; Georgel, Philippe; de Blay, Fréderic; Bahram, Seiamak

    2015-01-01

    Eosinophils are leukocytes that are released into the peripheral blood in a phenotypically mature state and are capable of being recruited into tissues in response to appropriate stimuli. Eosinophils, traditionally considered cytotoxic effector cells, are leukocytes recruited into the airways of asthma patients where they are believed to contribute to the development of many features of the disease. This perception, however, has been challenged by recent findings suggesting that eosinophils have also immunomodulatory functions and may be involved in tissue homeostasis and wound healing. Here we describe a transcriptome-based approach–in a limited number of patients and controls—to investigate the activation state of circulating human eosinophils isolated by flow cytometry. We provide an overview of the global expression pattern in eosinophils in various relevant conditions, e.g., eosinophilic asthma, hypereosinophilic dermatological diseases, parasitosis and pulmonary aspergillosis. Compared to healthy subjects, circulating eosinophils isolated from asthma patients differed in their gene expression profile which is marked by downregulation of transcripts involved in antigen presentation, pathogen recognition and mucosal innate immunity, whereas up-regulated genes were involved in response to non-specific stimulation, wounding and maintenance of homeostasis. Eosinophils from other hypereosinophilic disorders displayed a very similar transcriptional profile. Taken together, these observations seem to indicate that eosinophils exhibit non-specific immunomodulatory functions important for tissue repair and homeostasis and suggest new roles for these cells in asthma immunobiology. PMID:26524763

  2. Structural Basis for a Human Glycosylation Disorder Caused by Mutation of the COG4 Gene

    SciTech Connect

    Richardson, B.; Smith, R; Ungar, D; Nakamura, A; Jeffrey, P; Lupashin, V; Hughson, F

    2009-01-01

    The proper glycosylation of proteins trafficking through the Golgi apparatus depends upon the conserved oligomeric Golgi (COG) complex. Defects in COG can cause fatal congenital disorders of glycosylation (CDGs) in humans. The recent discovery of a form of CDG, caused in part by a COG4 missense mutation changing Arg 729 to Trp, prompted us to determine the 1.9 A crystal structure of a Cog4 C-terminal fragment. Arg 729 is found to occupy a key position at the center of a salt bridge network, thereby stabilizing Cog4's small C-terminal domain. Studies in HeLa cells reveal that this C-terminal domain, while not needed for the incorporation of Cog4 into COG complexes, is essential for the proper glycosylation of cell surface proteins. We also find that Cog4 bears a strong structural resemblance to exocyst and Dsl1p complex subunits. These complexes and others have been proposed to function by mediating the initial tethering between transport vesicles and their membrane targets; the emerging structural similarities provide strong evidence of a common evolutionary origin and may reflect shared mechanisms of action.

  3. Property of Regenerating Serotonin Fibers in the Hippocampus of Human Migration Disorders Model

    NASA Astrophysics Data System (ADS)

    Ueda, Shuichi; Ehara, Ayuka; Ohmomo, Hideki

    Individual mood and mental conditions exert a great influence on one's own kansei. Abnormality or dysfunction of the 5-HT neuron system in the developing and/or adult brain is closely associated with their conditions. Thus, the 5-HT neuron system may play an important role in the neuronal mechanisms underlying kansei. Interestingly, previous studies have shown that heterotopic clusters in the hippocampus (hippocampal heterotopia), deriving from neocortical neurons, after prenatally treated with methylazoxymethanol acetate in rat (MAM rat), exhibit abundant 5-HT innervation. After neonatal intracisternal 5, 7-dihydroxytryptamine (DHT) injection, these 5-HT fibers degenerate and disappear throughout the forebrain, and then regenerating 5-HT fibers densely innervate in the hippocampal heterotopia. The 5-HT fiber system in the hippocampal heterotopia of MAM rat provides useful experimental models for study the plasticity of human migration disorder. In the present study, to evaluate the properties of regenerating 5-HT fibers in the hippocampal heterotopia of MAM rats, we examined the origin of these projections by combined retrograde transport and immunohistochemical methods. Prenatal exposure to MAM resulted in the formation of hippocampal heterotopia in the dorsal hippocampus. Regenerating 5-HT fibers formed a dense innervation within the hippocampal heterotopia after neonatal DHT injection. These projections appeared to arise mainly from 5-HT neurons in the median raphe nucleus, with a small portion from 5-HT neurons in the dorsal raphe nucleus. These findings suggest a specific profile of regenerating 5-HT fibers, providing the new insights for serotonergic plasticity.

  4. Human male infertility: chromosome anomalies, meiotic disorders, abnormal spermatozoa and recurrent abortion.

    PubMed

    Egozcue, S; Blanco, J; Vendrell, J M; García, F; Veiga, A; Aran, B; Barri, P N; Vidal, F; Egozcue, J

    2000-01-01

    Human male infertility is often related to chromosome abnormalities. In chromosomally normal infertile males, the rates of chromosome 21 and sex chromosome disomy in spermatozoa are increased. Higher incidences of trisomy 21 (seldom of paternal origin) and sex chromosome aneuploidy are also found. XXY and XYY patients produce increased numbers of XY, XX and YY spermatozoa, indicating an increased risk of production of XXY, XYY and XXX individuals. Since XXYs can reproduce using intracytoplasmic sperm injection (ICSI), this could explain the slight increase of sex chromosome anomalies in ICSI series. Carriers of structural reorganizations produce unbalanced spermatozoa, and risk having children with duplications and/or deficiencies. In some cases, this risk is considerably lower or higher than average. These patients also show increased diploidy, and a higher risk of producing diandric triploids. Meiotic disorders are frequent in infertile males, and increase with severe oligoasthenozoospemia (OA) and/or high follicle stimulating hormone (FSH) concentrations. These patients produce spermatozoa with autosomal and sex chromosome disomies, and diploid spermatozoa. Their contribution to recurrent abortion depends on the production of trisomies, monosomies and of triploids. The most frequent sperm chromosome anomaly in infertile males is diploidy, originated by either meiotic mutations or by a compromised testicular environment. PMID:10711834

  5. The crystal structure of human GlnRS provides basis for the development of neurological disorders

    DOE PAGESBeta

    Ognjenovic, Jana; Wu, Jiang; Matthies, Doreen; Baxa, Ulrich; Subramaniam, Sriram; Ling, Jiqiang; Simonovic, Miljan

    2016-02-10

    Cytosolic glutaminyl-tRNA synthetase (GlnRS) is the singular enzyme responsible for translation of glutamine codons. Compound heterozygous mutations in GlnRS cause severe brain disorders by a poorly understood mechanism. Herein, we present crystal structures of the wild type and two pathological mutants of human GlnRS, which reveal, for the first time, the domain organization of the intact enzyme and the structure of the functionally important N-terminal domain (NTD). Pathological mutations mapping in the NTD alter the domain structure, and decrease catalytic activity and stability of GlnRS, whereas missense mutations in the catalytic domain induce misfolding of the enzyme. Our results suggestmore » that the reduced catalytic efficiency and a propensity of GlnRS mutants to misfold trigger the disease development. As a result, this report broadens the spectrum of brain pathologies elicited by protein misfolding and provides a paradigm for understanding the role of mutations in aminoacyl-tRNA synthetases in neurological diseases. Keywords« less

  6. Myofascial Temporomandibular Disorder.

    PubMed

    Fernandez-de-Las-Penas, César; Svensson, Peter

    2016-01-01

    Temporomandibular disorders (TMD) have been discussed for more than 70 years without reaching consensus on causes, etiological factors, pathophysiology, or rationale management. Indeed, TMD pain remains an enigma and a diagnostic and management challenge for many clinicians. Perhaps the many and often conflicting views on TMD pain by different health care providers are routed in professional traditions, personal beliefs, experience, and clinical training. This review aims to provide an updated and critical discussion on what is known and supported by scientific evidence about myofascial TMD pain and which gaps there still may be in our understanding of this condition. It has not been the intention to make a systematic review on all aspects of TMD but rather to point out some of the more recent (and important) pieces of information that may help us to better appreciate TMD pain as a complex and multifaceted pain disorder manifested in the craniofacial system. PMID:26717949

  7. The Nervous System Orchestrates and Integrates Craniofacial Development: A Review

    PubMed Central

    Adameyko, Igor; Fried, Kaj

    2016-01-01

    Development of a head is a dazzlingly complex process: a number of distinct cellular sources including cranial ecto- and endoderm, mesoderm and neural crest contribute to facial and other structures. In the head, an extremely fine-tuned developmental coordination of CNS, peripheral neural components, sensory organs and a musculo-skeletal apparatus occurs, which provides protection and functional integration. The face can to a large extent be considered as an assembly of sensory systems encased and functionally fused with appendages represented by jaws. Here we review how the developing brain, neurogenic placodes and peripheral nerves influence the morphogenesis of surrounding tissues as a part of various general integrative processes in the head. The mechanisms of this impact, as we understand it now, span from the targeted release of the morphogens necessary for shaping to providing a niche for cellular sources required in later development. In this review we also discuss the most recent findings and ideas related to how peripheral nerves and nerve-associated cells contribute to craniofacial development, including teeth, during the post- neural crest period and potentially in regeneration. PMID:26924989

  8. The Nervous System Orchestrates and Integrates Craniofacial Development: A Review.

    PubMed

    Adameyko, Igor; Fried, Kaj

    2016-01-01

    Development of a head is a dazzlingly complex process: a number of distinct cellular sources including cranial ecto- and endoderm, mesoderm and neural crest contribute to facial and other structures. In the head, an extremely fine-tuned developmental coordination of CNS, peripheral neural components, sensory organs and a musculo-skeletal apparatus occurs, which provides protection and functional integration. The face can to a large extent be considered as an assembly of sensory systems encased and functionally fused with appendages represented by jaws. Here we review how the developing brain, neurogenic placodes and peripheral nerves influence the morphogenesis of surrounding tissues as a part of various general integrative processes in the head. The mechanisms of this impact, as we understand it now, span from the targeted release of the morphogens necessary for shaping to providing a niche for cellular sources required in later development. In this review we also discuss the most recent findings and ideas related to how peripheral nerves and nerve-associated cells contribute to craniofacial development, including teeth, during the post- neural crest period and potentially in regeneration. PMID:26924989

  9. STRAIN-SPECIFIC MODIFIER GENES GOVERNING CRANIOFACIAL PHENOTYPES

    PubMed Central

    Mukhopadhyay, Partha; Brock, Guy; Webb, Cynthia; Pisano, M. Michele; Greene, Robert M

    2012-01-01

    BACKGROUND The presence of strain-specific modifier genes is known to modulate the phenotype and pathophysiology of mice harboring genetically engineered mutations. Thus, identification of genetic modifier genes is requisite to understanding control of phenotypic expression. c-Ski is a transcriptional regulator. Ski−/− mice on a C57BL6J (B6) background exhibit facial clefting, while Ski−/− mice on a 129P3 (129) background present with exencephaly. METHODS In the present study, oligonucleotide-based gene expression profiling was utilized to identify potential strain-specific modifier gene candidates present in wild-type mice of B6 and 129 genetic backgrounds. Changes in gene expression were verified by TaqMan quantitative real-time PCR. RESULTS Steady-state levels of 89 genes demonstrated a significantly higher level of expression, and those of 68 genes demonstrated a significantly lower level of expression in the developing neural tubes from E8.5, B6 embryos when compared to expression levels in neural tubes derived from E8.5, 129 embryos. CONCLUSIONS Based on the results from the current comparative microarray study, and taking into consideration a number of relevant published reports, several potential strain-specific gene candidates, likely to modify the craniofacial phenotypes in various knockout mouse models have been identified. PMID:22371338

  10. A standardized nomenclature for craniofacial and facial anthropometry.

    PubMed

    Caple, Jodi; Stephan, Carl N

    2016-05-01

    Standardized terms and methods have long been recognized as crucial to reduce measurement error and increase reliability in anthropometry. The successful prior use of craniometric landmarks makes extrapolation of these landmarks to the soft tissue context, as analogs, intuitive for forensic craniofacial analyses and facial photogrammetry. However, this extrapolation has not, so far, been systematic. Instead, varied nomenclature and definitions exist for facial landmarks, and photographic analyses are complicated by the generalization of 3D craniometric landmarks to the 2D face space where analogy is subsequently often lost, complicating anatomical assessments. For example, landmarks requiring palpation of the skull or the examination of the 3D surface typology are impossible to legitimately position; similar applies to median landmarks not visible in lateral photographs. To redress these issues without disposing of the craniometric framework that underpins many facial landmarks, we provide an updated and transparent nomenclature for facial description. This nomenclature maintains the original craniometric intent (and base abbreviations) but provides clear distinction of ill-defined (quasi) landmarks in photographic contexts, as produced when anatomical points are subjectively inferred from shape-from-shading information alone. PMID:26662189

  11. Health policy and craniofacial care: issues in resource allocation.

    PubMed

    Strauss, R P

    1994-01-01

    The distribution of health care services, including craniofacial services in the United States, is examined. The U.S. has a unique health care financing and organizational system in which persons are most commonly covered by health insurance as a benefit of their employment. Current estimates are that nearly 40 million Americans have no health insurance (Himmelstein et al., 1992). Approximately half of the uninsured persons are in low-wage employment that does not provide health insurance benefits nor allow them to qualify for Medicaid (Pepper Commission, 1990). Personal health care costs now exceed 11% of the U.S. gross domestic product, a significantly higher percentage than that found in other industrialized nations (Consumer Reports, 1990b). Within the current system, is health care distributed in a fair or moral manner? What are the effects of the allocation scheme? Possible changes in health care financing and delivery are examined and basic ethical and social issues associated with a changing U.S. health care delivery system are explored. PMID:8130247

  12. Classification and craniofacial features of gummy smile in adolescents.

    PubMed

    Wu, Hao; Lin, Jie; Zhou, Li; Bai, Ding

    2010-09-01

    Classification of gummy smile was tried first according to gingival exposure site during posed smile, then several items were measured on cephalometric radiograph to analyze the morphologic features in both sexes and further divided into subgroups. Two hundred twenty-eight adolescents with gingival display of more than 2 mm during smile were clustered according to gingival exposure site. Measurements of 18 pertinent items with great clinical concern or controversy in previous study in each groups were compared with corresponding references. Four distinctive types of gummy smile could be distinguished, and they exposed a continuous band, posterior parts, and one side or anterior part of upper gingiva, respectively. The type exposing a continuous band of upper gingiva took up the majority (200 cases, 88%) of all subjects and were chosen for further cephalometric analysis. Among the characteristic features of gummy smile, adolescents have skeletal class II relationship, vertical growth pattern, retrusive mandible, excessive anterior maxillary height, labially inclined upper incisors and upper lip, great overjet and overbite, and relatively short lip compared with anterior maxillary height. Skeletal class III relationship and horizontal growth pattern were absolutely absent. As a result, treatment planning should be adjusted according to the exposure site and craniofacial feature of each individual patient to obtain the best result. PMID:20856039

  13. Three-Dimensional Bioprinting for Regenerative Dentistry and Craniofacial Tissue Engineering.

    PubMed

    Obregon, F; Vaquette, C; Ivanovski, S; Hutmacher, D W; Bertassoni, L E

    2015-09-01

    Craniofacial tissues are organized with complex 3-dimensional (3D) architectures. Mimicking such 3D complexity and the multicellular interactions naturally occurring in craniofacial structures represents one of the greatest challenges in regenerative dentistry. Three-dimensional bioprinting of tissues and biological structures has been proposed as a promising alternative to address some of these key challenges. It enables precise manufacture of various biomaterials with complex 3D architectures, while being compatible with multiple cell sources and being customizable to patient-specific needs. This review describes different 3D bioprinting methods and summarizes how different classes of biomaterials (polymer hydrogels, ceramics, composites, and cell aggregates) may be used for 3D biomanufacturing of scaffolds, as well as craniofacial tissue analogs. While the fabrication of scaffolds upon which cells attach, migrate, and proliferate is already in use, printing of all the components that form a tissue (living cells and matrix materials together) to produce tissue constructs is still in its early stages. In summary, this review seeks to highlight some of the key advantages of 3D bioprinting technology for the regeneration of craniofacial structures. Additionally, it stimulates progress on the development of strategies that will promote the translation of craniofacial tissue engineering from the laboratory bench to the chair side. PMID:26124216

  14. Crude oil exposures reveal roles for intracellular calcium cycling in haddock craniofacial and cardiac development

    NASA Astrophysics Data System (ADS)

    Sørhus, Elin; Incardona, John P.; Karlsen, Ørjan; Linbo, Tiffany; Sørensen, Lisbet; Nordtug, Trond; van der Meeren, Terje; Thorsen, Anders; Thorbjørnsen, Maja; Jentoft, Sissel; Edvardsen, Rolf B.; Meier, Sonnich

    2016-08-01

    Recent studies have shown that crude oil exposure affects cardiac development in fish by disrupting excitation-contraction (EC) coupling. We previously found that eggs of Atlantic haddock (Melanogrammus aeglefinus) bind dispersed oil droplets, potentially leading to more profound toxic effects from uptake of polycyclic aromatic hydrocarbons (PAHs). Using lower concentrations of dispersed crude oil (0.7–7 μg/L ∑PAH), here we exposed a broader range of developmental stages over both short and prolonged durations. We quantified effects on cardiac function and morphogenesis, characterized novel craniofacial defects, and examined the expression of genes encoding potential targets underlying cardiac and craniofacial defects. Because of oil droplet binding, a 24-hr exposure was sufficient to create severe cardiac and craniofacial abnormalities. The specific nature of the craniofacial abnormalities suggests that crude oil may target common craniofacial and cardiac precursor cells either directly or indirectly by affecting ion channels and intracellular calcium in particular. Furthermore, down-regulation of genes encoding specific components of the EC coupling machinery suggests that crude oil disrupts excitation-transcription coupling or normal feedback regulation of ion channels blocked by PAHs. These data support a unifying hypothesis whereby depletion of intracellular calcium pools by crude oil-derived PAHs disrupts several pathways critical for organogenesis in fish.

  15. Crude oil exposures reveal roles for intracellular calcium cycling in haddock craniofacial and cardiac development.

    PubMed

    Sørhus, Elin; Incardona, John P; Karlsen, Ørjan; Linbo, Tiffany; Sørensen, Lisbet; Nordtug, Trond; van der Meeren, Terje; Thorsen, Anders; Thorbjørnsen, Maja; Jentoft, Sissel; Edvardsen, Rolf B; Meier, Sonnich

    2016-01-01

    Recent studies have shown that crude oil exposure affects cardiac development in fish by disrupting excitation-contraction (EC) coupling. We previously found that eggs of Atlantic haddock (Melanogrammus aeglefinus) bind dispersed oil droplets, potentially leading to more profound toxic effects from uptake of polycyclic aromatic hydrocarbons (PAHs). Using lower concentrations of dispersed crude oil (0.7-7 μg/L ∑PAH), here we exposed a broader range of developmental stages over both short and prolonged durations. We quantified effects on cardiac function and morphogenesis, characterized novel craniofacial defects, and examined the expression of genes encoding potential targets underlying cardiac and craniofacial defects. Because of oil droplet binding, a 24-hr exposure was sufficient to create severe cardiac and craniofacial abnormalities. The specific nature of the craniofacial abnormalities suggests that crude oil may target common craniofacial and cardiac precursor cells either directly or indirectly by affecting ion channels and intracellular calcium in particular. Furthermore, down-regulation of genes encoding specific components of the EC coupling machinery suggests that crude oil disrupts excitation-transcription coupling or normal feedback regulation of ion channels blocked by PAHs. These data support a unifying hypothesis whereby depletion of intracellular calcium pools by crude oil-derived PAHs disrupts several pathways critical for organogenesis in fish. PMID:27506155

  16. The face, the future, and dental practice: how research in craniofacial biology will influence patient care.

    PubMed

    Townsend, G C; Brook, A H

    2014-06-01

    It has been a privilege to assemble a group of Australian and international researchers to produce a special issue of the Australian Dental Journal that reflects the cutting edge of research in different aspects of craniofacial biology, and also considers how these advances will influence future education and practice within dentistry. The aim of this special issue is to provide a collection of concept papers and critical reviews on key topics that cover both fundamental and applied research in craniofacial biology and to consider the clinical implications. To do this, four questions have been addressed that lead to the four sections of this issue. These are: How have we come to the present exciting position in craniofacial biology with breakthroughs over the past 50 years? What are current fundamental research topics that are helping us to understand more about craniofacial and general development, possibly leading to future clinical developments? What are the current applied research topics that will influence future clinical practice? Looking forward, what new developments in craniofacial biology may come about that will change the face of dental education and practice? The refereed papers in this special issue are grouped into the four sections that seek to respond to these demanding questions. PMID:24646132

  17. Craniofacial morphometric analysis of individuals with X-linked hypohidrotic ectodermal dysplasia

    PubMed Central

    Goodwin, Alice F; Larson, Jacinda R; Jones, Kyle B; Liberton, Denise K; Landan, Maya; Wang, Zhifeng; Boekelheide, Anne; Langham, Margaret; Mushegyan, Vagan; Oberoi, Snehlata; Brao, Rosalie; Wen, Timothy; Johnson, Ramsey; Huttner, Kenneth; Grange, Dorothy K; Spritz, Richard A; Hallgrímsson, Benedikt; Jheon, Andrew H; Klein, Ophir D

    2014-01-01

    Hypohidrotic ectodermal dysplasia (HED) is the most prevalent type of ectodermal dysplasia (ED). ED is an umbrella term for a group of syndromes characterized by missing or malformed ectodermal structures, including skin, hair, sweat glands, and teeth. The X-linked recessive (XL), autosomal recessive (AR), and autosomal dominant (AD) types of HED are caused by mutations in the genes encoding ectodysplasin (EDA1), EDA receptor (EDAR), or EDAR-associated death domain (EDARADD). Patients with HED have a distinctive facial appearance, yet a quantitative analysis of the HED craniofacial phenotype using advanced three-dimensional (3D) technologies has not been reported. In this study, we characterized craniofacial morphology in subjects with X-linked hypohidrotic ectodermal dysplasia (XLHED) by use of 3D imaging and geometric morphometrics (GM), a technique that uses defined landmarks to quantify size and shape in complex craniofacial morphologies. We found that the XLHED craniofacial phenotype differed significantly from controls. Patients had a smaller and shorter face with a proportionally longer chin and midface, prominent midfacial hypoplasia, a more protrusive chin and mandible, a narrower and more pointed nose, shorter philtrum, a narrower mouth, and a fuller and more rounded lower lip. Our findings refine the phenotype of XLHED and may be useful both for clinical diagnosis of XLHED and to extend understanding of the role of EDA in craniofacial development. PMID:25333067

  18. Application of three-dimensional computed tomography in craniofacial clinical practice and research.

    PubMed

    Anderson, P J; Yong, R; Surman, T L; Rajion, Z A; Ranjitkar, S

    2014-06-01

    Following the invention of the first computed tomography (CT) scanner in the early 1970s, many innovations in three-dimensional (3D) diagnostic imaging technology have occurred, leading to a wide range of applications in craniofacial clinical practice and research. Three-dimensional image analysis provides superior and more detailed information compared with conventional plain two-dimensional (2D) radiography, with the added benefit of 3D printing for preoperative treatment planning and regenerative therapy. Current state-of-the-art multidetector CT (MDCT), also known as medical CT, has an important role in the diagnosis and management of craniofacial injuries and pathology. Three-dimensional cone beam CT (CBCT), pioneered in the 1990s, is gaining increasing popularity in dental and craniofacial clinical practice because of its faster image acquisition at a lower radiation dose, but sound guidelines are needed to ensure its optimal clinical use. Recent innovations in micro-computed tomography (micro-CT) have revolutionized craniofacial biology research by enabling higher resolution scanning of teeth beyond the capabilities of MDCT and CBCT, presenting new prospects for translational clinical research. Even after four decades of refinement, CT technology continues to advance and broaden the horizons of craniofacial clinical practice and phenomics research. PMID:24611727

  19. Perinatal stem cells: A promising cell resource for tissue engineering of craniofacial bone

    PubMed Central

    Si, Jia-Wen; Wang, Xu-Dong; Shen, Steve GF

    2015-01-01

    In facing the mounting clinical challenge and suboptimal techniques of craniofacial bone defects resulting from various conditions, such as congenital malformations, osteomyelitis, trauma and tumor resection, the ongoing research of regenerative medicine using stem cells and concurrent advancement in biotechnology have shifted the focus from surgical reconstruction to a novel stem cell-based tissue engineering strategy for customized and functional craniofacial bone regeneration. Given the unique ontogenetical and cell biological properties of perinatal stem cells, emerging evidence has suggested these extraembryonic tissue-derived stem cells to be a promising cell source for extensive use in regenerative medicine and tissue engineering. In this review, we summarize the current achievements and obstacles in stem cell-based craniofacial bone regeneration and subsequently we address the characteristics of various types of perinatal stem cells and their novel application in tissue engineering of craniofacial bone. We propose the promising feasibility and scope of perinatal stem cell-based craniofacial bone tissue engineering for future clinical application. PMID:25621114

  20. Crude oil exposures reveal roles for intracellular calcium cycling in haddock craniofacial and cardiac development

    PubMed Central

    Sørhus, Elin; Incardona, John P.; Karlsen, Ørjan; Linbo, Tiffany; Sørensen, Lisbet; Nordtug, Trond; van der Meeren, Terje; Thorsen, Anders; Thorbjørnsen, Maja; Jentoft, Sissel; Edvardsen, Rolf B.; Meier, Sonnich

    2016-01-01

    Recent studies have shown that crude oil exposure affects cardiac development in fish by disrupting excitation-contraction (EC) coupling. We previously found that eggs of Atlantic haddock (Melanogrammus aeglefinus) bind dispersed oil droplets, potentially leading to more profound toxic effects from uptake of polycyclic aromatic hydrocarbons (PAHs). Using lower concentrations of dispersed crude oil (0.7–7 μg/L ∑PAH), here we exposed a broader range of developmental stages over both short and prolonged durations. We quantified effects on cardiac function and morphogenesis, characterized novel craniofacial defects, and examined the expression of genes encoding potential targets underlying cardiac and craniofacial defects. Because of oil droplet binding, a 24-hr exposure was sufficient to create severe cardiac and craniofacial abnormalities. The specific nature of the craniofacial abnormalities suggests that crude oil may target common craniofacial and cardiac precursor cells either directly or indirectly by affecting ion channels and intracellular calcium in particular. Furthermore, down-regulation of genes encoding specific components of the EC coupling machinery suggests that crude oil disrupts excitation-transcription coupling or normal feedback regulation of ion channels blocked by PAHs. These data support a unifying hypothesis whereby depletion of intracellular calcium pools by crude oil-derived PAHs disrupts several pathways critical for organogenesis in fish. PMID:27506155

  1. The human genetics of eating disorders lessons from the leptin/melanocortin system.

    PubMed

    Costa, Jessica Lynn; Brennen, Miles B; Hochgeschwender, Ute

    2002-04-01

    Genetic analysis of eating disorders is complex phenotypically and genotypically. As seen in the leptin/melanocortin system, however, the results can lead to a deeper understanding and to new therapies. Benefits are expected for eating disorders that stem from genetic and psychologic causes. Finally, an awareness of possible genetic causes of eating disorders will help determine the causes--and thus the treatments--in children and adolescents with eating disorders, as exemplified by obese patients with mutations in the POMC, PC1, leptin, and MC4R loci. PMID:12109327

  2. Concise Review: Progress and Challenges in Using Human Stem Cells for Biological and Therapeutics Discovery: Neuropsychiatric Disorders.

    PubMed

    Panchision, David M

    2016-03-01

    In facing the daunting challenge of using human embryonic and induced pluripotent stem cells to study complex neural circuit disorders such as schizophrenia, mood and anxiety disorders, and autism spectrum disorders, a 2012 National Institute of Mental Health workshop produced a set of recommendations to advance basic research and engage industry in cell-based studies of neuropsychiatric disorders. This review describes progress in meeting these recommendations, including the development of novel tools, strides in recapitulating relevant cell and tissue types, insights into the genetic basis of these disorders that permit integration of risk-associated gene regulatory networks with cell/circuit phenotypes, and promising findings of patient-control differences using cell-based assays. However, numerous challenges are still being addressed, requiring further technological development, approaches to resolve disease heterogeneity, and collaborative structures for investigators of different disciplines. Additionally, since data obtained so far is on small sample sizes, replication in larger sample sets is needed. A number of individual success stories point to a path forward in developing assays to translate discovery science to therapeutics development. Stem Cells 2016;34:523-536. PMID:26840228

  3. An Interesting Case of Penetrating Craniofacial Trauma Involving a Wooden Stick

    PubMed Central

    Kulkarni, Ambadas; Chandrasala, Soumithran; Vishnudas, Praveesh; Dev, Arul

    2016-01-01

    Penetrating craniofacial trauma, although uncommon, has a high potential for death or catastrophic consequences from head injury or vital neurovascular injuries. The foreign body may cause significant challenge, especially when it is a large one. Airway obstruction, vascular injuries, intracranial communication, ocular injury and injuries to any other adjacent vital structures when involved may change the treatment objectives from simple foreign body retrieval to a comprehensive multidisciplinary approach to stabilize the patient. Retrieval of foreign bodies may be challenging because of many factors including the size of the object, its site, and the surrounding anatomical structures. Accurate localization of the foreign body before removal is essential in craniofacial region. We present a case of penetrating craniofacial trauma from a wooden stick, with an in situ foreign body, that was managed by emergency surgical exploration in general anaesthesia and retrieval of foreign body in Toto under antibiotic coverage and tetanus prophylaxis. PMID:27190963

  4. Clinical Application of Three-Dimensional Printing Technology in Craniofacial Plastic Surgery

    PubMed Central

    Kim, Namkug

    2015-01-01

    Three-dimensional (3D) printing has been particularly widely adopted in medical fields. Application of the 3D printing technique has even been extended to bio-cell printing for 3D tissue/organ development, the creation of scaffolds for tissue engineering, and actual clinical application for various medical parts. Of various medical fields, craniofacial plastic surgery is one of areas that pioneered the use of the 3D printing concept. Rapid prototype technology was introduced in the 1990s to medicine via computer-aided design, computer-aided manufacturing. To investigate the current status of 3D printing technology and its clinical application, a systematic review of the literature was conducted. In addition, the benefits and possibilities of the clinical application of 3D printing in craniofacial surgery are reviewed, based on personal experiences with more than 500 craniofacial cases conducted using 3D printing tactile prototype models. PMID:26015880

  5. SRF regulates craniofacial development through selective recruitment of MRTF cofactors by PDGF signaling

    PubMed Central

    Vasudevan, Harish N.; Soriano, Philippe

    2014-01-01

    Summary Receptor tyrosine kinase signaling is critical for mammalian craniofacial development, but the key downstream transcriptional effectors remain unknown. We demonstrate that SRF is induced by both PDGF and FGF signaling in mouse embryonic palatal mesenchyme cells, and Srf neural crest conditional mutants exhibit facial clefting accompanied by proliferation and migration defects. Srf and Pdgfra mutants interact genetically in craniofacial development, but Srf and Fgfr1 mutants do not. This signal specificity is recapitulated at the level of cofactor activation: while both PDGF and FGF target gene promoters show enriched genome-wide overlap with SRF ChIP-seq peaks, PDGF selectively activates a network of MRTF-dependent cytoskeletal genes. Collectively, our results identify a novel role for SRF in proliferation and migration during craniofacial development and delineate a mechanism of receptor tyrosine kinase specificity mediated through differential cofactor usage, leading to a unique PDGF-responsive SRF-driven transcriptional program in the midface. PMID:25453829

  6. Dental and Nondental Stem Cell Based Regeneration of the Craniofacial Region: A Tissue Based Approach

    PubMed Central

    Hughes, Declan; Song, Bing

    2016-01-01

    Craniofacial reconstruction may be a necessary treatment for those who have been affected by trauma, disease, or pathological developmental conditions. The use of stem cell therapy and tissue engineering shows massive potential as a future treatment modality. Currently in the literature, there is a wide variety of published experimental studies utilising the different stem cell types available and the plethora of available scaffold materials. This review investigates different stem cell sources and their unique characteristics to suggest an ideal cell source for regeneration of individual craniofacial tissues. At present, understanding and clinical applications of stem cell therapy remain in their infancy with numerous challenges to overcome. In spite of this, the field displays immense capacity and will no doubt be utilised in future clinical treatments of craniofacial regeneration. PMID:27143979

  7. An Interesting Case of Penetrating Craniofacial Trauma Involving a Wooden Stick.

    PubMed

    Kulkarni, Ambadas; Chandrasala, Soumithran; Nimbeni, Basavaraj; Vishnudas, Praveesh; Dev, Arul

    2016-04-01

    Penetrating craniofacial trauma, although uncommon, has a high potential for death or catastrophic consequences from head injury or vital neurovascular injuries. The foreign body may cause significant challenge, especially when it is a large one. Airway obstruction, vascular injuries, intracranial communication, ocular injury and injuries to any other adjacent vital structures when involved may change the treatment objectives from simple foreign body retrieval to a comprehensive multidisciplinary approach to stabilize the patient. Retrieval of foreign bodies may be challenging because of many factors including the size of the object, its site, and the surrounding anatomical structures. Accurate localization of the foreign body before removal is essential in craniofacial region. We present a case of penetrating craniofacial trauma from a wooden stick, with an in situ foreign body, that was managed by emergency surgical exploration in general anaesthesia and retrieval of foreign body in Toto under antibiotic coverage and tetanus prophylaxis. PMID:27190963

  8. 3D modeling, custom implants and its future perspectives in craniofacial surgery

    PubMed Central

    Parthasarathy, Jayanthi

    2014-01-01

    Custom implants for the reconstruction of craniofacial defects have gained importance due to better performance over their generic counterparts. This is due to the precise adaptation to the region of implantation, reduced surgical times and better cosmesis. Application of 3D modeling in craniofacial surgery is changing the way surgeons are planning surgeries and graphic designers are designing custom implants. Advances in manufacturing processes and ushering of additive manufacturing for direct production of implants has eliminated the constraints of shape, size and internal structure and mechanical properties making it possible for the fabrication of implants that conform to the physical and mechanical requirements of the region of implantation. This article will review recent trends in 3D modeling and custom implants in craniofacial reconstruction. PMID:24987592

  9. Stem cells of the suture mesenchyme in craniofacial bone development, repair and regeneration

    PubMed Central

    Maruyama, Takamitsu; Jeong, Jaeim; Sheu, Tzong-Jen; Hsu, Wei

    2016-01-01

    The suture mesenchyme serves as a growth centre for calvarial morphogenesis and has been postulated to act as the niche for skeletal stem cells. Aberrant gene regulation causes suture dysmorphogenesis resulting in craniosynostosis, one of the most common craniofacial deformities. Owing to various limitations, especially the lack of suture stem cell isolation, reconstruction of large craniofacial bone defects remains highly challenging. Here we provide the first evidence for an Axin2-expressing stem cell population with long-term self-renewing, clonal expanding and differentiating abilities during calvarial development and homeostastic maintenance. These cells, which reside in the suture midline, contribute directly to injury repair and skeletal regeneration in a cell autonomous fashion. Our findings demonstrate their true identity as skeletal stem cells with innate capacities to replace the damaged skeleton in cell-based therapy, and permit further elucidation of the stem cell-mediated craniofacial skeletogenesis, leading to revealing the complex nature of congenital disease and regenerative medicine. PMID:26830436

  10. Who decides? Patients, parents, or gatekeepers: pediatric decisions in the craniofacial setting.

    PubMed

    Mouradian, W E

    1995-11-01

    Special ethical issues arise for the craniofacial team dealing with pediatric patients, which include competency, surrogacy, and the "best interests" standard. Medical decisions for children are made by surrogates, usually parents, who must use the "best interests" standard. The team's primary responsibility is to the child, not the parents. Children should participate as abilities allow, especially for elective procedures. Increasingly, cost considerations also influence medical decisions. The craniofacial team is often a de factor gatekeeper. Ethically responsible team behavior includes: weighing risks and benefits of proposed interventions; promoting discussion with families and patients to identify "best interests;" monitoring outcomes; and advocacy for craniofacial patients individually and at a policy level. Care guidelines and definitions of basic levels of care should be developed to assist teams with decision-making and advocacy efforts. Ethical analysis is part of both good patient care and good policy formation, and should be a part of regular team deliberations. PMID:8547294

  11. Clinical application of three-dimensional printing technology in craniofacial plastic surgery.

    PubMed

    Choi, Jong Woo; Kim, Namkug

    2015-05-01

    Three-dimensional (3D) printing has been particularly widely adopted in medical fields. Application of the 3D printing technique has even been extended to bio-cell printing for 3D tissue/organ development, the creation of scaffolds for tissue engineering, and actual clinical application for various medical parts. Of various medical fields, craniofacial plastic surgery is one of areas that pioneered the use of the 3D printing concept. Rapid prototype technology was introduced in the 1990s to medicine via computer-aided design, computer-aided manufacturing. To investigate the current status of 3D printing technology and its clinical application, a systematic review of the literature was conducted. In addition, the benefits and possibilities of the clinical application of 3D printing in craniofacial surgery are reviewed, based on personal experiences with more than 500 craniofacial cases conducted using 3D printing tactile prototype models. PMID:26015880

  12. Scientific research in Latin America: experiences of collaborative projects on craniofacial anomalies.

    PubMed

    Trindade, Inge Elly Kiemle

    2006-11-01

    Scientists based in Latin America, particularly in Argentina, Brazil, Chile, and Mexico, substantially increased their rate of scientific publications during the past decades. Brazil experienced the most growth with the implementation of an efficient postgraduate system that is tripling the number of doctors every 10 years. Research on craniofacial anomalies is similarly increasing in Latin American countries. A PUBMED search using the key word "cleft" and a particular country's name showed that Brazil has published the most articles in that field during the past few years, many of which were published by research groups linked to the Hospital for Rehabilitation of Craniofacial Anomalies located in Bauru, which provides cleft and craniofacial care for more than 2500 new patients every year. Based on experiences with international collaboration, this report discusses obstacles to collaborative research and presents recommendations to enhance the possibility of creating successful partnerships among international research teams. PMID:17105326

  13. Craniofacial skeletal measurements based on computed tomography: Part I. Accuracy and reproducibility.

    PubMed

    Waitzman, A A; Posnick, J C; Armstrong, D C; Pron, G E

    1992-03-01

    Computed tomography (CT) is a useful modality for the management of craniofacial anomalies. A study was undertaken to assess whether CT measurements of the upper craniofacial skeleton accurately represent the bony region imaged. Measurements taken directly from five dry skulls (approximate ages: adults, over 18 years; child, 4 years; infant, 6 months) were compared to those from axial CT scans of these skulls. Excellent agreement was found between the direct (dry skull) and indirect (CT) measurements. The effect of head tilt on the accuracy of these measurements was investigated. The error was within clinically acceptable limits (less than 5 percent) if the angle was no more than +/- 4 degrees from baseline (0 degrees). Objective standardized information gained from CT should complement the subjective clinical data usually collected for the treatment of craniofacial deformities. PMID:1571344

  14. Frequent detection of high human papillomavirus DNA loads in oral potentially malignant disorders.

    PubMed

    Pierangeli, A; Cannella, F; Scagnolari, C; Gentile, M; Sciandra, I; Antonelli, G; Ciolfi, C; Russo, C; Palaia, G; Romeo, U; Polimeni, A

    2016-01-01

    Human papillomavirus (HPV) is estimated to be the cause of 40--80% of the squamous cell carcinoma of the oropharynx but only of a small fraction of the oral cavity cancers. The prevalence of oral HPV infection has significantly increased in the last decade, raising concerns about the role of HPV in progression of oral potentially malignant disorders (OPMD) toward squamous cell carcinomas. We sought to study HPV infection in patients with oral lesions, and in control individuals, using non-invasive and site-specific oral brushing and sensitive molecular methods. HPV DNA positivity and viral loads were evaluated in relation to patient data and clinical diagnosis. We enrolled 116 individuals attending Dental Clinics: 62 patients with benign oral lesions (e.g. fibromas, papillomatosis, ulcers) or OPMD (e.g. lichen, leukoplakia) and 54 controls. Oral cells were collected with Cytobrush and HPV-DNA was detected with quantitative real-time PCR for the more common high-risk (HR) and low-risk (LR) genotypes. HPV detection rate, percentage of HR HPVs and HPV-DNA loads (namely HPV16 and in particular, HPV18) were significantly higher in patients than in controls. Lichen planus cases had the highest HPV-positive rate (75.0%), hairy leukoplakia the lowest (33.3%). This study detected unexpectedly high rates of HPV infection in cells of the oral mucosa. The elevated HR HPV loads found in OPMD suggest the effectiveness of quantitative PCR in testing oral lesions. Prospective studies are needed to establish whether elevated viral loads represent a clinically useful marker of the risk of malignant progression. PMID:26408278

  15. Neuroethics of deep brain stimulation for mental disorders: brain stimulation reward in humans.

    PubMed

    Oshima, Hideki; Katayama, Yoichi

    2010-01-01

    The theoretical basis of some deep brain stimulation (DBS) trials undertaken in the early years was the phenomenon of "brain stimulation reward (BSR)," which was first identified in rats. The animals appeared to be rewarded by pleasure caused by the stimulation of certain brain regions (reward system), such as the septal area. "Self-stimulation" experiments, in which rats were allowed to stimulate their own brain by pressing a freely accessible lever, they quickly learned lever pressing and sometimes continued to stimulate until they exhausted themselves. BSR was also observed with DBS of the septal area in humans. DBS trials in later years were undertaken on other theoretical bases, but unexpected BSR was sometimes induced by stimulation of some areas, such as the locus coeruleus complex. When BSR was induced, the subjects experienced feelings that were described as "cheerful," "alert," "good," "well-being," "comfort," "relaxation," "joy," or "satisfaction." Since the DBS procedure is equivalent to a "self-stimulation" experiment, they could become "addicted to the stimulation itself" or "compulsive about the stimulation," and stimulate themselves "for the entire day," "at maximum amplitude" and, in some instances, "into convulsions." DBS of the reward system has recently been applied to alleviate anhedonia in patients with refractory major depression. Although this approach appears promising, there remains a difficult problem: who can adjust their feelings and reward-oriented behavior within the normal range? With a self-stimulation procedure, the BSR may become uncontrollable. To develop DBS to the level of a standard therapy for mental disorders, we need to discuss "Who has the right to control the mental condition?" and "Who makes decisions" on "How much control is appropriate?" in daily life. PMID:20885119

  16. Human olfactory bulb neural stem cells mitigate movement disorders in a rat model of Parkinson's disease.

    PubMed

    Marei, Hany E S; Lashen, Samah; Farag, Amany; Althani, Asmaa; Afifi, Nahla; A, Abd-Elmaksoud; Rezk, Shaymaa; Pallini, Roberto; Casalbore, Patrizia; Cenciarelli, Carlo

    2015-07-01

    Parkinson's disease (PD) is a neurological disorder characterized by the loss of midbrain dopaminergic (DA) neurons. Neural stem cells (NSCs) are multipotent stem cells that are capable of differentiating into different neuronal and glial elements. The production of DA neurons from NSCs could potentially alleviate behavioral deficits in Parkinsonian patients; timely intervention with NSCs might provide a therapeutic strategy for PD. We have isolated and generated highly enriched cultures of neural stem/progenitor cells from the human olfactory bulb (OB). If NSCs can be obtained from OB, it would alleviate ethical concerns associated with the use of embryonic tissue, and provide an easily accessible cell source that would preclude the need for invasive brain surgery. Following isolation and culture, olfactory bulb neural stem cells (OBNSCs) were genetically engineered to express hNGF and GFP. The hNFG-GFP-OBNSCs were transplanted into the striatum of 6-hydroxydopamin (6-OHDA) Parkinsonian rats. The grafted cells survived in the lesion environment for more than eight weeks after implantation with no tumor formation. The grafted cells differentiated in vivo into oligodendrocyte-like (25 ± 2.88%), neuron-like (52.63 ± 4.16%), and astrocyte -like (22.36 ± 1.56%) lineages, which we differentiated based on morphological and immunohistochemical criteria. Transplanted rats exhibited a significant partial correction in stepping and placing in non-pharmacological behavioral tests, pole and rotarod tests. Taken together, our data encourage further investigations of the possible use of OBNSCs as a promising cell-based therapeutic strategy for Parkinson's disease. PMID:25536543

  17. Colorectal Disorders in Acute Human Immunodeficiency Virus Infection: A Case Series

    PubMed Central

    Panichsillapakit, Theppharit; Patel, Derek; Santangelo, Joanne; Richman, Douglas D.; Little, Susan J.; Smith, Davey M.

    2016-01-01

    Background. The gastrointestinal (GI) tract is important in the pathogenesis of human immunodeficiency virus (HIV) infection. We report a case series of lower GI endoscopic and histopathologic findings of HIV-infected individuals after presentation with acute infection. Methods. We performed a retrospective case review of individuals infected with HIV who enrolled between August 2010 and April 2013 in a primary infection treatment trial. All participants started the trial during acute infection and underwent colonoscopy with biopsies at baseline and after the start of antiretroviral treatment. Results. Twenty acutely infected individuals were included in the study (mean age, 33 years; range, 20–54 years). All participants were male who reported having receptive anal sex as an HIV risk factor. Nine individuals (45%) had at least 1 finding by colorectal pathology; 1 person had 2 diagnoses (diverticulosis and focal active proctitis). The histopathological findings revealed anal dysplasia in 3 cases: 2 had high-grade anal intraepithelial neoplasia (AIN) and 1 had low-grade AIN. Two persons had a colorectal polyp, 1 hyperplastic and 1 adenomatous. Three persons were diagnosed with diverticulosis, and 2 persons were diagnosed with proctitis, including 1 with focal active proctitis and 1 with cytomegalovirus proctitis. Conclusions. To our knowledge, this is the first case series report of lower GI disorders in acute HIV-infected individuals. Although the causal relationship remains uncertain, we describe the endoscopic findings that were observed during acute HIV infection among men who have sex with men. Understanding the prevalence of these pathologies may likely shed light on how acute HIV infection damages the lower GI tract. PMID:26925432

  18. Craniofacial Sutures: Morphology, Growth, and In Vivo Masticatory Strains

    PubMed Central

    RAFFERTY, KATHERINE L.; HERRING, SUSAN W.

    2010-01-01

    The growth and morphology of craniofacial sutures are thought to reflect their functional environment. However, little is known about in vivo sutural mechanics. The present study investigates the strains experienced by the internasal, nasofrontal, and anterior interfrontal sutures during masticatory activity in 4–6-month-old miniature swine (Sus scrofa). Measurements of the bony/fibrous arrangements and growth rates of these sutures were then examined in the context of their mechanical environment. Large tensile strains were measured in the interfrontal suture (1,036 με ± 400 SD), whereas the posterior internasal suture was under moderate compression (−440 με ± 238) and the nasofrontal suture experienced large compression (−1,583 με ± 506). Sutural interdigitation was associated with compressive strain. The collagen fibers of the internasal and interfrontal sutures were clearly arranged to resist compression and tension, respectively, whereas those of the nasofrontal suture could not be readily characterized as either compression or tension resisting. The average linear rate of growth over a 1-week period at the nasofrontal suture (133.8 μm, ± 50.9 S.D) was significantly greater than that of both the internasal and interfrontal sutures (39.2 μm ± 11.4 and 65.5 μm ± 14.0, respectively). Histological observations suggest that the nasofrontal suture contains chondroid tissue, which may explain the unexpected combination of high compressive loading and rapid growth in this suture. PMID:10521876

  19. Craniofacial injuries in professional cricket: no more a red herring.

    PubMed

    Tripathi, Manjul; Shukla, Dhaval P; Bhat, Dhananjaya Ishwar; Bhagavatula, Indira Devi; Mishra, Tejesh

    2016-04-01

    The issue of head injury in a noncontact sport like cricket is a matter of great debate and it carries more questions than answers. Recent incidents of fatal head injuries in individuals wearing a helmet have caused some to question the protective value of the helmet. The authors discuss the pattern, type of injury, incidents, and location of cranio-facio-ocular injuries in professional cricket to date. They evaluate the history of usage of the helmet in cricket, changes in design, and the protective value, and they compare the efficacy of various sports' helmets with injury profiles similar to those in cricket. The drop test and air cannon test are compared for impact energy attenuation performance of cricket helmets. A total of 36 cases of head injuries were identified, of which 5 (14%) were fatal and 9 (22%) were career-terminating events. Batsmen are the most vulnerable to injury, bearing 86% of the burden, followed by wicketkeepers (8%) and fielders (5.5%). In 53% of cases, the ball directly hit the head, while in 19.5% of cases the ball entered the gap between the peak and the faceguard. Ocular injuries to 3 wicketkeepers proved to be career-terminating injuries. The air cannon test is a better test for evaluating cricket helmets than the drop test. Craniofacial injuries are more common than popularly believed. There is an urgent need to improve the efficacy and compliance of protective restraints in cricket. A strict injury surveillance system with universal acceptance is needed to identify the burden of injuries and modes for their prevention. PMID:27032914

  20. Heritability of Craniofacial Structures in Normal Subjects and Patients with Sleep Apnea

    PubMed Central

    Chi, Luqi; Comyn, Francois-Louis; Keenan, Brendan T.; Cater, Jacqueline; Maislin, Greg; Pack, Allan I.; Schwab, Richard J.

    2014-01-01

    Objectives: Accumulating evidence has shown that there is a genetic contribution to obstructive sleep apnea (OSA).The objectives were to use magnetic resonance imaging (MRI) cephalometry to (1) confirm heritability of craniofacial risk factors for OSA previously shown by cephalometrics; and (2) examine the heritability of new craniofacial structures that are measurable with MRI. Design: A sib pair “quad” design examining apneics, apneic siblings, controls, and control siblings. The study design used exact matching on ethnicity and sex, frequency matching on age, and statistical control for differences in age, sex, ethnicity, height, and weight. Setting: Academic medical center. Patients: We examined 55 apneic probands (apnea-hypopnea index [AHI]: 46.8 ± 33.5 events/h), 55 proband siblings (AHI: 11.1 ± 15.9 events/h), 55 controls (AHI: 2.2 ± 1.7 events/h), and 55 control siblings (AHI: 4.1 ± 4.0 events/h). Interventions: N/A. Measurements and Results: Five independent domains reflecting different aspects of the craniofacial structure were examined. We confirmed heritability of sella–nasion–subspinale (38%, P = 0.002), saddle angle (55%, P < 0.0001), mandibular length (24%, P = 0.02) and lower facial height (33%, P = 0.006) previously measured by cephalometry. In addition, the current study added new insights by demonstrating significant heritability of mandibular width (30%, P = 0.005), maxillary width (47%, P < 0.0001), distance from the hyoid bone to the retropogonion (36%, P = 0.0018) and size of the oropharyngeal space (31%, P = 0.004). Finally, our data indicate that heritability of the craniofacial structures is similar in normal patients and those with apnea. Conclusions: The data support our a priori hypothesis that the craniofacial structures that have been associated with obstructive sleep apnea (OSA) are heritable. We have demonstrated heritability for several intermediate craniofacial phenotypes for OSA. Thus, we believe that future studies