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Sample records for human craniofacial disorders

  1. Comparative gene expression analysis of avian embryonic facial structures reveals new candidates for human craniofacial disorders.

    PubMed

    Brugmann, S A; Powder, K E; Young, N M; Goodnough, L H; Hahn, S M; James, A W; Helms, J A; Lovett, M

    2010-03-01

    Mammals and birds have common embryological facial structures, and appear to employ the same molecular genetic developmental toolkit. We utilized natural variation found in bird beaks to investigate what genes drive vertebrate facial morphogenesis. We employed cross-species microarrays to describe the molecular genetic signatures, developmental signaling pathways and the spectrum of transcription factor (TF) gene expression changes that differ between cranial neural crest cells in the developing beaks of ducks, quails and chickens. Surprisingly, we observed that the neural crest cells established a species-specific TF gene expression profile that predates morphological differences between the species. A total of 232 genes were differentially expressed between the three species. Twenty-two of these genes, including Fgfr2, Jagged2, Msx2, Satb2 and Tgfb3, have been previously implicated in a variety of mammalian craniofacial defects. Seventy-two of the differentially expressed genes overlap with un-cloned loci for human craniofacial disorders, suggesting that our data will provide a valuable candidate gene resource for human craniofacial genetics. The most dramatic changes between species were in the Wnt signaling pathway, including a 20-fold up-regulation of Dkk2, Fzd1 and Wnt1 in the duck compared with the other two species. We functionally validated these changes by demonstrating that spatial domains of Wnt activity differ in avian beaks, and that Wnt signals regulate Bmp pathway activity and promote regional growth in facial prominences. This study is the first of its kind, extending on previous work in Darwin's finches and provides the first large-scale insights into cross-species facial morphogenesis.

  2. 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

  3. 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.

  4. 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

  5. Sleep disorders and chronic craniofacial pain: Characteristics and management possibilities.

    PubMed

    Almoznino, Galit; Benoliel, Rafael; Sharav, Yair; Haviv, Yaron

    2017-06-01

    Chronic craniofacial pain involves the head, face and oral cavity and is associated with significant morbidity and high levels of health care utilization. A bidirectional relationship is suggested in the literature for poor sleep and pain, and craniofacial pain and sleep are reciprocally related. We review this relationship and discuss management options. Part I reviews the relationship between pain and sleep disorders in the context of four diagnostic categories of chronic craniofacial pain: 1) primary headaches: migraines, tension-type headache (TTH), trigeminal autonomic cephalalgias (TACs) and hypnic headache, 2) secondary headaches: sleep apnea headache, 3) temporomandibular joint disorders (TMD) and 4) painful cranial neuropathies: trigeminal neuralgia, post-herpetic trigeminal neuropathy, painful post-traumatic trigeminal neuropathy (PTTN) and burning mouth syndrome (BMS). Part II discusses the management of patients with chronic craniofacial pain and sleep disorders addressing the factors that modulate the pain experience as well as sleep disorders and including both non-pharmacological and pharmacological modalities.

  6. 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

  7. 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.

  8. 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.

  9. Craniofacial Morphology Affects Bite Force in Patients with Painful Temporomandibular Disorders.

    PubMed

    Bavia, Paula Furlan; Vilanova, Larissa Soares Reis; Garcia, Renata Cunha Matheus Rodrigues

    2016-01-01

    Craniofacial morphology affects masticatory performance in healthy dentate subjects, but little is known about its effects in patients with painful temporomandibular disorders (TMDs). Forty-eight female patients (mean age of 28±5.8 years) with painful TMDs underwent lateral cephalometric radiography. Using Ricketts' cephalometric analysis and the Vert method, subjects were assigned to three groups according to their craniofacial morphology: brachyfacial (n=22), mesofacial (n=13), and dolichofacial (n=13). Research diagnostic criteria for TMD were used to confirm the TMD diagnosis for each patient. Pain intensity was reported by each patient based on a visual analog scale (VAS). Maximum bite force (MBF) was measured with pressure sensors placed on the first molar site. Masticatory performance (MP) was assessed by chewing a silicone-based artificial material and determining the resulting particle size by the sieve method. Chewing ability (CA) was evaluated for seven food types and analyzed by a VAS questionnaire. Data were analyzed by one-way ANOVA followed by a Tukey-Kramer test (p<0.05). MBF differed in each group, with brachyfacial patients having the highest MBF values. There was no difference in MP among the groups. The groups differed only in their ability to chew one of the seven evaluated food types. In summary, craniofacial morphology affects the MBF without impairing MP or CA in patients with painful TMDs.

  10. Orientation of craniofacial planes and temporomandibular disorder in young adults with normal occlusion.

    PubMed

    Ciancaglini, R; Colombo-Bolla, G; Gherlone, E F; Radaelli, G

    2003-09-01

    The aim of this study was to investigate the relationship between orientation of craniofacial planes relative to the true horizontal and temporomandibular disorder (TMD), in normal occlusion. Fourteen university dental students, with full natural dentition and bilateral Angle Class I occlusion, who exhibited signs and symptoms of TMD, were compared with 14 age- and sex-matched healthy controls. Frontal and lateral photographs were taken in natural head position with the subject standing up, clenching a Fox plane and having a facial arch positioned. Photographs were examined by a standardized image analysis. Inter-pupillary axis, Frankfurt, occlusal and Camper planes were evaluated. In frontal view, the Frankfurt plane was right rotated relative to the true horizontal both in TMD subjects (P < 0.01) and controls (P < 0.05), but rotation was larger in TMD subjects (mean difference between groups, 1.1 degrees, 95% confidence interval, 95% CI, 0.2-2.0 degrees ). No significant deviation from the horizontal or difference between groups was observed for the interpupillary axis and occlusal plane. In lateral view, the Frankfurt plane was upward-orientated relative to the true horizontal in TMD group (mean angular deviation 2.8 degrees, 95% CI, 1.0-4.6 degrees ). The occlusal and Camper planes were downward-orientated in both groups (P < 0.0001), but inclination of occlusal plane tended to be smaller in TMD subjects (mean difference between groups, -3.8 degrees, 95% CI, -7.6-0.1 degrees ). Angles between any craniofacial planes did not significantly differ between groups. The findings show that in young adults with normal occlusion, a weak association exists between the orientation of craniofacial planes in natural head position and signs and symptoms of TMD. Furthermore, they suggest that, within this population, TMD might be mainly associated with head posture rather than with craniofacial morphology.

  11. ID migraine questionnaire in temporomandibular disorders with craniofacial pain: a study by using a multidisciplinary approach.

    PubMed

    Di Paolo, Carlo; Di Nunno, Anna; Vanacore, Nicola; Bruti, Gianluca

    2009-08-01

    To evaluate the prevalence of migraine and related disability and the role of ID migraine questionnaire as a screening tool in patients with temporomandibular disorders (TMDs) and craniofacial pain (CFP). TMDs patients with CFP underwent stomatognathic (RDC/TMD criteria) and neurological visits (IHS criteria, 2004). ID migraine questionnaire and MIgraine Disability Assessment Scale (MIDAS) were also administered. Out of 45 patients, 69% met diagnosis of migraine plus chronic tension-type headache (CTTH); 9% presented CTTH and 20% were migraineurs. Out of 39 migraineurs who completed MIDAS, 56% presented the highest disability grade. Out of 37 patients who completed ID migraine questionnaire, 32 resulted affected by probable migraine with a diagnostic sensibility and specificity of 94% and 100%, respectively. Our findings showed a clinical association between TMDs and migraine. We support a clinical role of ID migraine and MIDAS in TMDs patients with CFP and we underline the importance of a multidisciplinary evaluation in this group of migraineurs.

  12. Dll3 and Notch1 genetic interactions model axial segmental and craniofacial malformations of human birth defects.

    PubMed

    Loomes, Kathleen M; Stevens, Stacey A; O'Brien, Megan L; Gonzalez, Dorian M; Ryan, Matthew J; Segalov, Michelle; Dormans, Nicholas J; Mimoto, Mizuho S; Gibson, Joshua D; Sewell, William; Schaffer, Alyssa A; Nah, Hyun-Duck; Rappaport, Eric F; Pratt, Stephen C; Dunwoodie, Sally L; Kusumi, Kenro

    2007-10-01

    Mutations in the Notch1 receptor and delta-like 3 (Dll3) ligand cause global disruptions in axial segmental patterning. Genetic interactions between members of the notch pathway have previously been shown to cause patterning defects not observed in single gene disruptions. We examined Dll3-Notch1 compound mouse mutants to screen for potential gene interactions. While mice heterozygous at either locus appeared normal, 30% of Dll3-Notch1 double heterozygous animals exhibited localized, segmental anomalies similar to human congenital vertebral defects. Unexpectedly, double heterozygous mice also displayed statistically significant reduction of mandibular height and decreased length of the [corrected] maxillary hard palate. Examination of somite-stage embryos and perinatal anatomy and histology did not reveal any organ defects, so we used microarray-based analysis of Dll3 and Notch1 mutant embryos to identify gene targets that may be involved in notch-regulated segmental or craniofacial development. Thus, Dll3-Notch1 double heterozygous mice model human congenital scoliosis and craniofacial disorders.

  13. Human Development Domain of the Ontology of Craniofacial Development and Malformation

    PubMed Central

    Mejino, Jose LV; Travillian, Ravensara S; Cox, Timothy C; Shapiro, Linda G; Brinkley, James F

    2017-01-01

    In this paper we describe an ontological scheme for representing anatomical entities undergoing morphological transformation and changes in phenotype during prenatal development. This is a proposed component of the Anatomical Transformation Abstraction (ATA) of the Foundational Model of Anatomy (FMA) Ontology that was created to provide an ontological framework for capturing knowledge about human development from the zygote to postnatal life. It is designed to initially describe the structural properties of the anatomical entities that participate in human development and then enhance their description with developmental properties, such as temporal attributes and developmental processes. This approach facilitates the correlation and integration of the classical but static representation of embryology with the evolving novel concepts of developmental biology, which primarily deals with the experimental data on the mechanisms of embryogenesis and organogenesis. This is important for describing and understanding the underlying processes involved in structural malformations. In this study we focused on the development of the lips and the palate in conjunction with our work on the pathogenesis and classification of cleft lip and palate (CL/P) in the FaceBase program. Our aim here is to create the Craniofacial Human Development Ontology (CHDO) to support the Ontology of Craniofacial Development and Malformation (OCDM), which provides the infrastructure for integrating multiple and disparate craniofacial data generated by FaceBase researchers.

  14. 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

  15. 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.

  16. Cis-regulatory underpinnings of human GLI3 expression in embryonic craniofacial structures and internal organs.

    PubMed

    Abbasi, Amir A; Minhas, Rashid; Schmidt, Ansgar; Koch, Sabine; Grzeschik, Karl-Heinz

    2013-10-01

    The zinc finger transcription factor Gli3 is an important mediator of Sonic hedgehog (Shh) signaling. During early embryonic development Gli3 participates in patterning and growth of the central nervous system, face, skeleton, limb, tooth and gut. Precise regulation of the temporal and spatial expression of Gli3 is crucial for the proper specification of these structures in mammals and other vertebrates. Previously we reported a set of human intronic cis-regulators controlling almost the entire known repertoire of endogenous Gli3 expression in mouse neural tube and limbs. However, the genetic underpinning of GLI3 expression in other embryonic domains such as craniofacial structures and internal organs remain elusive. Here we demonstrate in a transgenic mice assay the potential of a subset of human/fish conserved non-coding sequences (CNEs) residing within GLI3 intronic intervals to induce reporter gene expression at known regions of endogenous Gli3 transcription in embryonic domains other than central nervous system (CNS) and limbs. Highly specific reporter expression was observed in craniofacial structures, eye, gut, and genitourinary system. Moreover, the comparison of expression patterns directed by these intronic cis-acting regulatory elements in mouse and zebrafish embryos suggests that in accordance with sequence conservation, the target site specificity of a subset of these elements remains preserved among these two lineages. Taken together with our recent investigations, it is proposed here that during vertebrate evolution the Gli3 expression control acquired multiple, independently acting, intronic enhancers for spatiotemporal patterning of CNS, limbs, craniofacial structures and internal organs.

  17. Growth hormone therapy and craniofacial bones: a comprehensive review.

    PubMed

    Litsas, G

    2013-09-01

    Growth hormone (GH) has significant effects on linear bone growth, bone mass and bone metabolism. The primary role of GH supplementation in children with GH deficiency, those born small for gestational age or with other types of disorders in somatic development is to increase linear growth. However, GH therapy seems to elicit varying responses in the craniofacial region. Whereas the effects of GH administration on somatic development are well documented, comparatively little is known of its effects on the craniofacial region. The purpose of this review was to search the literature and compile results from both animal and human studies related to the impact of GH on craniofacial growth.

  18. 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

  19. [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.

  20. Craniofacial Microsomia

    PubMed Central

    Birgfeld, Craig B.; Heike, Carrie

    2012-01-01

    Craniofacial microsomia (CFM) is one of the most common congenital conditions treated in craniofacial centers worldwide. This condition is variably associated with anomalies of the jaws, ears, facial soft tissue, orbits, and facial nerve function and can be associated with extracranial anomalies. The cause of this condition is unknown, though CFM has been associated withprenatalexposures and genetic abnormalities. Diagnosis, treatment, and outcome assessment in CFM is challenging due to the wide phenotypic spectrum observed in this condition. Surgical treatment requires a coordinated team approach involving multiple specialties, which can include plastic surgery, craniofacial surgery, orthognathic surgery, and microsurgery. A wide variety of surgical options exist, and individual treatment plans should be based on the patient's needs. Although CFM can be challenging to treat, successful outcomes are rewarding. We provide a review of the common craniofacial surgical treatments for individuals with CFM. PMID:23633936

  1. Less known non-infectious and neuromusculoskeletal system-originated anterolateral neck and craniofacial pain disorders.

    PubMed

    Aydil, Utku; Kizil, Yusuf; Köybaşioğlu, Ahmet

    2012-01-01

    Pain syndromes of neuromusculoskeletal origin are not well-known by most of the clinicians working on head and neck area. As a result, most of the patients with these syndromes are either overlooked without having any treatment or they inappropriately have antibiotic treatments or surgical interventions such as dental extractions and tonsillectomies. Better recognition of the pain syndromes of the neck and face region or entities related to neuromusculoskeletal system may result in more appropriate and effective management of such conditions while avoiding unnecessary medical and surgical treatments. In this review, causes, clinical characteristics, diagnostic and treatment modalities of relatively less known craniofacial and neck pain entities including Eagle syndrome, carotidynia, glossopharyngeal neuralgia, superior laryngeal neuralgia, hyoid bone syndrome, acute calcific retropharyngeal tendinitis, temporal tendinitis, thyroid and cricoid cartilage syndromes, and mastoid process syndrome are summarized.

  2. 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.

  3. Translational genetics: advancing fronts for craniofacial health.

    PubMed

    D'Souza, R N; Dunnwald, M; Dunnvald, M; Frazier-Bowers, S; Polverini, P J; Wright, J T; de Rouen, T; Vieira, A R

    2013-12-01

    Scientific opportunities have never been better than today! The completion of the Human Genome project has sparked hope and optimism that cures for debilitating conditions can be achieved and tailored to individuals and communities. The availability of reference genome sequences and genetic variations as well as more precise correlations between genotype and phenotype have facilitated the progress made in finding solutions to clinical problems. While certain craniofacial and oral diseases previously deemed too difficult to tackle have benefited from basic science and technological advances over the past decade, there remains a critical need to translate the fruits of several decades' worth of basic and clinical research into tangible therapies that can benefit patients. The fifth Annual Fall Focused Symposium, "Translational Genetics - Advancing Fronts for Craniofacial Health", was created by the American Association for Dental Research (AADR) to foster its mission to advance interdisciplinary research that is directed toward improving oral health. The symposium showcased progress made in identifying molecular targets that are potential therapeutics for common and rare dental diseases and craniofacial disorders. Speakers focused on translational and clinical applications of their research and, where applicable, on strategies for new technologies and therapeutics. The critical needs to transfer new knowledge to the classroom and for further investment in the field were also emphasized. The symposium underscored the importance of basic research, chairside clinical observations, and population-based studies in driving the new translational connections needed for the development of cures for the most common and devastating diseases involving the craniofacial complex.

  4. Craniofacial morphogenesis workshop report.

    PubMed

    Solursh, M; Murray, J

    1994-05-01

    The following report highlights the discussions and interaction at the workshop on craniofacial morphogenesis, sponsored by The Human Frontier Science Program, held in April 1993 at the University of Iowa. A brief summary of selected sessions is included to exemplify the benefits of bringing together individuals from various disciplines and backgrounds in order to establish a unified theory of craniofacial morphogenesis. The synthesis of information and experience of a wide range of approaches made the 4-day period an invaluable experience for the participants from nine different countries.

  5. Old World sources of the first New World human inhabitants: A comparative craniofacial view

    PubMed Central

    Brace, C. Loring; Nelson, A. Russell; Seguchi, Noriko; Oe, Hiroaki; Sering, Leslie; Qifeng, Pan; Yongyi, Li; Tumen, Dashtseveg

    2001-01-01

    Human craniofacial data were used to assess the similarities and differences between recent and prehistoric Old World samples, and between these samples and a similar representation of samples from the New World. The data were analyzed by the neighbor-joining clustering procedure, assisted by bootstrapping and by canonical discriminant analysis score plots. The first entrants to the Western Hemisphere of maybe 15,000 years ago gave rise to the continuing native inhabitants south of the U.S.–Canadian border. These show no close association with any known mainland Asian population. Instead they show ties to the Ainu of Hokkaido and their Jomon predecessors in prehistoric Japan and to the Polynesians of remote Oceania. All of these also have ties to the Pleistocene and recent inhabitants of Europe and may represent an extension from a Late Pleistocene continuum of people across the northern fringe of the Old World. With roots in both the northwest and the northeast, these people can be described as Eurasian. The route of entry to the New World was at the northwestern edge. In contrast, the Inuit (Eskimo), the Aleut, and the Na-Dene speakers who had penetrated as far as the American Southwest within the last 1,000 years show more similarities to the mainland populations of East Asia. Although both the earlier and later arrivals in the New World show a mixture of traits characteristic of the northern edge of Old World occupation and the Chinese core of mainland Asia, the proportion of the latter is greater for the more recent entrants. PMID:11481450

  6. 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.

  7. Monogenic human skin disorders.

    PubMed

    Lemke, Johannes R; Kernland-Lang, Kristin; Hörtnagel, Konstanze; Itin, Peter

    2014-01-01

    Human genodermatoses represent a broad and partly confusing spectrum of countless rare diseases with confluent and overlapping phenotypes often impeding a precise diagnosis in an affected individual. High-throughput sequencing techniques have expedited the identification of novel genes and have dramatically simplified the establishment of genetic diagnoses in such heterogeneous disorders. The precise genetic diagnosis of a skin disorder is crucial for the appropriate counselling of patients and their relatives regarding the course of the disease, prognosis and recurrence risks. Understanding the underlying pathophysiology is a prerequisite to understanding the disease and developing specific, targeted or individualized therapeutic approaches. We aimed to create a comprehensive overview of human genodermatoses and their respective genetic aetiology known to date. We hope this may represent a useful tool in guiding dermatologists towards genetic diagnoses, providing patients with individual knowledge on the respective disorder and applying novel research findings to clinical practice.

  8. Human HOX gene disorders.

    PubMed

    Quinonez, Shane C; Innis, Jeffrey W

    2014-01-01

    The Hox genes are an evolutionarily conserved family of genes, which encode a class of important transcription factors that function in numerous developmental processes. Following their initial discovery, a substantial amount of information has been gained regarding the roles Hox genes play in various physiologic and pathologic processes. These processes range from a central role in anterior-posterior patterning of the developing embryo to roles in oncogenesis that are yet to be fully elucidated. In vertebrates there are a total of 39 Hox genes divided into 4 separate clusters. Of these, mutations in 10 Hox genes have been found to cause human disorders with significant variation in their inheritance patterns, penetrance, expressivity and mechanism of pathogenesis. This review aims to describe the various phenotypes caused by germline mutation in these 10 Hox genes that cause a human phenotype, with specific emphasis paid to the genotypic and phenotypic differences between allelic disorders. As clinical whole exome and genome sequencing is increasingly utilized in the future, we predict that additional Hox gene mutations will likely be identified to cause distinct human phenotypes. As the known human phenotypes closely resemble gene-specific murine models, we also review the homozygous loss-of-function mouse phenotypes for the 29 Hox genes without a known human disease. This review will aid clinicians in identifying and caring for patients affected with a known Hox gene disorder and help recognize the potential for novel mutations in patients with phenotypes informed by mouse knockout studies.

  9. Craniofacial muscle pain: review of mechanisms and clinical manifestations.

    PubMed

    Svensson, P; Graven-Nielsen, T

    2001-01-01

    Epidemiologic surveys of temporomandibular disorders (TMD) have demonstrated that a considerable proportion of the population--up to 5% or 6%--will experience persistent pain severe enough to seek treatment. Unfortunately, the current diagnostic classification of craniofacial muscle pain is based on descriptions of signs and symptoms rather than on knowledge of pain mechanisms. Furthermore, the pathophysiology and etiology of craniofacial muscle pain are not known in sufficient detail to allow causal treatment. Many hypotheses have been proposed to explain cause-effect relationships; however, it is still uncertain what may be the cause of muscle pain and what is the effect of muscle pain. This article reviews the literature in which craniofacial muscle pain has been induced by experimental techniques in animals and human volunteers and in which the effects on somatosensory and motor function have been assessed under standardized conditions. This information is compared to the clinical correlates, which can be derived from the numerous cross-sectional studies in patients with craniofacial muscle pain. The experimental literature clearly indicates that muscle pain has significant effects on both somatosensory and craniofacial motor function. Typical somatosensory manifestations of experimental muscle pain are referred pain and increased sensitivity of homotopic areas. The craniofacial motor function is inhibited mainly during experimental muscle pain, but phase-dependent excitation is also found during mastication to reduce the amplitude and velocity of jaw movements. The underlying neurobiologic mechanisms probably involve varying combinations of sensitization of peripheral afferents, hyperexcitability of central neurons, and imbalance in descending pain modulatory systems. Reflex circuits in the brain stem seem important for the adjustment of sensorimotor function in the presence of craniofacial pain. Changes in somatosensory and motor function may therefore be

  10. 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

  11. Diffuse noxious inhibitory control evoked by tonic craniofacial pain in humans.

    PubMed

    Sowman, P F; Wang, K; Svensson, P; Arendt-Nielsen, L

    2011-02-01

    Tonic pain in one body segment can inhibit the perception of pain in another body segment. This phenomenon is mediated by diffuse noxious inhibitory controls (DNIC), and its efficacy in craniofacial regions is investigated in this study. A compressive device that evoked a tonic, moderate/severe, headache-like, conditioning pain (∼8/10 on a visual analogue scale) was applied for 15min. Eleven males participated in the study. Pressure pain threshold (PPT) and pressure pain tolerance (PPTol) at multiple heterosegmental body sites (right masseter, splenius capitis, second intermediate phalange, brachioradialis and tibialis anterior) were measured before, during and at multiple time points (5, 20 and 35min) after the termination of the conditioning pain. PPTs and PPTols were compared within participants across two experimental sessions; one that included painful conditioning stimulation, and a separate control session on a different day. Painful conditioning increased PPT significantly during pain over the masseter (p<0.05) and over the tibialis anterior (p<0.01). PPTol was unchanged. In the period after the painful conditioning stimulation PPT was depressed compared to control. This study shows that pain evoked from the craniofacial region evokes DNIC-like mechanisms on segmental as well as heterosegmental sites.

  12. 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

  13. [Basic disorders in human communication].

    PubMed

    Peñaloza-López, Y; Gutiérrez-Silva, J; Andrade-Illañez, E N; Fierro-Evans, M A; Hernández-López, X

    1989-01-01

    This paper specifies the areas and disorders that concern human communication medicine. The frequency of the diverse disorders is analyzed in relation to age and sex, and the distribution in group ages of several disabling diseases is also discussed.

  14. Gene Therapy: Implications for Craniofacial Regeneration

    PubMed Central

    Scheller, Erica L.; Villa-Diaz, Luis G; Krebsbach, Paul H.

    2011-01-01

    Gene therapy in the craniofacial region provides a unique tool for delivery of DNA to coordinate protein production in both time and space. The drive to bring this technology to the clinic is derived from the fact that over 85% of the global population may at one time require repair or replacement of a craniofacial structure. This need ranges from mild tooth decay and tooth loss to temporomandibular joint disorders and large-scale reconstructive surgery. Our ability to insert foreign DNA into a host cell has been developing since early uses of gene therapy to alter bacterial properties for waste cleanup in the 1980s followed by successful human clinical trials in the 1990s to treat severe combined immunodeficiency. In the past twenty years the emerging field of craniofacial tissue engineering has adopted these techniques to enhance regeneration of mineralized tissues, salivary gland, periodontium, and to reduce tumor burden of head and neck squamous cell carcinoma. Studies are currently pursuing research on both biomaterial-mediated gene delivery as well as more clinically efficacious, though potentially more hazardous, viral methods. Though hundreds of gene therapy clinical trials have taken place in the past twenty years, we must still work to ensure an ideal safety profile for each gene and delivery method combination. With adequate genotoxicity testing, we can expect gene therapy to augment protein delivery strategies and potentially allow for tissue-specific targeting, delivery of multiple signals, and increased spatial and temporal control with the goal of natural tissue replacement in the craniofacial complex. PMID:22337437

  15. [Craniofacial fibrous dysplasia].

    PubMed

    Couturier, A; Aumaître, O; Mom, T; Gilain, L; André, M

    2016-12-01

    Fibrous dysplasia of bone is a benign, uncommon, sporadic, congenital skeletal disorder resulting in deformity. This disease arises from activating somatic mutation in GNAS which encodes the α subunit of the G stimulatory protein associated with proliferation of undifferentiated osteogenic cells resulting in marrow fibrosis, abnormal matrix production, and stimulation of osteoclastic resorption upon overproduction of IL-6 observed in dysplastic cells. Fibrous dysplasia may be monostotic or polyostotic. This mutation affecting many tissues, café au lait skin macules and endocrinopathies (precocious puberty, hyperthyroidism, growth hormone excess, Cushing syndrome) may be associated in McCune-Albright syndrome, but also myxoma in Mazabraud syndrome or phosphate diabetes. Diagnosis of craniofacial fibrous dysplasia should be considered in the presence of headache, neuralgia, sensory disorders (vision, hearing, balance, smelling), functional disorders (nasal obstruction, nasolacrimal duct obstruction, non-matching occlusion), infectious complications (sinusitis, otitis, mastoiditis). Such symptoms should lead to perform craniofacial CT scan completed with MRI. Bone biopsy is not systematic. Surgical treatment is discussed in cases of nervous complication, facial deformity or active lesions. In case of pain resistant to conventional analgesics, intravenous bisphosphonates can be proposed. In non-responder patients, several case reports suggest the efficacy of a monoclonal antibody directed against the IL-6 receptor which requires to be confirmed by randomized studies.

  16. Imaging of craniofacial fibrous dysplasia.

    PubMed

    Lisle, D A; Monsour, P A J; Maskiell, C D

    2008-08-01

    Fibrous dysplasia is a relatively common disorder of bone. It may affect the bones of the face and skull and, in so doing, produce a wide variety of clinical presentations. Plain film assessment of craniofacial fibrous dysplasia may be difficult because of varying appearances and complex, overlapping structures. The MRI appearances of fibrous dysplasia are often non-specific and may be confusing. Findings on CT are also variable, but more commonly lead to a specific diagnosis. This is because of the characteristic ground-glass appearance of woven bone, seen on CT in most if not all cases of craniofacial fibrous dysplasia.

  17. New insights into craniofacial malformations

    PubMed Central

    Twigg, Stephen R.F.; Wilkie, Andrew O.M.

    2015-01-01

    Development of the human skull and face is a highly orchestrated and complex three-dimensional morphogenetic process, involving hundreds of genes controlling the coordinated patterning, proliferation and differentiation of tissues having multiple embryological origins. Craniofacial malformations that occur because of abnormal development (including cleft lip and/or palate, craniosynostosis and facial dysostoses), comprise over one-third of all congenital birth defects. High-throughput sequencing has recently led to the identification of many new causative disease genes and functional studies have clarified their mechanisms of action. We present recent findings in craniofacial genetics and discuss how this information together with developmental studies in animal models is helping to increase understanding of normal craniofacial development. PMID:26085576

  18. New developments in craniofacial surgery research.

    PubMed

    Mehrara, B J; Longaker, M T

    1999-09-01

    The recent explosion in our understanding of developmental biology and genetics has enhanced our understanding of craniofacial biology. While it is not possible to summarize all new developments in craniofacial research, this article will review three areas: fetal models and surgery for craniofacial disorders, the biology of distraction osteogenesis, and the molecular mechanisms of cranial suture fusion. Numerous models of craniofacial disorders have been described, including small, short gestation and large, long gestation. The benefits and shortcomings of each are discussed. In addition, we discuss recent studies investigating the molecular mechanisms of mandibular distraction osteogenesis. Finally, we present a review of recent advances in the understanding of mechanisms of craniosynostosis, with particular emphasis on the biology of programmed cranial suture fusion in rodents.

  19. Face off against ROS: Tcof1/Treacle safeguards neuroepithelial cells and progenitor neural crest cells from oxidative stress during craniofacial development.

    PubMed

    Sakai, Daisuke; Trainor, Paul A

    2016-09-01

    One-third of all congenital birth defects affect the head and face, and most craniofacial anomalies are considered to arise through defects in the development of cranial neural crest cells. Cranial neural crest cells give rise to the majority of craniofacial bones, cartilages and connective tissues. Therefore, understanding the events that control normal cranial neural crest and subsequent craniofacial development is important for elucidating the pathogenetic mechanisms of craniofacial anomalies and for the exploring potential therapeutic avenues for their prevention. Treacher Collins syndrome (TCS) is a congenital disorder characterized by severe craniofacial anomalies. An animal model of TCS, generated through mutation of Tcof1, the mouse (Mus musculus) homologue of the gene primarily mutated in association with TCS in humans, has recently revealed significant insights into the pathogenesis of TCS. Apoptotic elimination of neuroepithelial cells including neural crest cells is the primary cause of craniofacial defects in Tcof1 mutant embryos. However, our understanding of the mechanisms that induce tissue-specific apoptosis remains incomplete. In this review, we describe recent advances in our understanding of the pathogenesis TCS. Furthermore, we discuss the role of Tcof1 in normal embryonic development, the correlation between genetic and environmental factors on the severity of craniofacial abnormalities, and the prospect for prenatal prevention of craniofacial anomalies.

  20. 4D-computerized visualisation of human craniofacial skeletal growth and of the development of the dentition.

    PubMed

    Radlanski, R J; van der Linden, F P; Ohnesorge, I

    1999-01-01

    The understanding of growth and developmental changes can be improved when shapes and changes in size, proportion, and relationships are visualized in 3 dimensions and at different stages. This applies particularly to craniofacial skeletal growth and the development of the dentition. For that purpose 3D-data were collected from prenatal human heads ranging from 18 up to 275 mm CRL and from a collection of macerated fetal and postnatal skulls. Computer-aided graphical reconstructions were obtained from histological serial sections of embryonic and early fetal specimens. Proportional changes in the growing skull were recorded by means of radiological and cephalometric evaluation. In addition, computed tomography was applied to fetal and postnatal skulls. Furthermore, the prenatal and postnatal development of the dentition was digitized. To that end 3D-polygone sets of these data were read into a workstation computer and animated by means of the software Soft Image (Microsoft). This comprehensive 4D insight into growth facilitates the understanding and teaching of normal and abnormal development.

  1. The ontogenetic trajectory of the phenotypic covariance matrix, with examples from craniofacial shape in rats and humans.

    PubMed

    Mitteroecker, Philipp; Bookstein, Fred

    2009-03-01

    Many classic quantitative genetic theories assume the covariance structure among adult phenotypic traits to be relatively static during evolution. But the cross-sectional covariance matrix arises from the joint variation of a large range of developmental processes and hence is not constant over the period during which a population of developing organisms is actually exposed to selection. To examine how development shapes the phenotypic covariance structure, we ordinate the age-specific covariance matrices of shape coordinates for craniofacial growth in rats and humans. The metric that we use for this purpose is given by the square root of the summed squared log relative eigenvalues. This is the natural metric on the space of positive-definite symmetric matrices, which we introduce and justify in a biometric context. In both species, the covariance matrices appear to change continually throughout the full period of postnatal development. The resulting ontogenetic trajectories alter their direction at major changes of the developmental programs whereas they are fairly straight in between. Consequently, phenotypic covariance matrices--and thus also response to selection--should be expected to vary both over ontogenetic and phylogenetic time scales as different phenotypes are necessarily produced by different developmental pathways.

  2. 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.

  3. 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.

  4. An immunohistochemical study of matrix proteins in the craniofacial cartilage in midterm human fetuses.

    PubMed

    Shibata, S; Sakamoto, Y; Baba, O; Qin, C; Murakami, G; Cho, B H

    2013-12-02

    Immunohistochemical localization of collagen types I, II, and X, aggrecan, versican, dentin matrix protein (DMP)-1, martix extracellular phosphoprotein (MEPE) were performed for Meckel's cartilage, cranial base cartilage, and mandibular condylar cartilage in human midterm fetuses; staining patterns within the condylar cartilage were compared to those within other cartilaginous structures. Mandibular condylar cartilage contained aggrecan; it also had more type I collagen and a thicker hypertrophic cell layer than the other two types of cartilage; these three characteristics are similar to those of the secondary cartilage of rodents. MEPE immunoreactivity was first evident in the cartilage matrix of all types of cartilage in the human fetuses and in Meckel's cartilage of mice and rats. MEPE immunoreactivity was enhanced in the deep layer of the hypertrophic cell layer and in the cartilaginous core of the bone trabeculae in the primary spongiosa. These results indicated that MEPE is a component of cartilage matrix and may be involved in cartilage mineralization. DMP-1 immunoreactivity first became evident in human bone lacunae walls and canaliculi; this pattern of expression was comparable to the pattern seen in rodents. In addition, chondroid bone was evident in the mandibular (glenoid) fossa of the temporal bone, and it had aggrecan, collagen types I and X, MEPE, and DMP-1 immunoreactivity; these findings indicated that chondroid bone in this region has phenotypic expression indicative of both hypertrophic chondrocytes and osteocytes.

  5. An Immunohistochemical Study of Matrix Proteins in the Craniofacial Cartilage in Midterm Human Fetuses

    PubMed Central

    Shibata, S.; Sakamoto, Y.; Baba, O.; Qin, C.; Murakami, G.; Cho, B.H.

    2013-01-01

    Immunohistochemical localization of collagen types I, II, and X, aggrecan, versican, dentin matrix protein (DMP)-1, martix extracellular phosphoprotein (MEPE) were performed for Meckel’s cartilage, cranial base cartilage, and mandibular condylar cartilage in human midterm fetuses; staining patterns within the condylar cartilage were compared to those within other cartilaginous structures. Mandibular condylar cartilage contained aggrecan; it also had more type I collagen and a thicker hypertrophic cell layer than the other two types of cartilage; these three characteristics are similar to those of the secondary cartilage of rodents. MEPE immunoreactivity was first evident in the cartilage matrix of all types of cartilage in the human fetuses and in Meckel’s cartilage of mice and rats. MEPE immunoreactivity was enhanced in the deep layer of the hypertrophic cell layer and in the cartilaginous core of the bone trabeculae in the primary spongiosa. These results indicated that MEPE is a component of cartilage matrix and may be involved in cartilage mineralization. DMP-1 immunoreactivity first became evident in human bone lacunae walls and canaliculi; this pattern of expression was comparable to the pattern seen in rodents. In addition, chondroid bone was evident in the mandibular (glenoid) fossa of the temporal bone, and it had aggrecan, collagen types I and X, MEPE, and DMP-1 immunoreactivity; these findings indicated that chondroid bone in this region has phenotypic expression indicative of both hypertrophic chondrocytes and osteocytes. PMID:24441192

  6. 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

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

    PubMed

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

    2015-08-01

    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.

  8. 77 FR 10540 - National Institute of Dental & Craniofacial Research; Notice of Closed Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-02-22

    ... 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; Collaborative Research on the Transition from Acute to Chronic Pain. Date: March 12,...

  9. 75 FR 7485 - National Institute of Dental & Craniofacial Research; Notice of Closed Meeting

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    2010-02-19

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  10. 78 FR 36556 - National Institute of Dental and Craniofacial Research; Notice of Closed Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

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  11. 77 FR 8268 - National Institute of Dental & Craniofacial Research; Notice of Closed Meeting

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  12. 78 FR 67178 - National Institute of Dental & Craniofacial Research; Notice of Closed Meetings

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-08

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  13. 77 FR 10539 - National Institute of Dental & Craniofacial Research; Notice of Closed Meeting

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  14. 77 FR 10539 - National Institute of Dental & Craniofacial Research Notice of Closed Meeting

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  15. 77 FR 74676 - National Institute of Dental and Craniofacial Research; Notice of Closed Meeting

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  16. 76 FR 58284 - National Institute of Dental and Craniofacial Research; Notice of Closed Meetings

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-20

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  17. 77 FR 11563 - National Institute of Dental and Craniofacial Research; Notice of Closed Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-02-27

    ... HUMAN SERVICES National Institutes of Health National Institute of Dental and Craniofacial Research... commercial property such as patentable material, and personal information concerning individuals associated... personal privacy. Name of Committee: National Institute of Dental and Craniofacial Research...

  18. 75 FR 52537 - National Institute of Dental & Craniofacial Research; Notice of Closed Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-08-26

    ... HUMAN SERVICES National Institutes of Health National Institute of Dental & Craniofacial Research... commercial property such as patentable material, and personal information concerning individuals associated... personal privacy. Name of Committee: National Institute of Dental and Craniofacial Research...

  19. 77 FR 6812 - National Institute of Dental and Craniofacial Research, Notice of Closed Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-02-09

    ... HUMAN SERVICES National Institutes of Health National Institute of Dental and Craniofacial Research... commercial property such as patentable material, and personal information concerning individuals associated... personal privacy. Name of Committee: National Institute of Dental and Craniofacial Research...

  20. 76 FR 1444 - National Institute of Dental & Craniofacial Research; Notice of Closed Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-10

    ... HUMAN SERVICES National Institutes of Health National Institute of Dental & Craniofacial Research... commercial property such as patentable material, and personal information concerning individuals associated... personal privacy. Name of Committee: National Institute of Dental and Craniofacial Research...

  1. 77 FR 40369 - National Institute of Dental & Craniofacial Research; Notice of Closed Meetings

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-09

    ... HUMAN SERVICES National Institutes of Health National Institute of Dental & Craniofacial Research... commercial property such as patentable material, and personal information concerning individuals associated... personal privacy. Name of Committee: National Institute of Dental and Craniofacial Research...

  2. 76 FR 28996 - National Institute of Dental & Craniofacial Research; Notice of Closed Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-05-19

    ... HUMAN SERVICES National Institutes of Health National Institute of Dental & Craniofacial Research... commercial property such as patentable material, and personal information concerning individuals associated... personal privacy. Name of Committee: National Institute of Dental and Craniofacial Research...

  3. 76 FR 78013 - National Institute of Dental and Craniofacial Research; Notice of Closed Meetings

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-15

    ... HUMAN SERVICES National Institutes of Health National Institute of Dental and Craniofacial Research... commercial property such as patentable material, and personal information concerning individuals associated... personal privacy. Name of Committee: National Institute of Dental and Craniofacial Research...

  4. Relationships between craniofacial pain and bruxism.

    PubMed

    Svensson, P; Jadidi, F; Arima, T; Baad-Hansen, L; Sessle, B J

    2008-07-01

    A still commonly held view in the literature and clinical practice is that bruxism causes pain because of overloading of the musculoskeletal tissue and craniofacial pain, on the other hand, triggers more bruxism. Furthermore, it is often believed that there is a dose-response gradient so that more bruxism (intensity, duration) leads to more overloading and pain. Provided the existence of efficient techniques to treat bruxism, it would be straightforward in such a simple system to target bruxism as the cause of pain and hence treat the pain. Of course, human biological systems are much more complex and therefore, it is no surprise that the relationship between bruxism and pain is far from being simple or even linear. Indeed, there are unexpected relationships, which complicate the establishment of adequate explanatory models. Part of the reason is the complexity of the bruxism in itself, which presents significant challenges related to operationalized criteria and diagnostic tools and underlying pathophysiology issues, which have been dealt with in other reviews in this issue. However, another important reason is the multifaceted nature of craniofacial pain. This review will address our current understanding of classification issues, epidemiology and neurobiological mechanisms of craniofacial pain. Experimental models of bruxism may help to further the understanding of the relationship between craniofacial pain and bruxism in addition to insights from intervention studies. The review will enable clinicians to understand the reasons why simple cause-effect relationships between bruxism and craniofacial pain are inadequate and the current implications for management of craniofacial pain.

  5. [Current gene study in etiological analysis of congenital craniofacial abnormalities].

    PubMed

    Feng, Yi-miao; Fang, Bing

    2007-04-01

    The cause of congenital craniofacial abnormalities are very complicated. Understanding of the gene mechanisms of abnormalities taking place are very important for prevention and therapy.DNA sequence analysis provides the fundaments of gene study of the congenital craniofacial abnormalities. Human genome project (HGP) paved the confirmation of candidate gene of the congenital craniofacial abnormalities.Transgenic animal models and gene knockout techniques are effective methods in study of gene function. This paper reviews current gene study in etiopathogenisis analysis of the congenital craniofacial abnormalities.

  6. Craniofacial bone tissue engineering.

    PubMed

    Wan, Derrick C; Nacamuli, Randall P; Longaker, Michael T

    2006-04-01

    Repair and reconstruction of the craniofacial skeleton represents a significant biomedical burden, with thousands of procedures per-formed annually secondary to injuries and congenital malformations. Given the multitude of current approaches, the need for more effective strategies to repair these bone deficits is apparent. This article explores two major modalities for craniofacial bone tissue engineering: distraction osteogenesis and cellular based therapies. Current understanding of the guiding principles for each of these modalities is elaborated on along with the knowledge gained from clinical and investigative studies. By laying this foundation, future directions for craniofacial distraction and cell-based bone engineering have emerged with great promise for the advancement of clinical practice.

  7. Craniofacial reconstruction - series (image)

    MedlinePlus

    Patients requiring craniofacial reconstruction have: birth defects (such as hypertelorism, Crouzon's disease, Apert's syndrome) injuries to the head, face, or jaws (maxillofacial) tumors deformities caused by treatments of tumors

  8. Hyponatremia in the postoperative craniofacial pediatric patient population: a connection to cerebral salt wasting syndrome and management of the disorder.

    PubMed

    Levine, J P; Stelnicki, E; Weiner, H L; Bradley, J P; McCarthy, J G

    2001-11-01

    Hyponatremia after cranial vault remodeling has been noted in a pediatric patient population. If left untreated, the patients may develop a clinical hypoosmotic condition that can lead to cerebral edema, increased intracranial pressure, and eventually, to central nervous system and circulatory compromise. The hyponatremia has traditionally been attributed to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH); however, in our patients the treatment has been resuscitation with normal saline as opposed to fluid restriction (the accepted treatment of SIADH), thus placing the diagnosis of SIADH in question. Patients who developed hyponatremia after intracranial injury or surgery were, until recently, grouped together as having SIADH. However, there are diagnosis and treatment differences between SIADH and another distinct but poorly understood disorder that is designated cerebral salt wasting syndrome (CSW). CSW is associated with increased urine output and increased urine sodium concentration and volume contraction, and it is frequently seen after a central nervous system trauma. We therefore developed a prospective study to evaluate the cause of the sodium imbalance.Ten consecutive pediatric patients who underwent intracranial surgery for various craniosynostotic disorders were postoperatively monitored in the pediatric intensive care unit for hemodynamic, respiratory, and fluid management. The first four patients were evaluated for electrolyte changes and overall fluid balance to determine the consistency with which these changes occurred. The remaining six patients had daily (including preoperative) measurement of serum electrolytes, urine electrolytes, urine osmolarity, serum antidiuretic hormone (ADH), aldosterone, and atrial natriuretic hormone (ANH). All patients received normal saline intravenous replacement fluid in the postoperative period. All of the patients developed a transient hyponatremia postoperatively, despite normal saline

  9. 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

  10. 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

    2014-01-02

    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.

  11. A survey of dentists in the United States regarding a specialty in craniofacial pain.

    PubMed

    Simmons, H Clifton; Kilpatrick, Steven R

    2004-01-01

    In an effort to explore whether a specialty for craniofacial pain is warranted, the American Academy of Craniofacial Pain (AACP) commissioned an opinion survey of dentists. The survey population (N=4000) was stratified by specialty, so that dentists in affected areas would be adequately represented: 500 orthodontists and dentofacial orthopedists, 500 oral and maxillofacial surgeons, 500 periodontists, 500 prosthodontists, and 2,000 general practitioners. A total of 930 dentists responded for a 23.2% response rate. The survey had multiple purposes: 1. to measure the percentage of craniofacial pain patients perceived in dental patient populations; 2. to determine whether each dentist prefers to treat the disorder or; 3. prefers to refer craniofacial pain patients to clinicians specializing in the disorder; and 4. whether dentists favor/oppose the formation of a craniofacial pain specialty. The respondents' perception of the prevalence of craniofacial pain among their patients was 13.9%. A majority of the responding dentists, 54.7%, are in favor of a craniofacial pain specialty. Overall, 65% of dentists treat craniofacial pain patients, although more than half, 55%, of all dentists also refer such patients. Even 43.6% of dentists who regularly treat craniofacial pain favor a specialty, while 76% of those who do not treat such patients favor the specialty. The data presented here advocate development of a dental specialty in craniofacial pain.

  12. 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

  13. A human YAC transgene rescues craniofacial and neural tube development in PDGFRalpha knockout mice and uncovers a role for PDGFRalpha in prenatal lung growth.

    PubMed

    Sun, T; Jayatilake, D; Afink, G B; Ataliotis, P; Nistér, M; Richardson, W D; Smith, H K

    2000-11-01

    The platelet-derived growth factor alpha-receptor (PDGFRalpha) plays a vital role in the development of vertebrate embryos, since mice lacking PDGFRalpha die in mid-gestation. PDGFRalpha is expressed in several types of migratory progenitor cells in the embryo including cranial neural crest cells, lung smooth muscle progenitors and oligodendrocyte progenitors. To study PDGFRalpha gene regulation and function during development, we generated transgenic mice by pronuclear injection of a 380 kb yeast artificial chromosome (YAC) containing the human PDGFRalpha gene. The YAC transgene was expressed in neural crest cells, rescued the profound craniofacial abnormalities and spina bifida observed in PDGFRalpha knockout mice and prolonged survival until birth. The ultimate cause of death was respiratory failure due to a defect in lung growth, stemming from failure of the transgene to be expressed correctly in lung smooth muscle progenitors. However, the YAC transgene was expressed faithfully in oligodendrocyte progenitors, which was not previously observed with plasmid-based transgenes containing only upstream PDGFRalpha control sequences. Our data illustrate the complexity of PDGFRalpha genetic control, provide clues to the location of critical regulatory elements and reveal a requirement for PDGF signalling in prenatal lung growth, which is distinct from the known requirement in postnatal alveogenesis. In addition, we found that the YAC transgene did not prolong survival of Patch mutant mice, indicating that genetic defects outside the PDGFRalpha locus contribute to the early embryonic lethality of Patch mice.

  14. 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

  15. The influence of gender and sex steroids on craniofacial nociception.

    PubMed

    Cairns, Brian E

    2007-02-01

    Several pain conditions localized to the craniofacial region show a remarkable sex-related difference in their prevalence. These conditions include temporomandibular disorders and burning mouth syndrome as well as tension-type, migraine, and cluster headaches. The mechanisms that underlie sex-related differences in the prevalence of these craniofacial pain conditions remain obscure and likely involve both physiological and psychosocial factors. In terms of physiological factors relevant to the development of headache, direct evidence of sex-related differences in the properties of dural afferent fibers or durally activated second-order trigeminal sensory neurons has yet to be provided. There is, however, evidence for sex-related differences in the response properties of afferent fibers and second-order trigeminal sensory neurons that convey nociceptive input from other craniofacial tissues associated with sex-related differences in chronic pain conditions, such as those that innervate the masseter muscle and temporomandibular joint. Further, modulation of craniofacial nociceptive input by opioidergic receptor mechanisms appears to be dependent on biological sex. Research into mechanisms that may contribute to sex-related differences in trigeminal nociceptive processing has primarily focused on effect of the female sex hormone estrogen, which appears to alter the excitability of trigeminal afferent fibers and sensory neurons to noxious stimulation of craniofacial tissues. This article discusses current knowledge of potential physiological mechanisms that could contribute to sex-related differences in certain craniofacial pain conditions.

  16. Secretory COPII coat component Sec23a is essential for craniofacial chondrocyte maturation.

    PubMed

    Lang, Michael R; Lapierre, Lynne A; Frotscher, Michael; Goldenring, James R; Knapik, Ela W

    2006-10-01

    An increasing number of human disorders have been linked to mutations in genes of the secretory pathway. The chemically induced zebrafish crusher variant results in malformed craniofacial skeleton, kinked pectoral fins and a short body length. By positional cloning, we identified a nonsense mutation converting leucine to a stop codon (L402X) in the sec23a gene, an integral component of the COPII complex, which is critical for anterograde protein trafficking between endoplasmic reticulum and Golgi apparatus. Zebrafish crusher mutants develop normally until the onset of craniofacial chondrogenesis. crusher chondrocytes accumulate proteins in a distended endoplasmic reticulum, resulting in severe reduction of cartilage extracellular matrix (ECM) deposits, including type II collagen. We demonstrate that the paralogous gene sec23b is also an essential component of the ECM secretory pathway in chondrocytes. In contrast, knockdown of the COPI complex does not hinder craniofacial morphogenesis. As SEC23A lesions cause the cranio-lenticulo-sutural dysplasia syndrome, crusher provides the first vertebrate model system that links the biology of endoplasmic reticulum to Golgi trafficking with a clinically relevant dysmorphology.

  17. The molecular basis of human keratin disorders.

    PubMed

    Arin, Meral Julia

    2009-05-01

    Keratins are cytoskeletal proteins that provide structural support to epithelial cells and tissues. Perturbation causes cell and tissue fragility and accounts for a large number of genetic disorders in humans. In humans, 54 functional keratin genes exist and 21 different keratin genes including hair keratins and hair follicle-specific epithelial keratins have been associated with hereditary disorders. Moreover, keratins have been implicated in more complex traits such as liver disease and inflammatory bowel disease. Understanding the molecular basis of keratin disorders has been the basis for improved diagnosis with prognostic implications, genetic counseling and prenatal testing for severe disorders. Besides their mechanical role, keratins have newly identified functions in apoptosis, cell growth, tissue polarity, wound healing and tissue remodeling. Improved understanding of the regulatory functions of keratins may offer novel approaches to overcome current treatment limitations.

  18. Emerging peripheral receptor targets for deep-tissue craniofacial pain therapies.

    PubMed

    Ambalavanar, R; Dessem, D

    2009-03-01

    While effective therapies are available for some types of craniofacial pain, treatments for deep-tissue craniofacial pain such as temporomandibular disorders are less efficacious. Several ion channels and receptors which are prominent in craniofacial nociceptive mechanisms have been identified on trigeminal primary afferent neurons. Many of these receptors and channels exhibit unusual distributions compared with extracranial regions. For example, expression of the ATP receptor P2X(3) is strongly implicated in nociception and is more abundant on trigeminal primary afferent neurons than analogous extracranial neurons, making them potentially productive targets specifically for craniofacial pain therapies. The initial part of this review therefore focuses on P2X(3) as a potential therapeutic target to treat deep-tissue craniofacial pain. In the trigeminal ganglion, P2X(3) receptors are often co-expressed with the nociceptive neuropeptides CGRP and SP. Therefore, we discuss the role of CGRP and SP in deep-tissue craniofacial pain and suggest that neuropeptide antagonists, which have shown promise for the treatment of migraine, may have wider therapeutic potential, including the treatment of deep-tissue craniofacial pain. P2X(3), TRPV1, and ASIC3 are often co-expressed in trigeminal neurons, implying the formation of functional complexes that allow craniofacial nociceptive neurons to respond synergistically to altered ATP and pH in pain. Future therapeutics for craniofacial pain thus might be more efficacious if targeted at combinations of P2X(3), CGRP, TRPV1, and ASIC3.

  19. Emerging Peripheral Receptor Targets for Deep-tissue Craniofacial Pain Therapies

    PubMed Central

    Ambalavanar, R.; Dessem, D.

    2009-01-01

    While effective therapies are available for some types of craniofacial pain, treatments for deep-tissue craniofacial pain such as temporomandibular disorders are less efficacious. Several ion channels and receptors which are prominent in craniofacial nociceptive mechanisms have been identified on trigeminal primary afferent neurons. Many of these receptors and channels exhibit unusual distributions compared with extracranial regions. For example, expression of the ATP receptor P2X3 is strongly implicated in nociception and is more abundant on trigeminal primary afferent neurons than analogous extracranial neurons, making them potentially productive targets specifically for craniofacial pain therapies. The initial part of this review therefore focuses on P2X3 as a potential therapeutic target to treat deep-tissue craniofacial pain. In the trigeminal ganglion, P2X3 receptors are often co-expressed with the nociceptive neuropeptides CGRP and SP. Therefore, we discuss the role of CGRP and SP in deep-tissue craniofacial pain and suggest that neuropeptide antagonists, which have shown promise for the treatment of migraine, may have wider therapeutic potential, including the treatment of deep-tissue craniofacial pain. P2X3, TRPV1, and ASIC3 are often co-expressed in trigeminal neurons, implying the formation of functional complexes that allow craniofacial nociceptive neurons to respond synergistically to altered ATP and pH in pain. Future therapeutics for craniofacial pain thus might be more efficacious if targeted at combinations of P2X3, CGRP, TRPV1, and ASIC3. PMID:19329451

  20. 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.

  1. Elastic Properties of Chimpanzee Craniofacial Cortical Bone.

    PubMed

    Gharpure, Poorva; Kontogiorgos, Elias D; Opperman, Lynne A; Ross, Callum F; Strait, David S; Smith, Amanda; Pryor, Leslie C; Wang, Qian; Dechow, Paul C

    2016-12-01

    Relatively few assessments of cranial biomechanics formally take into account variation in the material properties of cranial cortical bone. Our aim was to characterize the elastic properties of chimpanzee craniofacial cortical bone and compare these to the elastic properties of dentate human craniofacial cortical bone. From seven cranial regions, 27 cylindrical samples were harvested from each of five chimpanzee crania. Assuming orthotropy, axes of maximum stiffness in the plane of the cortical plate were derived using modified equations of Hooke's law in a Mathcad program. Consistent orientations among individuals were observed in the zygomatic arch and alveolus. The density of cortical bone showed significant regional variation (P < 0.001). The elastic moduli demonstrated significant differences between sites, and a distinct pattern where E3  > E2  > E1 . Shear moduli were significantly different among regions (P < 0.001). The pattern by which chimpanzee cranial cortical bone varies in elastic properties resembled that seen in humans, perhaps suggesting that the elastic properties of craniofacial bone in fossil hominins can be estimated with at least some degree of confidence. Anat Rec, 299:1718-1733, 2016. © 2016 Wiley Periodicals, Inc.

  2. Relative size of the eye and orbit: an evolutionary and craniofacial constraint model for examining the etiology and disparate incidence of juvenile-onset myopia in humans.

    PubMed

    Masters, Michael P

    2012-05-01

    The principal aim of this research is to provide a new model for investigating myopia in humans, and contribute to an understanding of the degree to which modern variation and evolutionary change in orbital and overall craniofacial morphology may help explain the common eye form association with this condition. Recent research into long and short-term evolution of the human orbit reveals a number of changes in this feature, and particularly since the Upper Paleolithic. These include a reduction in orbital depth, a decrease in anterior projection of the upper and lower orbital margins, and most notably, a reduction in orbital volume since the Holocene in East Asia. Reduced orbital volume in this geographic region could exacerbate an existing trend in recent hominin evolution toward larger eyes in smaller orbits, and may help explain the unusually high frequency of myopia in East Asian populations. The objective of the current study is to test a null hypothesis of no relationship between a ratio of orbit to eye volume and spherical equivalent refractive error (SER) in a sample of Chinese adults, and examine how relative size of the eye within the orbit relates to SER between the sexes and across the sample population. Analysis of the orbit, eye, and SER reveals a strong relationship between relative size of the eye within the orbit and the severity of myopic refractive error. An orbit/eye ratio of 3 for females and 3.5 for males (or an eye that occupies approximately 34% and 29% of the orbit, respectively), designates a clear threshold at which myopia develops, and becomes progressively worse as the eye continues to occupy a greater proportion of the orbital cavity. These results indicate that relative size of the eye within the orbit is an important factor in the development of myopia, and suggests that individuals with large eyes in small orbits lack space for adequate development of ocular tissues, leading to compression and distortion of the lithesome globe

  3. 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

  4. 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.

  5. Modeling autism spectrum disorders with human neurons.

    PubMed

    Beltrão-Braga, Patricia C B; Muotri, Alysson R

    2017-02-01

    Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by impaired social communication and interactions and by restricted and repetitive behaviors. Although ASD is suspected to have a heritable or sporadic genetic basis, its underlying etiology and pathogenesis are not well understood. Therefore, viable human neurons and glial cells produced using induced pluripotent stem cells (iPSC) to reprogram cells from individuals affected with ASD provide an unprecedented opportunity to elucidate the pathophysiology of these disorders, providing novel insights regarding ASD and a potential platform to develop and test therapeutic compounds. Herein, we discuss the state of art with regards to ASD modeling, including limitations of this technology, as well as potential future directions. This article is part of a Special Issue entitled SI: Exploiting human neurons.

  6. 75 FR 28031 - National Institute of Dental & Craniofacial Research; Notice of Closed Meetings

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-05-19

    ... 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... Management in Pain Research. Date: June 17, 2010. Time: 1 p.m. to 3 p.m. Agenda: To review and evaluate...

  7. 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 Emphasis Panel Review of R01 Application for RFA- DE-10-001, Oral Mucosal Vaccination against HIV...

  8. 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... confidential trade secrets or commercial property such as patentable material, and personal information... Institute of Dental and Craniofacial Research Special Emphasis Panel, Review of PAR-11-144 NIDCR...

  9. 78 FR 24761 - National Institute of Dental & Craniofacial Research; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-04-26

    ... 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... or other reasonable accommodations, should notify the Contact Person listed below in advance of...

  10. 76 FR 80953 - National Institute of Dental & Craniofacial Research; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-27

    ... 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... or other reasonable accommodations, should notify the Contact Person listed below in advance of...

  11. 75 FR 13561 - National Institute of Dental & Craniofacial Research; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-03-22

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  12. 76 FR 51995 - National Institute of Dental & Craniofacial Research; Notice of Meeting

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  19. 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

  20. 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

  1. 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.

  2. 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 States: ...

  3. 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

  4. 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

    2016-01-21

    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.

  5. Overdosage of Hand2 causes limb and heart defects in the human chromosomal disorder partial trisomy distal 4q.

    PubMed

    Tamura, Masaru; Hosoya, Masaki; Fujita, Motoi; Iida, Tomoko; Amano, Takanori; Maeno, Akiteru; Kataoka, Taro; Otsuka, Taketo; Tanaka, Shigekazu; Tomizawa, Shuichi; Shiroishi, Toshihiko

    2013-06-15

    Partial trisomy distal 4q (denoted 4q+) is a human chromosomal disorder caused by duplication of the distal end of the long arm of chromosome 4 (Chr4). This disorder manifests typical phenotypes, including craniofacial, renal, heart and thumb developmental defects. Although these clinical features are likely caused by a dosage imbalance in the gene network involving the trisomic region, the causative gene or genes and the molecular bases are largely unknown. Here, we report mouse Recombination-induced mutation 4 (Rim4) as a model animal of 4q+. The Rim4 genome contains an insertion of a 6.5 Mb fragment from mouse chromosome 8 into chromosome 6. This insertion fragment contains 17 genes, including Hand2, that encode the basic helix-loop-helix transcription factor and is syntenic to the distal end of human Chr4, 4q32.3 to 4q34.1, which is responsible for 4q+. A comparison of phenotypes between patients with Rim4 and 4q+ revealed that Rim4 shows direct parallels with many phenotypes of 4q+ such as craniofacial, heart, cervical vertebra and limb deformities. Rebalancing the gene dosage by a genetic cross with Hand2 knockout mice ameliorated symptoms of the heart and limb deformities of Rim4. Conversely, an increase in copy number of Hand2 in wild-type mice recaptures the heart and limb deformities of Rim4. Our results collectively demonstrate that overdosage of Hand2 is a major cause for at least the limb and heart phenotypes of 4q+ and that mouse Rim4 provides a unique animal model for understanding the molecular bases underlying the complex phenotypes of 4q+.

  6. Summarizing craniofacial genetics and developmental biology (SCGDB).

    PubMed

    Hall, Brian K

    2014-04-01

    This overview article highlights active areas of research in craniofacial genetics and developmental biology as reflected in presentations given at the 34th annual meeting of the Society of Craniofacial Genetics and Developmental Biology (SCGDB) in Montreal, Quebec on October 11, 2011. This 1-day meeting provided a stimulating occasion that demonstrated the present status of research in craniofacial genetics and developmental biology and where the field is heading. To accompany the abstracts published in this issue I have selected several themes that emerged from the meeting. After discussing the basis on which craniofacial defects/syndromes are classified and investigated, I address the multi-gene basis of craniofacial syndromes with an examination of the roles of Sox9 and FGF receptors in normal and abnormal craniofacial development. I then turn to the knowledge being gained from population-wide and longitudinal cohort studies and from the discovery of new signaling centers that regulate craniofacial development.

  7. Surgical treatment of craniofacial fibrous dysplasia in adults.

    PubMed

    Bowers, Christian A; Taussky, Philipp; Couldwell, William T

    2014-01-01

    Craniofacial fibrous dysplasia (FD) is a rare disorder that may require neurosurgical expertise for definitive management; however, surgical management of FD in adult patients is uncommon. Although other therapies have been shown to slow progression, the only definitive cure for adult craniofacial FD is complete resection with subsequent reconstruction. The authors review the biological, epidemiologic, clinical, genetic, and radiographic characteristics of adult FD, with an emphasis on surgical management of FD. They present a small series of three adult patients with complex FD that highlights the surgical complexity required in some adult patients with FD. Because of the complex nature of these adult polyostotic craniofacial cases, the authors used neurosurgical techniques specific to the different surgical indications, including a transsphenoidal approach for resection of sphenoidal sinus FD, a transmaxillary approach to decompress the maxillary branch of the trigeminal nerve with widening of the foramen rotundum, and complete calvarial craniectomy with cranioplasty reconstruction. These cases exemplify the diverse range of skull base techniques required in the spectrum of surgical management of adult FD and demonstrate that novel variations on standard neurosurgical approaches to the skull base can provide successful outcomes with minimal complications in adults with complex craniofacial FD.

  8. Neurophysiological assessment of craniofacial pain.

    PubMed

    Galeotti, Francesca; Truini, Andrea; Cruccu, Giorgio

    2006-04-01

    This review deals with the diagnostic usefulness of neurophysiological testing in patients with craniofacial pain. Neurophysiological testing of trigeminal nerve function relies on trigeminal reflexes and laser-evoked potentials (LEPs). This review briefly describes the physiology of trigeminal reflexes and LEPs, reports normal values and highlights the neurophysiological abnormalities in the main clinical conditions.

  9. 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

  10. 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

  11. Craniofacial clefting and sutural dystopia.

    PubMed

    Moore, M H; Edwards, T J; David, D J

    1991-07-01

    Sutural anomalies in conjunction with craniofacial clefting are unusual. A case of median frontal clefting is presented in which there was an absence of a normal metopic suture and replacement by paramedian frontal sutures. The association of an underlying brain anomaly, with attendant surgical difficulties, is noted, as are the radiological techniques of preoperative diagnosis.

  12. 76 FR 28793 - National Institute of Dental & Craniofacial Research; Notice of Closed Meetings

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-05-18

    ... HUMAN SERVICES National Institutes of Health National Institute of Dental & Craniofacial Research... commercial property such as patentable material, and personal information concerning individuals associated... review and evaluate grant applications. Place: The Dupont Hotel, 1500 New Hampshire Avenue,...

  13. Genetic basis of human circadian rhythm disorders.

    PubMed

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

    2013-05-01

    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.

  14. Desert dust and human health disorders.

    PubMed

    Goudie, Andrew S

    2014-02-01

    Dust storms may originate in many of the world's drylands and have an effect not only on human health in the drylands themselves but also in downwind environments, including some major urban centres, such as Phoenix, Kano, Athens, Madrid, Dubai, Jedda, Tehran, Jaipur, Beijing, Shanghai, Seoul, Taipei, Tokyo, Sydney, Brisbane and Melbourne. In some parts of the world dust storms occur frequently throughout the year. They can transport particulate material, pollutants, and potential allergens over thousands of km from source. The main sources include the Sahara, central and eastern Asia, the Middle East, and parts of the western USA. In some parts of the world, though not all, the frequency of dust storms is changing in response to land use and climatic changes, and in such locations the health implications may become more severe. Data on the PM10 and P2.5 loadings of dust events are discussed, as are various pollutants (heavy metals, pesticides, etc.) and biological components (spores, fungi, bacteria, etc.). Particulate loadings can far exceed healthy levels. Among the human health effects of dust storms are respiratory disorders (including asthma, tracheitis, pneumonia, allergic rhinitis and silicosis) cardiovascular disorders (including stroke), conjunctivitis, skin irritations, meningococcal meningitis, valley fever, diseases associated with toxic algal blooms and mortality and injuries related to transport accidents.

  15. Influence of prenatal EGCG treatment and Dyrk1a dosage reduction on craniofacial features associated with Down syndrome.

    PubMed

    McElyea, Samantha D; Starbuck, John M; Tumbleson-Brink, Danika M; Harrington, Emily; Blazek, Joshua D; Ghoneima, Ahmed; Kula, Katherine; Roper, Randall J

    2016-09-05

    Trisomy 21 (Ts21) affects craniofacial precursors in individuals with Down syndrome (DS). The resultant craniofacial features in all individuals with Ts21 may significantly affect breathing, eating and speaking. Using mouse models of DS, we have traced the origin of DS-associated craniofacial abnormalities to deficiencies in neural crest cell (NCC) craniofacial precursors early in development. Hypothetically, three copies of Dyrk1a (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A), a trisomic gene found in most humans with DS and mouse models of DS, may significantly affect craniofacial structure. We hypothesized that we could improve DS-related craniofacial abnormalities in mouse models using a Dyrk1a inhibitor or by normalizing Dyrk1a gene dosage. In vitro and in vivo treatment with Epigallocatechin-3-gallate (EGCG), a Dyrk1a inhibitor, modulated trisomic NCC deficiencies at embryonic time points. Furthermore, prenatal EGCG treatment normalized some craniofacial phenotypes, including cranial vault in adult Ts65Dn mice. Normalization of Dyrk1a copy number in an otherwise trisomic Ts65Dn mice normalized many dimensions of the cranial vault, but did not correct all craniofacial anatomy. These data underscore the complexity of the gene-phenotype relationship in trisomy and suggest that changes in Dyrk1a expression play an important role in morphogenesis and growth of the cranial vault. These results suggest that a temporally specific prenatal therapy may be an effective way to ameliorate some craniofacial anatomical changes associated with DS.

  16. Zebrafish Zic2a and Zic2b regulate neural crest and craniofacial development

    PubMed Central

    TeSlaa, Jessica J.; Keller, Abigail N.; Nyholm, Molly K.; Grinblat, Yevgenya

    2013-01-01

    Holoprosencephaly (HPE), the most common malformation of the human forebrain, is associated with defects of the craniofacial skeleton. ZIC2, a zinc-finger transcription factor, is strongly linked to HPE and to a characteristic set of dysmorphic facial features in humans. We have previously identified important functions for zebrafish Zic2 in the developing forebrain. Here, we demonstrate that ZIC2 orthologs zic2a and zic2b also regulate the forming zebrafish craniofacial skeleton, including the jaw and neurocranial cartilages, and use the zebrafish to study Zic2-regulated processes that may contribute to the complex etiology of HPE. Using temporally controlled Zic2a overexpression, we show that the developing craniofacial cartilages are sensitive to Zic2 elevation prior to 24hpf. This window of sensitivity overlaps the critical expansion and migration of the neural crest (NC) cells, which migrate from the developing neural tube to populate vertebrate craniofacial structures. We demonstrate that zic2b influences the induction of NC at the neural plate border, while both zic2a and zic2b regulate NC migratory onset and strongly contribute to chromatophore development. Both Zic2 depletion and early ectopic Zic2 expression cause moderate, incompletely penetrant mispatterning of the NC-derived jaw precursors at 24hpf, yet by 2dpf these changes in Zic2 expression result in profoundly mispatterned chondrogenic condensations. We attribute this discrepancy to an additional role for Zic2a and Zic2b in patterning the forebrain primordium, an important signaling source during craniofacial development. This hypothesis is supported by evidence that transplanted Zic2-deficient cells can contribute to craniofacial cartilages in a wild-type background. Collectively, these data suggest that zebrafish Zic2 plays a dual role during craniofacial development, contributing to two disparate aspects of craniofacial morphogenesis: (1) Neural crest induction and migration, and (2) early

  17. 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.

  18. Virtual Surgical Planning in Craniofacial Surgery

    PubMed Central

    Chim, Harvey; Wetjen, Nicholas; Mardini, Samir

    2014-01-01

    The complex three-dimensional anatomy of the craniofacial skeleton creates a formidable challenge for surgical reconstruction. Advances in computer-aided design and computer-aided manufacturing technology have created increasing applications for virtual surgical planning in craniofacial surgery, such as preoperative planning, fabrication of cutting guides, and stereolithographic models and fabrication of custom implants. In this review, the authors describe current and evolving uses of virtual surgical planning in craniofacial surgery. PMID:25210509

  19. Human rights, bioethics, and mental disorder.

    PubMed

    Fennell, Phil

    2008-03-01

    This article considers the international human rights instruments which set minimum standards for the content and use of mental health legislation, and the extent to which they represent 'hard law' (binding and enforceable in domestic or international courts) or 'soft law' which is not strictly binding in the same sense but which may provide persuasive authority or may be used in debate to embarrass a Government into compliance. The article considers the extent to which these various instruments impose both 'negative obligations' on states not to interfere with rights such as physical integrity or protection against arbitrary detention and 'positive' obligations on states to take positive steps to uphold the rights of individuals. The article on the case law under the European Convention on Human Rights showing how 'soft law' sources are increasingly used by the Strasbourg Court as aids to construing the scope of Convention rights. The article concludes by suggesting that whilst mentally disordered people may be afforded different treatment in relation to general bioethics instruments on the international plane, they are also entitled to rights under Disability Conventions which enjoin states to take positive steps to promote equal treatment, social inclusion and protection against discrimination and stigma.

  20. The Oral and Craniofacial Relevance of Chemically Modified RNA Therapeutics

    PubMed Central

    Kormann, Michael S.D.; Khorsand, Behnoush

    2016-01-01

    Several tissue engineering strategies in the form of protein therapy, gene therapy, cell therapy and its combinations are currently being explored for oral and cranio-facial 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

  1. [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.

  2. 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.

  3. The role of sonic hedgehog in normal and abnormal craniofacial morphogenesis.

    PubMed

    Hu, D; Helms, J A

    1999-11-01

    There is growing evidence that implicates a role for Sonic hedgehog (SHH) in morphogenesis of the craniofacial complex. Mutations in human and murine SHH cause midline patterning defects that are manifested in the head as holoprosencephaly and cyclopia. In addition, teratogens such as jervine, which inhibit the response of tissues to SHH, also produce cyclopia. Thus, the loss of SHH signaling during early stages of neural plate patterning has a profound influence of craniofacial morphogenesis. However, the severity of these defects precludes analyses of SHH function during later stages of craniofacial development. We have used an embryonic chick system to study the role of SHH during these later stages of craniofacial development. Using a combination of surgical and molecular experiments, we show here that SHH is essential for morphogenesis of the frontonasal and maxillary processes (FNP and MXPs), which give rise to the mid- and upper face. Transient loss of SHH signaling in the embryonic face inhibits growth of the primordia and results in defects analogous to hypotelorism and cleft lip/palate, characteristics of the mild forms of holoprosencephaly. In contrast, excess SHH leads to a mediolateral widening of the FNP and a widening between the eyes, a condition known as hypertelorism. In severe cases, this widening is accompanied by facial duplications. Collectively, these experiments demonstrate that SHH has multiple and profound effects on the entire spectrum of craniofacial development, and perturbations in SHH signaling are likely to underlie a number of human craniofacial anomalies.

  4. 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

  5. Craniofacial skeletal architecture and obstructive sleep apnoea syndrome severity.

    PubMed

    Costa E Sousa, Rui Augusto; dos Santos Gil, Nuno Alexandre

    2013-12-01

    Obstructive sleep apnoea syndrome (OSAS) is a sleep related breathing disorder caused by pharynx obstruction that often terminates in abrupt arousals and is capable of disrupting physiological sleep profile. Its' severity has been associated, among others, with craniofacial skeletal morphology. To investigate this relationship and elucidate craniofacial skeleton patterns in individuals without obvious maxillofacial abnormalities, 171 OSAS patients were studied with nocturnal polysomnographic record and cephalometric X-ray (24 variables). Cephalometric variables were compared between three apnoea/hypopnoea index (AHI) groups (AHI ≤ 15; 15 < AHI < 30; AHI ≥ 30) and uni/multivariate analysis between cephalometric variables and AHI were performed. The patients were predominantly men (83%), with a mean age of 48.1 years. Mean BMI and AHI were 28.4 kg/m(2) and 26.2, respectively. Most cephalometric variables differed among the three AHI groups. Fifteen cephalometric variables showed a correlation with AHI. Five cephalometric variables and BMI were independent AHI predictors. Cephalometric variables were better AHI predictors in normal weight patients. Significant evidence of craniofacial skeleton influence was found on OSAS severity, caudalization of the hyoid and lower sagittal facial projection being the most important patterns. From the cephalometric variables analysed, the hypopharynx calibre demonstrated a higher predictive value for AHI, independently of BMI.

  6. Human Communication and Its Disorders - An Overview.

    ERIC Educational Resources Information Center

    1969

    Communication is defined and the neurological bases of it and its disorders are discussed. The prevalence and costs of communicative disorders are described; current research and financial support for it and for training of investigators are reviewed. Details are then given concerning research on hearing, including the auditory system and its…

  7. 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

  8. 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

  9. 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.

  10. A Preliminary Classification of Human Functional Sexual Disorders

    ERIC Educational Resources Information Center

    Sharpe, Lawrence; And Others

    1976-01-01

    A preliminary classification is presented for functional human sexual disorders. This system is based on objective behavior and reports of distress. Five categories of sexual disorders are proposed, including the behavioral, psychological and informational components of sexual functioning in the individual and the couple. (Author)

  11. Common mechanisms in development and disease: BMP signaling in craniofacial development

    PubMed Central

    Graf, Daniel; Malik, Zeba; Hayano, Satoru; Mishina, Yuji

    2015-01-01

    BMP signaling is one of the key pathways regulating craniofacial development. It is involved in the early pattering of the head, the development of cranial neural crest cells, and facial patterning. It regulates development of its mineralized structures, such as cranial bones, maxilla, mandible, palate, and teeth. Targeted mutations in the mouse have been instrumental to delineate the functional involvement of this signaling network in different aspects of craniofacial development. Gene polymorphisms and mutations in BMP pathway genes have been associated with various non-syndromic and syndromic human craniofacial malformations. The identification of intricate cellular interactions and underlying molecular pathways illustrate the importance of local fine-regulation of Bmp signaling to control proliferation, apoptosis, epithelial-mesenchymal interactions, and stem/progenitor differentiation during craniofacial development. Thus, BMP signaling contributes both to shape and functionality of our facial features. BMP signaling also regulates postnatal craniofacial growth and is associated with dental structures life-long. A more detailed understanding of BMP function in growth, homeostasis, and repair of postnatal craniofacial tissues will contribute to our ability to rationally manipulate this signaling network in the context of tissue engineering. PMID:26747371

  12. Craniofacial Tissue Engineering by Stem Cells

    PubMed Central

    Mao, J.J.; Giannobile, W.V.; Helms, J.A.; Hollister, S.J.; Krebsbach, P.H.; Longaker, M.T.; Shi, S.

    2008-01-01

    Craniofacial tissue engineering promises the regeneration or de novo formation of dental, oral, and craniofacial structures lost to congenital anomalies, trauma, and diseases. Virtually all craniofacial structures are derivatives of mesenchymal cells. Mesenchymal stem cells are the offspring of mesenchymal cells following asymmetrical division, and reside in various craniofacial structures in the adult. Cells with characteristics of adult stem cells have been isolated from the dental pulp, the deciduous tooth, and the periodontium. Several craniofacial structures—such as the mandibular condyle, calvarial bone, cranial suture, and subcutaneous adipose tissue—have been engineered from mesenchymal stem cells, growth factor, and/or gene therapy approaches. As a departure from the reliance of current clinical practice on durable materials such as amalgam, composites, and metallic alloys, biological therapies utilize mesenchymal stem cells, delivered or internally recruited, to generate craniofacial structures in temporary scaffolding biomaterials. Craniofacial tissue engineering is likely to be realized in the foreseeable future, and represents an opportunity that dentistry cannot afford to miss. PMID:17062735

  13. Hematologic disorders associated with human immunodeficiency virus and AIDS.

    PubMed

    Cosby, Cecily D

    2007-01-01

    Nurses encounter patients with human immunodeficiency virus infection at various stages of their infection and in a variety of settings. This article focuses on the most common hematologic disorders associated with human immunodeficiency virus infection and acquired immunodeficiency syndrome, which can precipitate complications and frequently accompany hospitalization. It is important for nurses to have a solid foundation as to the cause of these disorders, their impact on quality of life and outcomes, and management strategies.

  14. Surgical options for complex craniofacial pain.

    PubMed

    Sharma, Mayur; Shaw, Andrew; Deogaonkar, Milind

    2014-10-01

    Complex craniofacial pain can be a challenging condition to manage both medically and surgically, but there is a resurgence of interest in the role of neurostimulation therapy. Surgical options for complex craniofacial pain syndromes include peripheral nerve/field stimulation, ganglion stimulation, spinal cord stimulation, dorsal nerve root entry zone lesioning, motor cortex stimulation, and deep brain stimulation. Peripheral nerve/field stimulation is rapidly being explored and is preferred by both patients and surgeons. Technological advances and improved understanding of the interactions of pain pathways with its affective component will widen the scope of neurostimulation therapy for craniofacial pain syndromes.

  15. Untapped Potential of Disordered Proteins in Current Druggable Human Proteome.

    PubMed

    Hu, Gang; Wu, Zhonghua; Wang, Kui; Uversky, Vladimir N; Kurgan, Lukasz

    2016-01-01

    Current efforts in design and characterization of drugs often rely on the structure of their protein targets. However, a large fraction of proteins lack unique 3-D structures and exist as highly dynamic structural ensembles. These intrinsically disordered proteins are involved in pathogenesis of various human diseases and are highly abundant in eukaryotes. Based on a comprehensive analysis of the current druggable human proteome covering 12 drug classes and 18 major classes of drug targets we show a significant bias toward high structural coverage and low abundance of intrinsic disorder. We review reasons for this bias including widespread use of the structural information in various stages of drug development and characterization process and difficulty with attaining structures for the intrinsically disordered proteins. We also discuss future of intrinsically disordered proteins as drug targets. Given the overall high disorder content of the human proteome and current bias of the druggable human proteome toward structural proteins, it is inevitable that disordered proteins will have to raise up on the list of prospective drug targets. The protein disorder-assisted drug design can draw from current rational drug design techniques and would also need novel approaches that no longer rely on a unique protein structure.

  16. 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.

  17. Working with DICOM craniofacial images

    PubMed Central

    Grauer, Dan; Cevidanes, Lucia S. H.; Proffit, William R.

    2009-01-01

    The increasing use of cone-beam computed tomography (CBCT) requires changes in our diagnosis and treatment planning methods as well as additional training. The standard for digital computed tomography images is called digital imaging and communications in medicine (DICOM). In this article we discuss the following concepts: visualization of CBCT images in orthodontics, measurement in CBCT images, creation of 2-dimensional radiographs from DICOM files, segmentation engines and multimodal images, registration and superimposition of 3-dimensional (3D) images, special applications for quantitative analysis, and 3D surgical prediction. CBCT manufacturers and software companies are continually working to improve their products to help clinicians diagnose and plan treatment using 3D craniofacial images. PMID:19732681

  18. Osteodistraction in the craniofacial region.

    PubMed

    Bertelè, G; Mercanti, M; Stella, F; Albanese, M; De Santis, D

    2005-04-01

    In the specific field of maxillofacial surgery, the use of osseous distraction is always more and more helpful not only in the rehabilitation of malformation pathologies, but also in the clinical situations that require bone deficit correction resulting from traumatic events and postsurgical effects, for example oncologic surgery. The reason for this versatility in the distraction protocols is, undoubtedly, due to the fact that, at present, they are valid surgical methods in alternative to or supporting maxillofacial surgery, since they are feasible from a very early age and they obtain a level of distraction that is often higher than with orthopedic devices or conventional surgery. There are multiple indications for osteodistraction and they range from cases of hyper- or hypodevelopment of the maxilla and mandible, of both their anteroposterior and transverse components, to complex syndromes such as cleft lip and palate. Even the clinical distraction of the upper and middle thirds of the cranium, through a coronal craniotomy, has been shown to be a safe surgical procedure and it allows, for example, the successful rehabilitation of adult patients suffering from hemifacial microsomia or craniosynostosis. With the continuous and constant evolution of the integration of osteodistraction principles in the rehabilitation of the craniofacial region, an ever-more effective interdisciplinary relationship between orthodontics and osteodistraction has been seen with growing interest. More often treatment plans are programmed in which the orthodontic and osteodistractive phases are integrated and complete each other, each supporting the other. Scientific and clinical progress achieved in this field in recent years, allows more and more refined therapeutic solutions to be programmed, permitting craniofacial operations and to repair an ankylotic dental arch or reposition osteointegrated implants to the most convenient bone sites.

  19. 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

  20. 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

  1. Photographic protocol for image acquisition in craniofacial microsomia

    PubMed Central

    2011-01-01

    Craniofacial microsomia (CFM) is a congenital condition associated with orbital, mandibular, ear, nerve, and soft tissue anomalies. We present a standardized, two-dimensional, digital photographic protocol designed to capture the common craniofacial features associated with CFM. PMID:22208766

  2. SEARCHING HUMAN BRAIN FOR MECHANISMS OF PSYCHIATRIC DISORDERS

    PubMed Central

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

    2014-01-01

    In the past 25 years, 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 human brain. PMID:25458567

  3. Craniofacial reconstruction evaluation by geodesic network.

    PubMed

    Zhao, Junli; Liu, Cuiting; Wu, Zhongke; Duan, Fuqing; Wang, Kang; Jia, Taorui; Liu, Quansheng

    2014-01-01

    Craniofacial reconstruction is to estimate an individual's face model from its skull. It has a widespread application in forensic medicine, archeology, medical cosmetic surgery, and so forth. However, little attention is paid to the evaluation of craniofacial reconstruction. This paper proposes an objective method to evaluate globally and locally the reconstructed craniofacial faces based on the geodesic network. Firstly, the geodesic networks of the reconstructed craniofacial face and the original face are built, respectively, by geodesics and isogeodesics, whose intersections are network vertices. Then, the absolute value of the correlation coefficient of the features of all corresponding geodesic network vertices between two models is taken as the holistic similarity, where the weighted average of the shape index values in a neighborhood is defined as the feature of each network vertex. Moreover, the geodesic network vertices of each model are divided into six subareas, that is, forehead, eyes, nose, mouth, cheeks, and chin, and the local similarity is measured for each subarea. Experiments using 100 pairs of reconstructed craniofacial faces and their corresponding original faces show that the evaluation by our method is roughly consistent with the subjective evaluation derived from thirty-five persons in five groups.

  4. Distraction Osteogenesis of the Craniofacial Skeleton.

    PubMed

    Yu, Jack C.; Fearon, Jeffrey; Havlik, Robert J.; Buchman, Steve R.; Polley, John W.

    2004-07-01

    LEARNING OBJECTIVES:: After studying this article, the participant should be able to: 1. Review the biomechanical principles and pertinent cellular and molecular biology of distraction osteogenesis of the craniofacial skeleton. 2. Describe the clinical indications and applications of distraction osteogenesis of the craniofacial skeleton. 3. Describe maxillary, mandibular, midface, and calvarial procedures in distraction osteogenesis. 4. Discuss the clinical outcomes and complications of distraction osteogenesis of the craniofacial skeleton.The year 2002 marked the end of the first decade in clinical distraction osteogenesis of the craniofacial skeleton. In this short period, its application has increased exponentially. More than 3000 cases have been performed according to a recent survey, and more than 700 articles have been written on this subject in the MEDLINE database since 1996. It is a powerful surgical tool and enables surgeons to achieve results not previously attainable. Despite all this, distraction osteogenesis is practiced by only a small number of plastic surgeons. This article reviews the biomechanical principles; the pertinent cellular and molecular biology; and the clinical indications, applications, controversies, and complications of distraction osteogenesis of the craniofacial skeleton.

  5. Distraction osteogenesis in craniofacial surgery: a review.

    PubMed

    Tavakoli, K; Stewart, K J; Poole, M D

    1998-01-01

    Distraction osteogenesis is a technique of new bone formation by the gradual separation of bony fragments. The method, although initially developed for limb lengthening, is now being applied in the treatment of craniofacial deformities. A number of principles have been established through careful scientific study to guide clinical practice, such as the ideal rate and rhythm of distraction, the need for periosteal preservation during bone division, a "latent period" of neutral fixation before, and a "consolidation period" after distraction. The technique is being applied in craniofacial surgery particularly for mandibular deformities and offers considerable advantages over previous methods such as osteotomy and inlay bone grafting. Donor site morbidity is avoided, the investing soft tissue envelope is concurrently expanded, and the magnitude of the procedure is less. However, the technique is still in its infancy and requires further modification and refinement before widespread acceptance as a treatment in mainstream craniofacial surgery. Problems with cutaneous scarring and socially undesirable external hardware, particularly in the pediatric population, have led to the emergence of intraoral miniature devices, with the ultimate goal of development of a multiplanar internal autodistractor. Furthermore, many principles well established in leg lengthening, such as the rate and rhythm of distraction, need to be reexamined and the parameters redefined with particular reference to the craniofacial skeleton. Distraction osteogenesis has an expanding role in craniofacial surgery.

  6. Craniofacial neurofibromatosis: treatment of the midface deformity.

    PubMed

    Singhal, Dhruv; Chen, Yi-Chieh; Tsai, Yueh-Ju; Yu, Chung-Chih; Chen, Hung Chang; Chen, Yu-Ray; Chen, Philip Kuo-Ting

    2014-07-01

    Craniofacial Neurofibromatosis is a benign but devastating disease. While the most common location of facial involvement is the orbito-temporal region, patients often present with significant mid-face deformities. We reviewed our experience with Craniofacial Neurofibromatosis from June 1981 to June 2011 and included patients with midface soft tissue deformities defined as gross alteration of nasal or upper lip symmetry. Data reviewed included the medical records and photobank. Over 30 years, 52 patients presented to and underwent surgical management for Craniofacial Neurofibromatosis at the Chang Gung Craniofacial Center. 23 patients (43%) demonstrated gross mid-facial deformities at initial evaluation. 55% of patients with lip deformities and 28% of patients with nasal deformities demonstrated no direct tumour involvement. The respective deformity was solely due to secondary gravitational effects from neurofibromas of the cheek subunit. Primary tumour infiltration of the nasal and/or labial subunits was treated with excision followed by various methods of reconstruction including lower lateral cartilage repositioning, forehead flaps, free flaps, and/or oral commissure suspension. Soft tissue deformities of the midface are very common in patients with Craniofacial Neurofibromatosis and profoundly affect overall aesthetic outcomes. Distinguishing primary from secondary involvement of the midface assists in surgical decision making.

  7. Antioxidant therapy in human endocrine disorders.

    PubMed

    Golbidi, Saeid; Laher, Ismail

    2010-01-01

    Reactive oxygen species (ROS) have deleterious or beneficial effects; this dual nature of ROS means that ROS act as intracellular signaling molecules and as defense mechanisms against micro-organisms. An overproduction of ROS results in oxidative stress, a deleterious process that damages cell structures, including lipids, proteins, and DNA. Oxidative stress plays a major role in various human disease states, including endocrine dysfunction. As a safeguard against oxidative stress, several endogenous nonenzymatic and enzymatic antioxidant systems exist. Antioxidants can delay or prevent oxidative stress and are widely used in the hope of maintaining health and preventing diseases. Although early studies suggested that antioxidant supplements promoted health, later clinical trials revealed that it may not be true in all cases. In this article, we provide a brief review of the pathophysiologic aspects of oxidative stress in a number of the most commonly human endocrionopathies (diabetes, male and female infertility and thyroid diseases) and review the therapeutic potentials of existing antioxidant strategies. We focus on human clinical trials and discuss the implications of their results. Based on the data reported so far, we conclude that the results reported challenge us to design better antioxidant trials in future, with a particular emphasis on identifying 1) appropriate doses 2) selecting the right populations 3) treating for optimal durations and 4) specific intracellular targeting mechanisms.

  8. PUF60 variants cause a syndrome of ID, short stature, microcephaly, coloboma, craniofacial, cardiac, renal and spinal features.

    PubMed

    Low, Karen J; Ansari, Morad; Abou Jamra, Rami; Clarke, Angus; El Chehadeh, Salima; FitzPatrick, David R; Greenslade, Mark; Henderson, Alex; Hurst, Jane; Keller, Kory; Kuentz, Paul; Prescott, Trine; Roessler, Franziska; Selmer, Kaja K; Schneider, Michael C; Stewart, Fiona; Tatton-Brown, Katrina; Thevenon, Julien; Vigeland, Magnus D; Vogt, Julie; Willems, Marjolaine; Zonana, Jonathan; Study, D D D; Smithson, Sarah F

    2017-03-22

    PUF60 encodes a nucleic acid-binding protein, a component of multimeric complexes regulating RNA splicing and transcription. In 2013, patients with microdeletions of chromosome 8q24.3 including PUF60 were found to have developmental delay, microcephaly, craniofacial, renal and cardiac defects. Very similar phenotypes have been described in six patients with variants in PUF60, suggesting that it underlies the syndrome. We report 12 additional patients with PUF60 variants who were ascertained using exome sequencing: six through the Deciphering Developmental Disorders Study and six through similar projects. Detailed phenotypic analysis of all patients was undertaken. All 12 patients had de novo heterozygous PUF60 variants on exome analysis, each confirmed by Sanger sequencing: four frameshift variants resulting in premature stop codons, three missense variants that clustered within the RNA recognition motif of PUF60 and five essential splice-site (ESS) variant. Analysis of cDNA from a fibroblast cell line derived from one of the patients with an ESS variants revealed aberrant splicing. The consistent feature was developmental delay and most patients had short stature. The phenotypic variability was striking; however, we observed similarities including spinal segmentation anomalies, congenital heart disease, ocular colobomata, hand anomalies and (in two patients) unilateral renal agenesis/horseshoe kidney. Characteristic facial features included micrognathia, a thin upper lip and long philtrum, narrow almond-shaped palpebral fissures, synophrys, flared eyebrows and facial hypertrichosis. Heterozygote loss-of-function variants in PUF60 cause a phenotype comprising growth/developmental delay and craniofacial, cardiac, renal, ocular and spinal anomalies, adding to disorders of human development resulting from aberrant RNA processing/spliceosomal function.European Journal of Human Genetics advance online publication, 22 March 2017; doi:10.1038/ejhg.2017.27.

  9. Human GRIN2B variants in neurodevelopmental disorders

    PubMed Central

    Hu, Chun; Chen, Wenjuan; Myers, Scott J.; Yuan, Hongjie; Traynelis, Stephen F.

    2016-01-01

    The development of whole exome/genome sequencing technologies has given rise to an unprecedented volume of data linking patient genomic variability to brain disorder phenotypes. A surprising number of variants have been found in the N-methyl-D-aspartate receptor (NMDAR) gene family, with the GRIN2B gene encoding the GluN2B subunit being implicated in many cases of neurodevelopmental disorders, which are psychiatric conditions originating in childhood and include language, motor, and learning disorders, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), developmental delay, epilepsy, and schizophrenia. The GRIN2B gene plays a crucial role in normal neuronal development and is important for learning and memory. Mutations in human GRIN2B were distributed throughout the entire gene in a number of patients with various neuropsychiatric and developmental disorders. Studies that provide functional analysis of variants are still lacking, however current analysis of de novo variants that segregate with disease cases such as intellectual disability, developmental delay, ASD or epileptic encephalopathies reveal altered NMDAR function. Here, we summarize the current reports of disease-associated variants in GRIN2B from patients with multiple neurodevelopmental disorders, and discuss implications, highlighting the importance of functional analysis and precision medicine therapies. PMID:27818011

  10. The etiology and molecular genetics of human pigmentation disorders

    PubMed Central

    Baxter, Laura L.; Pavan, William J.

    2012-01-01

    Pigmentation, defined as the placement of pigment in skin, hair, and eyes for coloration, is distinctive because the location, amount, and type of pigmentation provides a visual manifestation of genetic heterogeneity in pathways regulating the pigment-producing cells, melanocytes. The scope of this genetic heterogeneity in humans ranges from normal to pathological pigmentation phenotypes. Clinically normal human pigmentation encompasses a variety of skin and hair color as well as with punctate pigmentation such as melanocytic nevi (moles) or ephelides (freckles), while clinically abnormal human pigmentation exhibits markedly reduced or increased pigment levels, known as hypopigmentation and hyperpigmentation, respectively. Elucidation of the molecular genetics underlying pigmentation has revealed genes important for melanocyte development and function. Furthermore, many pigmentation disorders show additional defects in cells other than melanocytes, and identification of the genetic insults in these disorders has revealed pleiotropic genes, where a single gene is required for various functions, often in different cell types. Thus unravelling the genetics of easily visualized pigmentation disorders has identified molecular similarities between melanocytes and less visible cell types/tissues, revealing a common cellular origin and/or common genetic regulatory pathways. Herein we discuss notable human pigmentation disorders and their associated genetic alterations, focusing on the fact that the developmental genetics of pigmentation abnormalities is instructive for understanding normal pathways governing development and function of melanocytes. PMID:23799582

  11. 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

  12. 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

  13. The craniofacial complex in 47, XXX females.

    PubMed

    Krusinskiene, Viktorija; Krusinskie, Viktorija; Alvesalo, Lassi; Sidlauskas, Antanas

    2005-08-01

    A study of the craniofacial complex in four 47, XXX Finnish females, or females with an extra X chromosome, was carried out using cephalometric analysis comprising linear and angular measurements. The lengths of the anterior and posterior cranial bases, the calvarium, mandibular ramus and posterior and upper anterior face heights were found to be significantly shorter than in female controls, while the angles between the foraminal and clival planes, the mandibular plane and cranial base, the maxillary and occlusal planes, the maxillary and mandibular planes and the foraminal and mandibular planes, and also the gonial angle, were significantly enlarged. The present findings of reduced linear measurements, together with the results of studies on the craniofacial complex of 47, XXY and 47, XYY males, suggest dimensional variation between these groups from the promoting effect of an extra Y chromosome and the retarding effect of an extra X chromosome on craniofacial growth.

  14. Ovine craniofacial malformation: a morphometrical study.

    PubMed

    Eriksen, T; Kuiper, H; Pielmeier, R; Ganter, M; Distl, O; Staszyk, C

    2012-12-01

    Craniofacial malformation in 64 sheep was phenotypically described as mandibular distoclusion. Digital radiographs were examined in order to determine the degree of morphological changes in certain bones of the skull. Therefore, laterolateral standardised digital radiographs were used to determine anatomic reference points. Subsequently, five reference lines were defined and 16 linear and seven angular measurements were determined to describe malformations in the bones of the skull. Statistical analysis revealed a significant shortening of the rostral part of the corpus mandibulae and of the ramus mandibulae. However, the molar part of the mandible remained unchanged. These morphological changes caused premolar and molar malocclusion. No further craniofacial abnormalities, such as an elongation of the maxilla or of the incisive bone, were identified. In conclusion, the phenotypically observed mandibular distoclusion is caused by a shortening of specific parts of the mandible. This form of ovine craniofacial malformation is therefore best described as brachygnathia inferior.

  15. 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

  16. 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

  17. 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.

  18. 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

  19. 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

  20. Functional diversity and structural disorder in the human ubiquitination pathway.

    PubMed

    Bhowmick, Pallab; Pancsa, Rita; Guharoy, Mainak; Tompa, Peter

    2013-01-01

    The ubiquitin-proteasome system plays a central role in cellular regulation and protein quality control (PQC). The system is built as a pyramid of increasing complexity, with two E1 (ubiquitin activating), few dozen E2 (ubiquitin conjugating) and several hundred E3 (ubiquitin ligase) enzymes. By collecting and analyzing E3 sequences from the KEGG BRITE database and literature, we assembled a coherent dataset of 563 human E3s and analyzed their various physical features. We found an increase in structural disorder of the system with multiple disorder predictors (IUPred - E1: 5.97%, E2: 17.74%, E3: 20.03%). E3s that can bind E2 and substrate simultaneously (single subunit E3, ssE3) have significantly higher disorder (22.98%) than E3s in which E2 binding (multi RING-finger, mRF, 0.62%), scaffolding (6.01%) and substrate binding (adaptor/substrate recognition subunits, 17.33%) functions are separated. In ssE3s, the disorder was localized in the substrate/adaptor binding domains, whereas the E2-binding RING/HECT-domains were structured. To demonstrate the involvement of disorder in E3 function, we applied normal modes and molecular dynamics analyses to show how a disordered and highly flexible linker in human CBL (an E3 that acts as a regulator of several tyrosine kinase-mediated signalling pathways) facilitates long-range conformational changes bringing substrate and E2-binding domains towards each other and thus assisting in ubiquitin transfer. E3s with multiple interaction partners (as evidenced by data in STRING) also possess elevated levels of disorder (hubs, 22.90% vs. non-hubs, 18.36%). Furthermore, a search in PDB uncovered 21 distinct human E3 interactions, in 7 of which the disordered region of E3s undergoes induced folding (or mutual induced folding) in the presence of the partner. In conclusion, our data highlights the primary role of structural disorder in the functions of E3 ligases that manifests itself in the substrate/adaptor binding functions as well

  1. Understanding Human Glycosylation Disorders: Biochemistry Leads the Charge*

    PubMed Central

    Freeze, Hudson H.

    2013-01-01

    Nearly 70 inherited human glycosylation disorders span a breathtaking clinical spectrum, impacting nearly every organ system and launching a family-driven diagnostic odyssey. Advances in genetics, especially next generation sequencing, propelled discovery of many glycosylation disorders in single and multiple pathways. Interpretation of whole exome sequencing results, insights into pathological mechanisms, and possible therapies will hinge on biochemical analysis of patient-derived materials and animal models. Biochemical diagnostic markers and readouts offer a physiological context to confirm candidate genes. Recent discoveries suggest novel perspectives for textbook biochemistry and novel research opportunities. Basic science and patients are the immediate beneficiaries of this bidirectional collaboration. PMID:23329837

  2. The future of research in craniofacial biology and what this will mean for oral health professional education and clinical practice.

    PubMed

    Slavkin, H C

    2014-06-01

    Today, and looking to the future, scientific discoveries from cellular, developmental and molecular biology inform our understanding of cell, tissue and organ morphogenesis as exemplified in skin, bone, cartilage, dentine, enamel, muscle, nerve and many organs such as salivary glands and teeth. Present day biomedical science yields principles for the biomimetic design and fabrication of cells, tissues and organs. Bioengineering has become a strategy that can 'mimic' biological processes, and inform clinical procedures for tissue and organ replacements. The future of regenerative craniofacial biology holds enormous promise for the diagnosis and treatment of congenital birth defects, traumatic injuries, degenerative chronic diseases as well as for Mendelian single gene and complex multigene diseases and disorders. The past 50 years have heralded the completion of the human genome and the introduction of 'personalized medicine and dentistry', the utilization of stem cell therapy for an array of diseases and disorders, the 'proof of principle' to reverse select inherited diseases such as anhidrotic ectodermal dysplasia (ED), and the fruits from interdisciplinary research drawn from the diverse biomedical sciences. Looking to the future, we can readily anticipate as major goals to emphasize the clinician's role in identifying clinical phenotypes that can lead to differential diagnosis, and rejuvenate missing or damaged tissues by establishing processes for the utilization of gene, cell and/or protein therapies. The future is replete with remarkable opportunities to enhance clinical outcomes for congenital as well as acquired craniofacial malformations. Clinicians play a pivotal role because critical thinking and sound clinical acumen substantially improve diagnostic precision and thereby clinical health outcomes.

  3. 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.

  4. 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.

  5. 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

  6. Progress in stem cell therapy for major human neurological disorders.

    PubMed

    Martínez-Morales, P L; Revilla, A; Ocaña, I; González, C; Sainz, P; McGuire, D; Liste, I

    2013-10-01

    Human neurological disorders such as Alzheimer's disease (AD), Parkinson's disease, stroke or spinal cord injury are caused by the loss of neurons and glial cells in the brain or spinal cord in the Central Nervous System (CNS). Stem cell technology has become an attractive option to investigate and treat these diseases. Several types of neurons and glial cells have successfully been generated from stem cells, which in some cases, have ameliorated some dysfunctions both in animal models of neurological disorders and in patients at clinical level. Stem cell-based therapies can be beneficial by acting through several mechanisms such as cell replacement, modulation of inflammation and trophic actions. Here we review recent and current remarkable clinical studies involving stem cell-based therapy for AD and stroke and provide an overview of the different types of stem cells available nowadays, their main properties and how they are developing as a possible therapy for neurological disorders.

  7. 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…

  8. 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.

  9. 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...

  10. 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.

  11. 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

  12. A new autosomal dominant craniofacial deafness syndrome.

    PubMed

    Kassutto, S; Kassutto, Z; Ben-Ami, T; Goodman, R M

    1987-11-01

    A Jewish family is reported in which the proband and her father had congenital hearing loss and unusual facies consisting of facial asymmetry, temporal alopecia with frontal bossing, a broad nasal root and small nasal alae. In addition, both were born with a short frenulum of the tongue. We believe these findings represent a new autosomal dominant deafness syndrome with distinct craniofacial features.

  13. Translational genetics for diagnosis of human disorders of sex development.

    PubMed

    Baxter, Ruth M; Vilain, Eric

    2013-01-01

    Disorders of sex development (DSDs) are congenital conditions with discrepancies between the chromosomal, gonadal, and phenotypic sex of the individual. Such disorders have historically been difficult to diagnose and cause great stress to patients and their families. Genetic analysis of human samples has been instrumental in elucidating the molecules and pathways involved in the development of the bipotential gonad into a functioning testis or ovary. However, many DSD patients still do not receive a genetic diagnosis. New genetic and genomic technologies are expanding our knowledge of the underlying mechanism of DSDs and opening new avenues for clinical diagnosis. We review the genetic technologies that have elucidated the genes that are well established in sex determination in humans, discuss findings from more recent genomic technologies, and propose a new paradigm for clinical diagnosis of DSDs.

  14. Translational Genetics for Diagnosis of Human Disorders of Sex Development

    PubMed Central

    Baxter, Ruth M.; Vilain, Eric

    2015-01-01

    Disorders of sex development (DSDs) are congenital conditions with discrepancies between the chromosomal, gonadal, and phenotypic sex of the individual. Such disorders have historically been difficult to diagnose and cause great stress to patients and their families. Genetic analysis of human samples has been instrumental in elucidating the molecules and pathways involved in the development of the bipotential gonad into a functioning testis or ovary. However, many DSD patients still do not receive a genetic diagnosis. New genetic and genomic technologies are expanding our knowledge of the underlying mechanism of DSDs and opening new avenues for clinical diagnosis. We review the genetic technologies that have elucidated the genes that are well established in sex determination in humans, discuss findings from more recent genomic technologies, and propose a new paradigm for clinical diagnosis of DSDs. PMID:23875799

  15. Mentally disordered offenders and the European Court of Human Rights.

    PubMed

    Prior, Pauline M

    2007-01-01

    Mentally disordered offenders find themselves at the intersection of the healthcare system and the criminal justice system in most European countries. Decisions on their care often involve lengthy discussions in relation to care versus control in society. In this article, the focus is on one aspect of this debate - that of human rights. An analysis of cases, taken to the European Court of Human Rights by mentally disordered offenders, demonstrates the difficulties inherent in ensuring appropriate care to individuals and safeguards to the public at the same time. The issues raised include the problems raised by indeterminate sentences, the use of detention for preventive purposes, and debates about treatment. The countries represented in this selection of cases are Belgium, Norway, Poland, the Netherlands, Russia and the United Kingdom.

  16. Ribosomal protein gene mapping and human chromosomal disorders

    SciTech Connect

    Kenmochi, N.; Goodman, N.; Page, D.C.

    1994-09-01

    In Drosophila, the Minute phenotype (reduced body size, diminished viability and fertility, and short, thin bristles) results from heterozygous deficiencies (deletions) at any one of 50 loci scattered about the genome. A handful of these Minute loci have been molecularly characterized, and all have been found to encode ribosomal proteins. Thus, the Minute phenotype appears to result from reduced protein synthetic capacity in flies with one rather than two copies of a given ribosomal protein (rp) gene. We are pursuing the possibility that similar reductions in protein synthetic capacity--again resulting from rp gene deficiencies--might underlie phenotypes associated with certain chromosomal disorders in humans. We and our colleagues have reported findings consistent with a role for RPS4 deficiency in the etiology of certain features of Turner syndrome, a complex human disorder classically associated with an XO karyotype. We are intrigued by the possibility that deficiencies of other human rp genes might cause phenotypic abnormalities similar to those seen in Turner syndrome--just as deficiencies of any of a number of Drosophila rp genes cause the Minute phenotype. We must first learn the chromosomal map position of each of the estimated 83 human rp genes. The task of mapping the functional (intron-containing) rp genes is complicated by the existence of processed pseudogenes elsewhere in the genome. To date, we have assigned (or confirmed the previous assignment of) 38 rp genes to individual human chromosomes by PCR analysis of human-rodent somatic cell hybrids containing subsets of human chromosomes, with all but four chromosomes carrying at least one rp gene. We have also identified more than 100 large-insert human YAC (yeast artificial chromosome) clones that contain individual rp genes. Such screening of YAC libraries will result in precise positioning of the rp genes on the emerging physical map of the human genome.

  17. Studies on Aplysia neurons suggest treatments for chronic human disorders.

    PubMed

    Abrams, Thomas W

    2012-09-11

    For decades, the marine snail Aplysia has proven to be a powerful system for analyzing basic neurobiological mechanisms, particularly cellular and molecular mechanisms of neural plasticity. Three new findings on Aplysia may be relevant for the understanding and treatment of chronic human disorders. This research on this simple molluscan nervous system may lead to new therapeutic approaches for spinal cord injury, Fragile X syndrome, and genetic learning deficits more generally.

  18. Anterior throat pain syndromes: causes for undiagnosed craniofacial pain.

    PubMed

    Shankland, Wesley E

    2010-01-01

    It is not uncommon for practitioners who treat craniofacial pain to see patients with undiagnosed throat and submandibular pain. Usually, these patients will already have been seen by their primary care physician and frequently, several others doctors including otolaryngologists, oral and maxillofacial surgeons, and even neurologists. Far too often these patients have three common features: 1. they have endured multiple expensive diagnostic tests; 2. they have received treatment of multiple courses of antibiotics; and 3. no specific diagnosis for their pain complaints has been determined and their pain persists. In this article, five disorders, Ernest syndrome, Eagle's syndrome, carotid artery syndrome, hyoid bone syndrome and superior pharyngeal constrictor syndrome are briefly described. All five produce common symptoms, making diagnosis difficult, which is often followed by ineffective or no treatment being provided to the patient. Diagnostic criteria and suggested treatment modalities are also presented.

  19. The emerging roles of ribosome biogenesis in craniofacial development

    PubMed Central

    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

  20. 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.

  1. 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.

  2. 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.

  3. The craniofacial team and the Navajo patient.

    PubMed

    Smoot, E C; Kucan, J O; Cope, J S; Aase, J M

    1988-10-01

    The craniofacial team at the University of New Mexico Medical Center in Albuquerque, New Mexico has treated a large population of Navajo Indians. Team awareness of the Navajo concept of health as man in balance with his environment has resulted in more expedient treatment of the Navajo children. An understanding of Navajo concerns with ghosts, skinwalkers, and rules for orderly living has allowed team members to integrate the family and the Navajo medicine man in caring for the children with craniofacial disease. Special concerns for informed surgical consent and genetic counseling of the Navajo are reviewed. Respect for the traditional Navajo healing ceremonies and special handling of disposed body parts in surgery are required of the health professionals caring for these people.

  4. 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.

  5. Contribution of FGFR1 Variants to Craniofacial Variations in East Asians

    PubMed Central

    Yamaguchi, Tetsutaro; Tomita, Daisuke; Nakawaki, Takatoshi; Kim, Yong-Il; Hikita, Yu; Haga, Shugo; Takahashi, Masahiro; Nadim, Mohamed A.; Kawaguchi, Akira; Isa, Mutsumi; El-Kenany, Walid H.; El-Kadi, Abbadi A.; Park, Soo-Byung; Ishida, Hajime; Maki, Koutaro; Kimura, Ryosuke

    2017-01-01

    FGFR1 plays an important role in the development of the nervous system as well as the regulation of the skeletal development and bone homeostasis. Mutations in FGFR1 genes affect skull development, specifically suture and synchondrosis, resulting in craniosynostosis and facial abnormalities. We examined subjects with normal skull morphology for genetic polymorphisms that might be associated with normal craniofacial variations. Genomic DNA was obtained from 216 Japanese and 227 Korean subjects. Four FGFR1 SNPs, namely, rs881301, rs6996321, rs4647905, and rs13317, were genotyped. These SNPs were tested for association with craniofacial measurements obtained from lateral and posteroanterior cephalometries, in which principle component analysis was performed to compress the data of the craniofacial measurements. We observed that SNPs rs13317 and rs6996321 were correlated with the overall head size and midfacial development, indicating that FGFR1 SNPs played crucial roles in the normal variation of human craniofacial morphology. Subjects with the derived alleles of SNPs rs13317 and rs6996321 had a small face and a facial pattern associated with a retruded midface and relatively wide-set eyes. These facial features were similar to but were milder than those of individuals with Pfeiffer syndrome, which is caused by a dysfunctional mutation in FGFR1. PMID:28129408

  6. Elastic properties of external cortical bone in the craniofacial skeleton of the rhesus monkey.

    PubMed

    Wang, Qian; Dechow, Paul C

    2006-11-01

    Knowledge of elastic properties and of their variation in the cortical bone of the craniofacial skeleton is indispensable for creating accurate finite-element models to explore the biomechanics and adaptation of the skull in primates. In this study, we measured elastic properties of the external cortex of the rhesus monkey craniofacial skeleton, using an ultrasonic technique. Twenty-eight cylindrical cortical specimens were removed from each of six craniofacial skeletons of adult Macaca mulatta. Thickness, density, and a set of longitudinal and transverse ultrasonic velocities were measured on each specimen to allow calculation of the elastic properties in three dimensions, according to equations derived from Newton's second law and Hooke's law. The axes of maximum stiffness were determined by fitting longitudinal velocities measured along the perimeter of each cortical specimen to a sinusoidal function. Results showed significant differences in elastic properties between different functional areas of the rhesus cranium, and that many sites have a consistent orientation of maximum stiffness among specimens. Overall, the cortical bones of the rhesus monkey skull can be modeled as orthotropic in many regions, and as transversely isotropic in some regions, e.g., the supraorbital region. There are differences from human crania, suggesting that structural differences in skeletal form relate to differences in cortical material properties across species. These differences also suggest that we require more comparative data on elastic properties in primate craniofacial skeletons to explore effectively the functional significance of these differences, especially when these differences are elucidated through modeling approaches, such as finite-element modeling.

  7. Craniofacial ballpoint pen injury: endoscopic management.

    PubMed

    LaFrentz, J R; Mair, E A; Casler, J D

    2000-02-01

    Penetrating facial injuries are not infrequent. There have been isolated case reports of unusual penetrating craniofacial trauma. We describe an unusual case of a 22-month-old child who suffered an external orbital injury from a ballpoint pen that penetrated the orbit, lamina papyracea, posterior ethmoid sinuses, and sphenoid sinus. Endoscopic sinus surgery was performed to extract the ballpoint pen nib after localization with computed tomography. Careful pediatric endoscopic sinus surgery techniques permitted safe foreign body extraction with minimal morbidity.

  8. The craniofacial complex in 47,XYY males.

    PubMed

    Grön, M; Pietilä, K; Alvesalo, L

    1997-08-01

    Eight adult, Finnish 47,XYY males were compared with population male and female controls and, in addition, three of them were compared with first-degree male relatives. Linear and angular measurements were made from standardized lateral cephalograms of patients and normal population controls from the "Kvantti" study series. In both comparisons the craniofacial dimensions in 47,XYY males were larger than those in population male and female controls. Their craniofacial proportions and plane angles were similar to those of normal men except for a larger lower facial height with posterior rotation of the mandible and a tendency to bimaxillary protrusion, a longer cranial base and a lesser cranial-base angle. Thus the supernumerary Y chromosomal gene(s) in 47,XYY males may result in larger craniofacial dimensions than in normal males, without substantial effects on dimensional ratios and plane angles. This general metric pattern is similar to that observed in relation to many adult body and head dimensions, and the dental arches and tooth crowns, of 47,XYY males. The foramen magnum in 47,XYY males was smaller in the sagittal plane than that of normal males and females.

  9. 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

  10. Airway adequacy, head posture, and craniofacial morphology.

    PubMed

    Solow, B; Siersbaek-Nielsen, S; Greve, E

    1984-09-01

    Previous studies of different samples have demonstrated associations between craniocervical angulation and craniofacial morphology, between airway obstruction by adenoids and craniofacial morphology, and between airway obstruction and craniocervical angulation. A hypothesis to account for the different sets of associations was suggested by Solow and Kreiborg in 1977. In the present study, the three sets of associations were examined in a single group of nonpathologic subjects with no history of airway obstruction. Cephalometric radiographs taken in the natural head position and rhinomanometric recordings were obtained from twenty-four children 7 to 9 years of age. Correlations were calculated between twenty-seven morphologic, eight postural, and two airway variables. A large craniocervical angle was, on the average, seen in connection with small mandibular dimensions, mandibular retrognathism, and a large mandibular inclination. Obstructed nasopharyngeal airways (defined as a small pm-ad 2 radiographic distance and a large nasal respiratory resistance, NRR, determined rhinomanometrically) were, on the average, seen in connection with a large craniocervical angle and with small mandibular dimensions, mandibular retrognathism, a large mandibular inclination, and retroclination of the upper incisors. The observed correlations were in agreement with the predicted pattern of associations between craniofacial morphology, craniocervical angulation, and airway resistance, thus suggesting the simultaneous presence of such associations in the sample of nonpathologic subjects with no history of airway obstruction.

  11. 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

  12. Biochemical Analysis of Pathogenic Ligand-Dependent FGFR2 Mutations Suggests Distinct Pathophysiological Mechanisms for Craniofacial and Limb Abnormalities in Human Skeletal Disorders

    SciTech Connect

    Ibrahimi,O.; Zhang, F.; Eliseenkova, A.; Itoh, N.; Linhardt, R.; Mohammadi, M.

    2004-01-01

    Gain-of-function missense mutations in FGF receptor 2 (FGFR2) are responsible for a variety of craniosynostosis syndromes including Apert syndrome (AS), Pfeiffer syndrome (PS) and Crouzon syndrome (CS). Unlike the majority of FGFR2 mutations, S252W and P253R AS mutations and a D321A PS mutation retain ligand-dependency and are also associated with severe limb pathology. In addition, a recently identified ligand-dependent S252L/A315S double mutation in FGFR2 was shown to cause syndactyly in the absence of craniosynostosis. Here, we analyze the effect of the canonical AS mutations, the D321A PS mutation and the S252L/A315S double mutation on FGFR2 ligand binding affinity and specificity using surface plasmon resonance. Both AS mutations and the D321A PS mutation, but not the S252L/A315S double mutation, increase the binding affinity of FGFR2c to multiple FGFs expressed in the cranial suture. Additionally, all four pathogenic mutations also violate FGFR2c ligand binding specificity and enable this receptor to bind FGF10. Based on our data, we propose that an increase in mutant FGFR2c binding to multiple FGFs results in craniosynostosis, whereas binding of mutant FGFR2c to FGF10 results in severe limb pathology. Structural and biophysical analysis shows that AS mutations in FGFR2b also enhance and violate FGFR2b ligand binding affinity and specificity, respectively. We suggest that elevated AS mutant FGFR2b signaling may account for the dermatological manifestations of AS.

  13. Patients seeking treatment for craniofacial pain: a retrospective study of 300 patients.

    PubMed

    Shankland, Wesley E

    2008-10-01

    Those engaged in any type of pain practice will encounter patients who have seen many practitioners. This is especially true for clinicians who treat craniofacial pain and temporomandibular disorders. In this retrospective study of 300 patients seeking treatment for various types of craniofacial pain, the average age was 43.05 years. A mean average of 3.92 clinicians was consulted with the range of practitioners being one to 26. The average time of pain was 4.15 years. Most of the subjects (210) were in the age groups 21 years to 60 years old. Females comprised 85.30% of the subjects with a mean average age of 43.43 years; 14.70% were male with a mean average age of 41.02 years.

  14. Epigenetic crosstalk: a molecular language in human metabolic disorders.

    PubMed

    Martinez-Jimenez, Celia P; Sandoval, Juan

    2015-06-01

    Technological breakthroughs are emphasizing the impact of epigenetic mechanisms in human health highlighting the importance of a fine-tune orchestration of DNA methylation, micro RNAs, histone modifications, and chromatin structure. Transcriptional regulators sense the concentration of intermediary metabolites associated to a wide variety of biological processes including the long-term imprinting and heritable DNA methylation. Recent epigenetic mechanisms associated with cholesterol and lipid homeostasis have a critical impact in the susceptibility, development and progression of complex diseases such as type 2 diabetes mellitus, non-alcoholic fatty liver, obesity and metabolic syndrome. The heritability of epigenetic states emerge as an additional level of complexity where the extension of somatic as well as inherited epigenetic modifications may require a thoughtful reconsideration in many human diseases related with metabolic disorders.

  15. Modeling human neurological disorders with induced pluripotent stem cells.

    PubMed

    Imaizumi, Yoichi; Okano, Hideyuki

    2014-05-01

    Human induced pluripotent stem (iPS) cells obtained by reprogramming technology are a source of great hope, not only in terms of applications in regenerative medicine, such as cell transplantation therapy, but also for modeling human diseases and new drug development. In particular, the production of iPS cells from the somatic cells of patients with intractable diseases and their subsequent differentiation into cells at affected sites (e.g., neurons, cardiomyocytes, hepatocytes, and myocytes) has permitted the in vitro construction of disease models that contain patient-specific genetic information. For example, disease-specific iPS cells have been established from patients with neuropsychiatric disorders, including schizophrenia and autism, as well as from those with neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. A multi-omics analysis of neural cells originating from patient-derived iPS cells may thus enable investigators to elucidate the pathogenic mechanisms of neurological diseases that have heretofore been unknown. In addition, large-scale screening of chemical libraries with disease-specific iPS cells is currently underway and is expected to lead to new drug discovery. Accordingly, this review outlines the progress made via the use of patient-derived iPS cells toward the modeling of neurological disorders, the testing of existing drugs, and the discovery of new drugs. The production of human induced pluripotent stem (iPS) cells from the patients' somatic cells and their subsequent differentiation into specific cells have permitted the in vitro construction of disease models that contain patient-specific genetic information. Furthermore, innovations of gene-editing technologies on iPS cells are enabling new approaches for illuminating the pathogenic mechanisms of human diseases. In this review article, we outlined the current status of neurological diseases-specific iPS cell research and described recently obtained

  16. 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

  17. 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

  18. Computer vision and soft computing for automatic skull-face overlay in craniofacial superimposition.

    PubMed

    Campomanes-Álvarez, B Rosario; Ibáñez, O; Navarro, F; Alemán, I; Botella, M; Damas, S; Cordón, O

    2014-12-01

    Craniofacial superimposition can provide evidence to support that some human skeletal remains belong or not to a missing person. It involves the process of overlaying a skull with a number of ante mortem images of an individual and the analysis of their morphological correspondence. Within the craniofacial superimposition process, the skull-face overlay stage just focuses on achieving the best possible overlay of the skull and a single ante mortem image of the suspect. Although craniofacial superimposition has been in use for over a century, skull-face overlay is still applied by means of a trial-and-error approach without an automatic method. Practitioners finish the process once they consider that a good enough overlay has been attained. Hence, skull-face overlay is a very challenging, subjective, error prone, and time consuming part of the whole process. Though the numerical assessment of the method quality has not been achieved yet, computer vision and soft computing arise as powerful tools to automate it, dramatically reducing the time taken by the expert and obtaining an unbiased overlay result. In this manuscript, we justify and analyze the use of these techniques to properly model the skull-face overlay problem. We also present the automatic technical procedure we have developed using these computational methods and show the four overlays obtained in two craniofacial superimposition cases. This automatic procedure can be thus considered as a tool to aid forensic anthropologists to develop the skull-face overlay, automating and avoiding subjectivity of the most tedious task within craniofacial superimposition.

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

    PubMed Central

    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

  20. The relationship of bruxism with craniofacial pain and symptoms from the masticatory system in the adult population.

    PubMed

    Ciancaglini, R; Gherlone, E F; Radaelli, G

    2001-09-01

    The association of bruxism with craniofacial pain and symptoms of dysfunction of the masticatory system was assessed in a sample of 483 adult subjects, aged 18-75 years and selected from the general population living in the municipality of Segrate, a metropolitan area in northern Italy. Subjects were interviewed by a questionnaire about oral conditions, occurrence of symptoms of masticatory disturbances, craniofacial and neck pain. The overall prevalence of bruxism was 31;4% (95% confidence interval (CI): 27;3-35;5%). At univariate analysis bruxism was significantly associated with craniofacial pain, difficulty in closing the mouth, difficulty in opening the mouth wide or in locking the mouth, temporomandibular joint sounds, pain on movement, a feeling of stiffness or fatigue of the jaws, and neck pain. After adjustment for reciprocal influences and confounding variables, logistic regression analysis disclosed a strong independent association of bruxism with difficulty in closing the mouth (adjusted odds ratio, (OR): 2;84, 95% CI: 1;68-4;48), and a weaker relationship with craniofacial pain (adjusted OR: 1;84, 95% CI: 1;16-2;93) and temporomandibular joint sounds (adjusted OR: 1;64, 95% CI: 1;00-2;69). The findings show that in the general adult population there is a complex connection among bruxism, craniofacial pain and symptoms of masticatory disturbances. Furthermore, they suggest that the most direct relationship of bruxism may be with difficulties in mouth movements, but also an independent association may exist with craniofacial pain and other symptoms of temporomandibular disorder.

  1. The ticking clock of Cayo Santiago macaques and its implications for understanding human circadian rhythm disorders.

    PubMed

    Zhdanova, Irina V; Rogers, Jeffrey; González-Martínez, 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.

  2. 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.

  3. 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.

  4. 76 FR 30373 - National Institute of Dental & Craniofacial Research; Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-05-25

    ... Institute of Dental & Craniofacial Research; Meeting Notice of Closed Meeting Pursuant to section 10(d) of... could disclose confidential trade secrets or commercial property such as patentable material, and... Institute of Dental and Craniofacial Research Special Emphasis Panel; Review of NIDCR R03 Applications....

  5. Survey of the human acetylator polymorphism in spontaneous disorders.

    PubMed Central

    Evans, D A

    1984-01-01

    There is ample evidence that the human acetylator phenotypes are associated with drug induced phenomena. It is principally the slow acetylators who exhibit toxic adverse effects because of their relative inability to detoxify the original drug compounds. In rare instances, however, it is the rapid acetylators who are at a disadvantage. In the matter of association of spontaneous disease with either acetylator phenotype, there are two groups of disorders to consider. First, disorders in which carcinogenic amines are known to be an aetiological factor. This is because these amines are substrates for the polymorphic N-acetyltransferase activity and hence there is a possible rational basis for searching for an association. Secondly, other disorders where searches for associations are based more on hunches. In the first group there is a definite statistical association between cancer of the bladder and the slow acetylator phenotype. In prevalence studies the slow phenotype is 39% more associated with bladder cancer than is the rapid phenotype. On the basis of the evidence now available it is not possible to say whether this association is because slow acetylators develop the disease more frequently or whether they survive longer. In the second group the relevant studies show (1) a greatly increased prevalence of slow acetylators in Gilbert's disease; (2) a confirmed association between the rapid acetylator phenotype and diabetes; (3) a possible association between the rapid acetylator phenotype and breast cancer; (4) a possible association between the slow acetylator phenotype and leprosy in Chinese patients; (5) an earlier age of onset of thyrotoxicosis (Graves' disease) in slow acetylators than in rapid acetylators; (6) no evidence of an association between either phenotype and spontaneous systemic lupus erythematosus. PMID:6387123

  6. Pediatric craniofacial surgery: a review for the multidisciplinary team.

    PubMed

    Taub, Peter J; Lampert, Joshua A

    2011-11-01

    Pediatric craniofacial surgery is a specialty that grew dramatically in the 20th century and continues to evolve today. Out of the efforts to correct facial deformities encountered during World War II, the techniques of modern craniofacial surgery developed. An analysis of the relevant literature allowed the authors to explore this historical progression. Current advances in technology, tissue engineering, and molecular biology have further refined pediatric craniofacial surgery. The development of distraction osteogenesis and the progressive study of craniosynostosis provide remarkable examples of this momentum. The growing study of genetics, biotechnology, the influence of growth factors, and stem cell research provide additional avenues of innovation for the future. The following article is intended to reveal a greater understanding of pediatric craniofacial surgery by examining the past, present, and possible future direction. It is intended both for the surgeon, as well as for the nonsurgical individual specialists vital to the multidisciplinary craniofacial team.

  7. Craniofacial Bone Grafting: Wolff's Law Revisited

    PubMed Central

    Oppenheimer, Adam J.; Tong, Lawrence; Buchman, Steven R.

    2008-01-01

    Bone grafts are used for the reconstruction of congenital and acquired deformities of the facial skeleton and, as such, comprise a vital component of the craniofacial surgeon's armamentarium. A thorough understanding of bone graft physiology and the factors that affect graft behavior is therefore essential in developing a more intelligent use of bone grafts in clinical practice. This article presents a review of the basic physiology of bone grafting along with a survey of pertinent concepts and current research. The factors responsible for bone graft survival are emphasized. PMID:22110789

  8. Positional changes of the ocular organs during craniofacial development.

    PubMed

    Osaka, Miho; Ishikawa, Aoi; Yamada, Shigehito; Uwabe, Chigako; Imai, Hirohiko; Matsuda, Tetsuya; Yoneyama, Akio; Takeda, Tohoru; Takakuwa, Tetsuya

    2017-03-13

    The present study aimed to describe the positional changes of the ocular organs during craniofacial development; moreover, we examined the relationships among the ocular organs and other internal structures. To do this, we traced the positions of the ocular organs in 56 human early fetal samples at different stages of development using high-resolution magnetic resonance imaging and phase-contrast X-ray computed tomography. The eyes were located on the lateral side in the ventral view at Carnegie stage (CS) 16, and then changed their positions medially during development. The eyes remained in the neurocranium until CS17. However, the eyes changed their positions medially and caudally in the viscerocranium after CS18. The positional relationship between the eyes and pituitary gland changed in the lateral view as development progressed. Specifically, they were close to each other at CS17, but moved apart during the later stages of development. These positional changes were also demonstrated quantitatively with morphometric analyses. Based on the present data, the positional changes of the eyes can be categorized into phases, as follows: phase 1, dramatic positional changes (early fetal period until CS23); and phase 2, mild positional changes (stabilized; early fetal period after CS23). Notably, all absolute lengths measured in the present study linearly increased as the crown-rump length increased irrespective of the phase, while features of the measured angles and ratios differentially changed in phases 1 and 2. The present data may help improve our understanding of both the normal and abnormal development of the ocular organs and craniofacial area. This article is protected by copyright. All rights reserved.

  9. 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

  10. Is somnambulism a distinct disorder of humans and not seen in non-human primates?

    PubMed

    Kantha, S S

    2003-01-01

    Though somnambulism (sleepwalking) is a well-recognized sleep disorder in humans, a biomedical literature search in Medline and Primate Literature bibliographic databases showed no publications on sleepwalking in non-human primates. From this finding, two inferences can be made. First is that somnambulism may be present in non-human primates; but due to limitations in expertise and methodological resources as well as narrow focus of research interest, until now researchers have not detected it in wild and/or captive conditions. Second, somnambulism does not exist in non-human primates including apes (chimpanzee, gorilla, orang-utan and gibbon); and thus, it is a unique behavioral disorder present only in humans. It is premature to conclude which of these two inferences is correct. In Jane Goodall's view, sleepwalking behavior is absent in chimpanzees. If further field observations can confirm Goodall's assertion that somnambulism is indeed absent in chimpanzees, it will be of evolutionary and medical interest to know why this parasomnic behavior became established in humans during the past 5.5 million years or so.

  11. Differences in Craniofacial Shape Among A/J and C57BL/6J Mice and Their F1 Crosses

    DTIC Science & Technology

    2006-05-31

    Many authors have found relationships between various craniofacial measurements and the occurrence of cleft lip (CL) in humans. Other authors have...found similar relationships in mice. Although it is widely recognized that a relationship exists between oral clefting and facial shape, this

  12. Disruption of RAB40AL function leads to Martin–Probst syndrome, a rare X-linked multisystem neurodevelopmental human disorder

    PubMed Central

    Bedoyan, Jirair Krikor; Schaibley, Valerie M; Peng, Weiping; Bai, Yongsheng; Mondal, Kajari; Shetty, Amol C; Durham, Mark; Micucci, Joseph A; Dhiraaj, Arti; Skidmore, Jennifer M; Kaplan, Julie B; Skinner, Cindy; Schwartz, Charles E; Antonellis, Anthony; Zwick, Michael E; Cavalcoli, James D; Li, Jun Z

    2012-01-01

    Background and aim Martin–Probst syndrome (MPS) is a rare X-linked disorder characterised by deafness, cognitive impairment, short stature and distinct craniofacial dysmorphisms, among other features. The authors sought to identify the causative mutation for MPS. Methods and results Massively parallel sequencing in two affected, related male subjects with MPS identified a RAB40AL (also called RLGP) missense mutation (chrX:102,079,078-102,079,079AC→GA p.D59G; hg18). RAB40AL encodes a small Ras-like GTPase protein with one suppressor of cytokine signalling box. The p.D59G variant is located in a highly conserved region of the GTPase domain between β-2 and β-3 strands. Using RT-PCR, the authors show that RAB40AL is expressed in human fetal and adult brain and kidney, and adult lung, heart, liver and skeletal muscle. RAB40AL appears to be a primate innovation, with no orthologues found in mouse, Xenopus or zebrafish. Western analysis and fluorescence microscopy of GFP-tagged RAB40AL constructs from transiently transfected COS7 cells show that the D59G missense change renders RAB40AL unstable and disrupts its cytoplasmic localisation. Conclusions This is the first study to show that mutation of RAB40AL is associated with a human disorder. Identification of RAB40AL as the gene mutated in MPS allows for further investigations into the molecular mechanism(s) of RAB40AL and its roles in diverse processes such as cognition, hearing and skeletal development. PMID:22581972

  13. 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

  14. MEPROCS framework for Craniofacial Superimposition: Validation study.

    PubMed

    Ibáñez, O; Vicente, R; Navega, D; Campomanes-Álvarez, C; Cattaneo, C; Jankauskas, R; Huete, M I; Navarro, F; Hardiman, R; Ruiz, E; Imaizumi, K; Cavalli, F; Veselovskaya, E; Humpire, D; Cardoso, J; Collini, F; Mazzarelli, D; Gibelli, D; Damas, S

    2016-11-01

    Craniofacial Superimposition (CFS) involves the process of overlaying a skull with a number of ante-mortem images of an individual and the analysis of their morphological correspondence. The lack of unified working protocols and the absence of commonly accepted standards, led to contradictory consensus regarding its reliability. One of the more important aims of 'New Methodologies and Protocols of Forensic Identification by Craniofacial Superimposition (MEPROCS)' project was to propose a common framework for CFS, what can be considered the first international standard in the field. The framework aimed to serve as a roadmap for avoiding particular assumptions that could bias the process. At the same time, it provides some empirical support to certain practices, technological means, and morphological criteria expected to facilitate the application of the CFS task and to improve its reliability. In order to confirm the utility and potential benefits of the framework use, there is a need to empirically evaluate it in CFS identification scenarios as close as possible to the reality. Thus, the purpose of this study is to validate the CFS framework developed. For that aim 12 participants were asked to report about a variable number of CFS following all the recommendations of the framework. The results are analysed and discussed according to the framework understanding and fulfilment, the participants' performance, and the correlation between expected decisions and those given by the participants. In view of the quantitative results and qualitative examination criteria we can conclude that those who follow the MEPROCS recommendations improve their performance.

  15. Computer-assisted innovations in craniofacial surgery.

    PubMed

    Rudman, Kelli; Hoekzema, Craig; Rhee, John

    2011-08-01

    Reconstructive surgery for complex craniofacial defects challenges even the most experienced surgeons. Preoperative reconstructive planning requires consideration of both functional and aesthetic properties of the mandible, orbit, and midface. Technological innovations allow for computer-assisted preoperative planning, computer-aided manufacturing of patient-specific implants (PSIs), and computer-assisted intraoperative navigation. Although many case reports discuss computer-assisted preoperative planning and creation of custom implants, a general overview of computer-assisted innovations is not readily available. This article reviews innovations in computer-assisted reconstructive surgery including anatomic considerations when using PSIs, technologies available for preoperative planning, work flow and process of obtaining a PSI, and implant materials available for PSIs. A case example follows illustrating the use of this technology in the reconstruction of an orbital-frontal-temporal defect with a PSI. Computer-assisted reconstruction of complex craniofacial defects provides the reconstructive surgeon with innovative options for challenging reconstructive cases. As technology advances, applications of computer-assisted reconstruction will continue to expand.

  16. Interrogating the mouse thalamus to correct human neurodevelopmental disorders

    PubMed Central

    Schmitt, L. Ian; Halassa, Michael M.

    2016-01-01

    While localizing sensory and motor deficits is one of the cornerstones of clinical neurology, behavioral and cognitive deficits in psychiatry remain impervious to this approach. In psychiatry, major challenges include the relative subtlety by which neural circuits are perturbed, and the limited understanding of how basic circuit functions relate to thought and behavior. Neurodevelopmental disorders offer a window to addressing the first challenge given their strong genetic underpinnings, which can be linked to biological mechanisms. Such links have benefited from genetic modeling in the mouse, and in this review we highlight how this small mammal is now allowing us to crack neural circuits as well. We review recent studies of mouse thalamus, discussing how they revealed general principles that may underlie human perception and attention. Controlling the magnitude (gain) of thalamic sensory responses is a mechanism of attention, and the mouse has enabled its functional dissection at an unprecedented resolution. Further, modeling human genetic neurodevelopmental disease in the mouse has shown how diminished thalamic gain control can lead to attention deficits. This breaks new ground in how we untangle the complexity of psychiatric diseases; by making thalamic circuits accessible to mechanistic dissection, the mouse has not only taught us how they fundamentally work, but also how their dysfunction can be precisely mapped onto behavioral and cognitive deficits. Future studies promise even more progress, with the hope that principled targeting of identified thalamic circuits can be uniquely therapeutic. PMID:27725660

  17. Frequency of craniofacial pain in patients with ischemic heart disease

    PubMed Central

    Bakhshi, Mahin; Rezaei, Rezvan; Baharvand, Maryam

    2017-01-01

    Background Referred craniofacial pain of cardiac origin might be the only symptom of ischemic heart accidents. This study aimed to determine the frequency of craniofacial pain in patients with ischemic heart disease. Material and Methods This cross-sectional study was accomplished on 296 patients who met the criteria of having ischemic heart disease. Data regarding demographics, medical history and referred craniofacial pain were recorded in data forms. In addition, patients underwent oral examination to preclude any source of dental origin. Chi-square test, Student’s t-test and backward regression model were used to analyze the data by means of SPSS software version 21. P<0.05 was considered significant. Results A total of 296 patients were studied comprising of 211 men (71%) and 85 women (29%) with the mean age of 55.8. Craniofacial pain was experienced by 53 patients out of 296, 35 (66%) of whom were male and 18 (34%) were female. None of the patients experienced craniofacial pain solely. The most common sites of craniofacial pain were occipital and posterior neck (52.8%), head (43.3%), throat and anterior neck (41.5%) respectively. We found no relationship between craniofacial pain of cardiac origin with age, diabetes, hypertension, and family history. On the other hand, there was a significant relationship between hyperlipidemia and smoking with craniofacial pain of cardiac origin. Conclusions Radiating pain to face and head can be expected quite commonly during a cardiac ischemic event. Dental practitioners should be thoroughly aware of this symptomatology to prevent misdirected dental treatment and delay of medical care. Key words:Craniofacial pain, ischemic heart disease, myocardial infarction, angina pectoris, referred pain. PMID:28149470

  18. Non-human Primate Models for Brain Disorders - Towards Genetic Manipulations via Innovative Technology.

    PubMed

    Qiu, Zilong; Li, Xiao

    2017-04-01

    Modeling brain disorders has always been one of the key tasks in neurobiological studies. A wide range of organisms including worms, fruit flies, zebrafish, and rodents have been used for modeling brain disorders. However, whether complicated neurological and psychiatric symptoms can be faithfully mimicked in animals is still debatable. In this review, we discuss key findings using non-human primates to address the neural mechanisms underlying stress and anxiety behaviors, as well as technical advances for establishing genetically-engineered non-human primate models of autism spectrum disorders and other disorders. Considering the close evolutionary connections and similarity of brain structures between non-human primates and humans, together with the rapid progress in genome-editing technology, non-human primates will be indispensable for pathophysiological studies and exploring potential therapeutic methods for treating brain disorders.

  19. Peripheral nerve stimulation for the treatment of neuropathic craniofacial pain.

    PubMed

    Slavin, K V

    2007-01-01

    Treatment of neuropathic pain in the region of head and face presents a challenging problem for pain specialists. In particular, those patients who do not respond to conventional treatment modalities usually continue to suffer from pain due to lack of reliable medical and surgical approaches. Peripheral nerve stimulation (PNS) has been used for treatment of neuropathic pain for many decades, but only recently it has been systematically applied to the craniofacial region. Here we summarize published experience with PNS in treatment of craniofacial pain and discuss some technical details of the craniofacial PNS procedure.

  20. A Phenotype-Driven ENU Mutagenesis Screen Identifies Novel Alleles With Functional Roles in Early Mouse Craniofacial Development

    PubMed Central

    Sandell, Lisa L.; Iulianella, Angelo; Melton, Kristin R.; Lynn, Megan; Walker, Macie; Inman, Kimberly E.; Bhatt, Shachi; Leroux-Berger, Margot; Crawford, Michelle; Jones, Natalie C.; Dennis, Jennifer F.; Trainor, Paul A.

    2012-01-01

    Summary Proper craniofacial development begins during gastrulation and requires the coordinated integration of each germ layer tissue (ectoderm, mesoderm, and endoderm) and its derivatives in concert with the precise regulation of cell proliferation, migration, and differentiation. Neural crest cells, which are derived from ectoderm, are a migratory progenitor cell population that generates most of the cartilage, bone, and connective tissue of the head and face. Neural crest cell development is regulated by a combination of intrinsic cell autonomous signals acquired during their formation, balanced with extrinsic signals from tissues with which the neural crest cells interact during their migration and differentiation. Although craniofacial anomalies are typically attributed to defects in neural crest cell development, the cause may be intrinsic or extrinsic. Therefore, we performed a phenotype-driven ENU mutagenesis screen in mice with the aim of identifying novel alleles in an unbiased manner, that are critically required for early craniofacial development. Here we describe 10 new mutant lines, which exhibit phenotypes affecting frontonasal and pharyngeal arch patterning, neural and vascular development as well as sensory organ morphogenesis. Interestingly, our data imply that neural crest cells and endothelial cells may employ similar developmental programs and be interdependent during early embryogenesis, which collectively is critical for normal craniofacial morphogenesis. Furthermore our novel mutants that model human conditions such as exencephaly, craniorachischisis, DiGeorge, and Velocardiofacial sydnromes could be very useful in furthering our understanding of the complexities of specific human diseases. PMID:21305688

  1. [Management of craniofacial type 1 neurofibromatosis].

    PubMed

    Bachelet, J T; Combemale, P; Devic, C; Foray, N; Jouanneau, E; Breton, P

    2015-09-01

    Type I neurofibromatosis (NF) is the most common autosomal dominant disease. It concerns one in 3000 births, the penetrance is close to 100% and 50% of new cases are de novo mutations (17q11.2 chromosome 17 location). Cranio-maxillofacial region is concerned in 10% of the cases, in different forms: molluscum neurofibroma, plexiform neurofibroma, cranio-orbital neurofibroma, parotido-jugal neurofibroma, cervical neurofibroma. These lesions have different prognosis depending on the craniofacial localization: ocular functional risk, upper airway compressive risk, nerve compression risk, aesthetic and social impact. The maxillofacial surgeon in charge of patients with type I NF should follow the patient from the diagnosis and organize the different surgical times in order to take care about the different issues: vital, functional and aesthetic. We describe the treatment of facial localizations of type 1 NF as it is done at the University Hospital of Lyon and at the Rhône-Alpes-Auvergne neurofibromatosis reference center.

  2. Craniofacial Secular Change in Recent Mexican Migrants.

    PubMed

    Spradley, Katherine; Stull, Kyra E; Hefner, Joseph T

    2016-01-01

    Research by economists suggests that recent Mexican migrants are better educated and have higher socioeconomic status (SES) than previous migrants. Because factors associated with higher SES and improved education can lead to positive secular changes in overall body form, secular changes in the craniofacial complex were analyzed within a recent migrant group from Mexico. The Mexican group represents individuals in the act of migration, not yet influenced by the American environment, and thus can serve as a starting point for future studies of secular change in this population group. The excavation of a historic Hispanic cemetery in Tucson, Arizona, also allows for a comparison between historic Hispanics and recent migrants to explore craniofacial trends over a broad time period, as both groups originate from Mexico. The present research addresses two main questions: (1) Are cranial secular changes evident in recent Mexican migrants? (2) Are historic Hispanics and recent Mexican migrants similar? By studying secular changes within a migrant population group, secular trends may be detected, which will be important for understanding the biological variation of the migrants themselves and will serve as a preliminary investigation of secular change within Mexican migrants. The comparison of a sample of recent Mexican migrants with a historic Hispanic sample, predominantly of Mexican origin, allows us to explore morphological similarities and differences between early and recent Mexicans within the United States. Vault and face size and a total of 82 craniofacial interlandmark distances were used to explore secular changes within the recent Mexican migrants (females, n = 38; males, n = 178) and to explore the morphological similarities between historic Hispanics (females, n = 54; males, n = 58) and recent migrants. Sexes were separated, and multivariate adaptive regression splines and basis splines (quadratic with one knot) were used to assess the direction and magnitude

  3. Reforming craniofacial orthodontics via stem cells.

    PubMed

    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.

  4. Peroxisome biogenesis and human peroxisome-deficiency disorders

    PubMed Central

    FUJIKI, Yukio

    2016-01-01

    Peroxisome is a single-membrane-bounded ubiquitous organelle containing a hundred different enzymes that catalyze various metabolic pathways such as β-oxidation of very long-chain fatty acids and synthesis of plasmalogens. To investigate peroxisome biogenesis and human peroxisome biogenesis disorders (PBDs) including Zellweger syndrome, more than a dozen different complementation groups of Chinese hamster ovary (CHO) cell mutants impaired in peroxisome biogenesis are isolated as a model experimental system. By taking advantage of rapid functional complementation assay of the CHO cell mutants, successful cloning of PEX genes encoding peroxins required for peroxisome assembly invaluably contributed to the accomplishment of cloning of pathogenic genes responsible for PBDs. Peroxins are divided into three groups: 1) peroxins including Pex3p, Pex16p and Pex19p, are responsible for peroxisome membrane biogenesis via Pex19p- and Pex3p-dependent class I and Pex19p- and Pex16p-dependent class II pathways; 2) peroxins that function in matrix protein import; 3) those such as Pex11pβ are involved in peroxisome division where DLP1, Mff, and Fis1 coordinately function. PMID:27941306

  5. The genetics of disorders of sex development in humans.

    PubMed

    Ohnesorg, Thomas; Vilain, Eric; Sinclair, Andrew H

    2014-01-01

    One of the defining events during human embryonic development with the most far-reaching effects for the individual is whether the embryo develops as male or female. The crucial step in this process is the differentiation of the bipotential embryonic gonads into either testes or ovaries. If the embryo inherits X and Y sex chromosomes, the Y-linked SRY (sex determining region in Y) gene initiates a network of genes that results in a functional testis and ultimately a male phenotype. By contrast, in an embryo with 2 X chromosomes, the undifferentiated gonad develops as an ovary resulting in a female phenotype. Perturbation of any of the genes in either the testicular or ovarian developmental pathway can result in individuals with disorders of sex development. In this review, we provide a summary of known components of testicular or ovarian pathways and their antagonistic actions and give a brief overview of new technologies currently used to identify the missing pieces of the sex development network.

  6. Modeling complex neuropsychiatric disorders with human induced pluripotent stem cells.

    PubMed

    Tobe, Brian T D; Snyder, Evan Y; Nye, Jeffrey S

    2011-10-01

    Identifying the molecular and cellular basis of complex neuropsychiatric disorders (cNPDs) has been limited by the inaccessibility of central neurons, variability within broad diagnostic classifications, and the interplay of genetic and environmental factors. Recent work utilizing neuronally differentiated human induced pluripotent stem cells (hiPSCs) from Mendelian and polygenic cNPDs is beginning to illuminate neuritic, synaptic or cell body variations accompanied by specific gene or protein expression alterations largely mimicking known pathology. In some cases, phenotypes have only emerged after application of cellular stress or long duration of differentiation. Pathological and cellular expression features are fully or partially responsive to pharmacological treatment highlighting the potential utility of differentiated hiPSCs for discovery of personalized therapeutics and for identifying pathogenetically relevant targets in subgroups of patients within a broad syndromic classification. Because of the inherent variability in developing and differentiating hiPSC lines and the multiple comparisons implicit in 'omics' technologies, rigorous algorithms for assuring statistical significance and independent confirmation of results, will be required for robust modeling of cNPDs.

  7. Quality difference in craniofacial pain of cardiac vs. dental origin.

    PubMed

    Kreiner, M; Falace, D; Michelis, V; Okeson, J P; Isberg, A

    2010-09-01

    Craniofacial pain, whether odontogenic or caused by cardiac ischemia, is commonly referred to the same locations, posing a diagnostic challenge. We hypothesized that the validity of pain characteristics would be high in assessment of differential diagnosis. Pain quality, intensity, and gender characteristics were assessed for referred craniofacial pain from dental (n = 359) vs. cardiac (n = 115) origin. The pain descriptors "pressure" and "burning" were statistically associated with pain from cardiac origin, while "throbbing" and "aching" indicated an odontogenic cause. No gender differences were found. These data should now be added to those craniofacial pain characteristics already known to point to acute cardiac disease rather than dental pathology, i.e., pain provocation/aggravation by physical activity, pain relief at rest, and bilateralism. To initiate prompt and appropriate treatment, dental and medical clinicians as well as the public should be alert to those clinical characteristics of craniofacial pain of cardiac origin.

  8. [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

  9. Craniofacial Features Resembling Frontonasal Dysplasia with a Tubulonodular Interhemispheric Lipoma in the Adult 3H1 tuft Mouse

    PubMed Central

    Fong, Keith S. K.; Cooper, Tiffiny Baring; Drumhiller, Wallace C.; Somponpun, Jack; Yang, Shiming; Ernst, Thomas; Chang, Linda; Lozanoff, Scott

    2012-01-01

    Intracranial lipomas are rare, but 45% of them occur along the midline cisterns between the hemispheres and are often associated with corpus callosum hypoplasia and craniofacial defects. They are difficult to detect, as they are generally asymptomatic and visible by MRI or by postmortem examination. The exact cause of these interhemispheric lipomas is not known, but they arise from a developmental defect resulting in the maldifferentiation of mesenchymal cells into mesodermal derivatives that are not normally present. We have identified a new mouse mutant called tuft, exhibiting a forebrain, intracranial lipoma with midline craniofacial defects resembling frontonasal dysplasia (FND) that arose spontaneously in our wild-type 3H1 colony. The tuft trait appears to be transmitted in recessive fashion, but approximately 80% less frequent than the expected Mendelian 25%, due to either incomplete penetrance or prenatal lethality. MRI and histological analysis revealed that the intracranial lipoma occurred between the hemispheres and often protruded through the sagittal suture. We also observed a lesion at the lamina terminalis that may indicate improper closure of the anterior neuropore. We have mapped the tuft trait to within an 18 cM region on mouse chromosome 10 by microsatellite linkage analysis and identified several candidate genes involved with craniofacial development and cellular differentiation of adipose tissue. tuft is the only known mouse model for midline craniofacial defects with an intracranial lipoma. Identifying the gene(s) and mutation(s) causing this early developmental defect will help us understand the pathogenesis of FND and related craniofacial disorders. PMID:22246904

  10. 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

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

    PubMed

    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.

  12. 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

  13. 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

  14. 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.

  15. The aponeurotic tension model of craniofacial growth in man.

    PubMed

    Standerwick, Richard G; Roberts, W Eugene

    2009-05-22

    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.

  16. Computational Biomechanics of Human Red Blood Cells in Hematological Disorders.

    PubMed

    Li, Xuejin; Li, He; Chang, Hung-Yu; Lykotrafitis, George; Em Karniadakis, George

    2017-02-01

    We review recent advances in multiscale modeling of the biomechanical characteristics of red blood cells (RBCs) in hematological diseases, and their relevance to the structure and dynamics of defective RBCs. We highlight examples of successful simulations of blood disorders including malaria and other hereditary disorders, such as sickle-cell anemia, spherocytosis, and elliptocytosis.

  17. Exocrine pancreatic disorders in transsgenic mice expressing human keratin 8

    PubMed Central

    Casanova, M. Llanos; Bravo, Ana; Ramírez, Angel; Escobar, Gabriela Morreale de; Were, Felipe; Merlino, Glenn; Vidal, Miguel; Jorcano, José L.

    1999-01-01

    Keratins K8 and K18 are the major components of the intermediate-filament cytoskeleton of simple epithelia. Increased levels of these keratins have been correlated with various tumor cell characteristics, including progression to malignancy, invasive behavior, and drug sensitivity, although a role for K8/K18 in tumorigenesis has not yet been demonstrated. To examine the function of these keratins, we generated mice expressing the human K8 (hk8) gene, which leads to a moderate keratin-content increase in their simple epithelia. These mice displayed progressive exocrine pancreas alterations, including dysplasia and loss of acinar architecture, redifferentiation of acinar to ductal cells, inflammation, fibrosis, and substitution of exocrine by adipose tissue, as well as increased cell proliferation and apoptosis. Histological changes were not observed in other simple epithelia, such as the liver. Electron microscopy showed that transgenic acinar cells have keratins organized in abundant filament bundles dispersed throughout the cytoplasm, in contrast to control acinar cells, which have scarce and apically concentrated filaments. The phenotype found was very similar to that reported for transgenic mice expressing a dominant-negative mutant TGF-β type II receptor (TGFβRII mice). We show that these TGFβRII mutant mice also have elevated K8/K18 levels. These results indicate that simple epithelial keratins play a relevant role in the regulation of exocrine pancreas homeostasis and support the idea that disruption of mechanisms that normally regulate keratin expression in vivo could be related to inflammatory and neoplastic pancreatic disorders. PMID:10359568

  18. Human iPSC-derived neurons and lymphoblastoid cells for personalized medicine research in neuropsychiatric disorders.

    PubMed

    Gurwitz, David

    2016-09-01

    The development and clinical implementation of personalized medicine crucially depends on the availability of high-quality human biosamples; animal models, although capable of modeling complex human diseases, cannot reflect the large variation in the human genome, epigenome, transcriptome, proteome, and metabolome. Although the biosamples available from public biobanks that store human tissues and cells may represent the large human diversity for most diseases, these samples are not always sufficient for developing biomarkers for patient-tailored therapies for neuropsychiatric disorders. Postmortem human tissues are available from many biobanks; nevertheless, collections of neuronal human cells from large patient cohorts representing the human diversity remain scarce. Two tools are gaining popularity for personalized medicine research on neuropsychiatric disorders: human induced pluripotent stem cell-derived neurons and human lymphoblastoid cell lines. This review examines and contrasts the advantages and limitations of each tool for personalized medicine research.

  19. Human iPSC-derived neurons and lymphoblastoid cells for personalized medicine research in neuropsychiatric disorders

    PubMed Central

    Gurwitz, David

    2016-01-01

    The development and clinical implementation of personalized medicine crucially depends on the availability of high-quality human biosamples; animal models, although capable of modeling complex human diseases, cannot reflect the large variation in the human genome, epigenome, transcriptome, proteome, and metabolome. Although the biosamples available from public biobanks that store human tissues and cells may represent the large human diversity for most diseases, these samples are not always sufficient for developing biomarkers for patient-tailored therapies for neuropsychiatric disorders. Postmortem human tissues are available from many biobanks; nevertheless, collections of neuronal human cells from large patient cohorts representing the human diversity remain scarce. Two tools are gaining popularity for personalized medicine research on neuropsychiatric disorders: human induced pluripotent stem cell-derived neurons and human lymphoblastoid cell lines. This review examines and contrasts the advantages and limitations of each tool for personalized medicine research. PMID:27757061

  20. Craniofacial osteoblast responses to polycaprolactone produced using a novel boron polymerisation technique and potassium fluoride post-treatment.

    PubMed

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

    2003-12-01

    There is no ideal material for craniofacial bone repair at present. The aim of this study was to test the biocompatibility of polycaprolactone (PCL) synthesised by a novel method allowing control of molecular weight and degradation rate, with regard to it being used as matrix for a biodegradable composite for craniofacial bone repair. Human primary craniofacial cells were used, isolated from paediatric skull after surgery. Cell responses were analysed using various assays and antibody staining. Cells attached and spread on the PCL in a similar manner to the Thermanox controls as shown by phalloidin staining of F-actin. Cells maintained the osteoblast phenotype as demonstrated by alkaline phosphatase assay and antibody staining throughout the time points studied, up to 28 days. Cells proliferated on the PCL as shown by a DNA assay. Collagen-1 staining showed extensive production of a collagen-1 containing extracellular matrix, which was also shown to be mineralised by alizarin red staining. Short-term (up to 48 h) attachment studies and long-term (up to 28 days) expression of markers of the osteoblast phenotype have been demonstrated on the PCL. This new method of synthesising PCL shows biocompatibility characteristics that give it potential to be used for craniofacial bone repair.

  1. Human immunoglobulin 10 % with recombinant human hyaluronidase: replacement therapy in patients with primary immunodeficiency disorders.

    PubMed

    Sanford, Mark

    2014-08-01

    Human immunoglobulin is an established replacement therapy for patients with primary immunodeficiency disorders (PIDs). Recombinant human hyaluronidase (rHuPH20) is a spreading factor that temporarily digests hyaluronan in the skin interstitium enabling large volumes of fluid or drug solutions to be infused and absorbed subcutaneously. HyQvia® (IGHy) is a new combination product whereby rHuPH20 is injected subcutaneously, followed by human immunoglobulin 10 % infused through the same needle. Thus, IGHy can be administered at a reduced frequency compared with non-facilitated subcutaneous injection of human immunoglobulin, and with a lower frequency of infusion reactions than with intravenous administration. Home-based administration of IGHy is also feasible for adequately trained patients. IGHy was compared with intravenous human immunoglobulin 10 % in a non-randomized, open-label, phase 3 study in patients aged ≥2 years with PIDs who were receiving human immunoglobulin replacement therapy (n = 87). In this study, trough IgG concentrations, acute serious bacterial infection rates (primary endpoint) and occurrences of adverse events during the IGHy treatment period were generally similar to those observed during an intravenous treatment period. IGHy was associated with a numerically lower rate of systemic adverse events and a numerically higher rate of localized adverse events than those observed with intravenous treatment. Compared with intravenous administration, IGHy was administered at a significantly higher maximum flow rate and at a similar frequency. Most patients preferred IGHy over intravenous administration. IGHy offers a new method for subcutaneous delivery of human immunoglobulin replacement therapy in patients with PIDs.

  2. Psychiatric disorders biochemical pathways unraveled by human brain proteomics.

    PubMed

    Saia-Cereda, Verônica M; Cassoli, Juliana S; Martins-de-Souza, Daniel; Nascimento, Juliana M

    2017-02-01

    Approximately 25 % of the world population is affected by a mental disorder at some point in their life. Yet, only in the mid-twentieth century a biological cause has been proposed for these diseases. Since then, several studies have been conducted toward a better comprehension of those disorders, and although a strong genetic influence was revealed, the role of these genes in disease mechanism is still unclear. This led most recent studies to focus on the molecular basis of mental disorders. One line of investigation that has risen in the post-genomic era is proteomics, due to its power of revealing proteins and biochemical pathways associated with biological systems. Therefore, this review compiled and analyzed data of differentially expressed proteins, which were found in postmortem brain studies of the three most prevalent psychiatric diseases: schizophrenia, bipolar disorder and major depressive disorders. Overviewing both the proteomic methods used in postmortem brain studies, the most consistent metabolic pathways found altered in these diseases. We have unraveled those disorders share about 21 % of proteins affected, and though most are related to energy metabolism pathways deregulation, the main differences found are 14-3-3-mediated signaling in schizophrenia, mitochondrial dysfunction in bipolar disorder and oxidative phosphorylation in depression.

  3. 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 =…

  4. The role of serotonin and neurotransmitters during craniofacial development.

    PubMed

    Moiseiwitsch, J R

    2000-01-01

    Several neurotransmitters, in particular serotonin (5-HT), have demonstrated multiple functions during early development and mid-gestational craniofacial morphogenesis. Early studies indicated that 5-HT is present in the oocyte, where it appears to function as a regulator of cell cleavage. Later, it has a significant role during gastrulation, during which there are significant areas of 5-HT uptake in the primitive streak. Subsequently, in association with neurulation, 5-HT uptake is seen in the floor plate of the developing neural tube. During neural crest formation and branchial arch formation, 5-HT has been demonstrated to facilitate cell migration and stimulate cell differentiation. During morphogenesis of the craniofacial structures, 5-HT stimulates dental development and may aid in cusp formation. All of the most commonly prescribed antidepressant drugs inhibit serotonin uptake, yet they do not appear to cause major craniofacial malformations in vivo. Given the wide spectrum of effects that 5-HT has during development, it is difficult to understand why these anti-depressants are not major teratogens. Redundancy within the system may allow receptor and uptake pathways to function normally even with lower than normal levels of circulating serotonin. Serotonin-binding proteins, that are expressed in most craniofacial regions at critical times during craniofacial development, may have a buffering capacity that maintains adequate 5-HT tissue concentrations over a wide range of 5-HT serum concentrations. Dental development appears to be particularly sensitive to even small fluctuations in concentrations of 5-HT. Therefore, it may be that children of patients who have received selective serotonergic re-uptake inhibitors (such as Prozac and Zoloft) or the less selective tricyclic anti-depressant drugs (such as Elavil) would be at a higher risk for developmental dental defects such as anodontia and hypodontia. In this review, the evidence supporting a role for 5-HT

  5. Morphometrics, 3D Imaging, and Craniofacial Development

    PubMed Central

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

    2017-01-01

    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

  6. Convergent integration of animal model and human studies of bipolar disorder (manic-depressive illness).

    PubMed

    Le-Niculescu, Helen; Patel, Sagar D; Niculescu, Alexander B

    2010-10-01

    Animal models and human studies of bipolar disorder and other psychiatric disorders are becoming increasingly integrated, prompted by recent successes. Particularly for genomics, the convergence and integration of data across species, experimental modalities and technical platforms is providing a fit-to-disease way of extracting reproducible and biologically important signal, in sharp contrast to the fit-to-cohort effect, disappointing findings to date, and limited reproducibility of human genetic analyses alone. Such work in psychiatry can provide an example of how to address other genetically complex disorders, and in turn will benefit by incorporating concepts from other areas, such as cancer biology and diabetes.

  7. 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.

  8. 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

  9. 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…

  10. Vagus nerve pain referred to the craniofacial region. A case report and literature review with implications for referred cardiac pain.

    PubMed

    Myers, D E

    2008-02-23

    The pain of angina pectoris and myocardial infarction is sometimes referred to the head and neck region. The mechanism for this effect remains obscure. A case is presented here that reports that electrical stimulation of a cardiac branch of the left vagus nerve in humans can cause referred craniofacial pain. This leads to the hypothesis that the vagus nerve plays a role in mediating this pain. A review of the clinical and physiologic literature supports this hypothesis.

  11. 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…

  12. Deciphering the cause of evolutionary variance within intrinsically disordered regions in human proteins.

    PubMed

    Banerjee, Sanghita; Chakraborty, Sandip; De, Rajat K

    2017-02-01

    Why the intrinsically disordered regions evolve within human proteome has became an interesting question for a decade. Till date, it remains an unsolved yet an intriguing issue to investigate why some of the disordered regions evolve rapidly while the rest are highly conserved across mammalian species. Identifying the key biological factors, responsible for the variation in the conservation rate of different disordered regions within the human proteome, may revisit the above issue. We emphasized that among the other biological features (multifunctionality, gene essentiality, protein connectivity, number of unique domains, gene expression level and expression breadth) considered in our study, the number of unique protein domains acts as a strong determinant that negatively influences the conservation of disordered regions. In this context, we justified that proteins having a fewer types of domains preferably need to conserve their disordered regions to enhance their structural flexibility which in turn will facilitate their molecular interactions. In contrast, the selection pressure acting on the stretches of disordered regions is not so strong in the case of multi-domains proteins. Therefore, we reasoned that the presence of conserved disordered stretches may compensate the functions of multiple domains within a single domain protein. Interestingly, we noticed that the influence of the unique domain number and expression level acts differently on the evolution of disordered regions from that of well-structured ones.

  13. Craniofacial Ciliopathies Reveal Specific Requirements for GLI Proteins during Development of the Facial Midline

    PubMed Central

    Chang, Ching-Fang; Brugmann, Samantha A.

    2016-01-01

    Ciliopathies represent a broad class of disorders that affect multiple organ systems. The craniofacial complex is among those most severely affected when primary cilia are not functional. We previously reported that loss of primary cilia on cranial neural crest cells, via a conditional knockout of the intraflagellar transport protein KIF3a, resulted in midfacial widening due to a gain of Hedgehog (HH) activity. Here, we examine the molecular mechanism of how a loss of primary cilia can produce facial phenotypes associated with a gain of HH function. We show that loss of intraflagellar transport proteins (KIF3a or IFT88) caused aberrant GLI processing such that the amount of GLI3FL and GLI2FL was increased, thus skewing the ratio of GLIFL to GLIR in favor of the FL isoform. Genetic addition of GLI3R partially rescued the ciliopathic midfacial widening. Interestingly, despite several previous studies suggesting midfacial development relies heavily on GLI3R activity, the conditional loss of GLI3 alone did not reproduce the ciliopathic phenotype. Only the combined loss of both GLI2 and GLI3 was able to phenocopy the ciliopathic midfacial appearance. Our findings suggest that ciliopathic facial phenotypes are generated via loss of both GLI3R and GLI2R and that this pathology occurs via a de-repression mechanism. Furthermore, these studies suggest a novel role for GLI2R in craniofacial development. PMID:27802276

  14. Bleeding management for pediatric craniotomies and craniofacial surgery.

    PubMed

    Goobie, Susan M; Haas, Thorsten

    2014-07-01

    Pediatric patients when undergoing craniotomies and craniofacial surgery may potentially have significant blood loss. The amount and extent will be dictated by the nature of the surgical procedure, the proximity to major blood vessels, and the age, and weight of the patient. The goals should be to maintain hemodynamic stability and oxygen carrying capacity and to prevent and treat hyperfibrinolysis and dilutional coagulopathy. Over transfusion and transfusion-related side effects should be minimized. This article will highlight the pertinent considerations for managing massive blood loss in pediatric patients undergoing craniotomies and craniofacial surgery. North American and European guidelines for intraoperative administration of fluid and blood products will be discussed.

  15. The fourth dimension in simulation surgery for craniofacial surgical procedures.

    PubMed

    Kurihara, T

    2001-03-01

    The intracranial volume was measured in all 18 cases of craniosynostosis and craniofacial synostosis with 3DCT using a modification of Miyake's formula, with a 6 years' follow-up. 1: There were no cases where the intracranial volume was less than the modified Miyake's formula. 2: Total cranial reshaping, compared to the local forehead advancement, was effective in increasing the intracranial cavity and growth postoperatively. 3: In cases of craniofacial synostosis, there is a possibility that mental retardation will develop if the intracranial volume tends to increase rapidly and more than expected.

  16. An annotated history of craniofacial surgery and intentional cranial deformation.

    PubMed

    Goodrich, J T; Tutino, M

    2001-01-01

    The history of craniofacial surgery and the use of intentional cranial deformation is a long and varied one. Researching some of the earliest medical writings and reviews of early terracotta and stone figures from throughout the world clearly revealed that these two forms of treatment were widely extant. Intentional cranial deformation was used for a number of reasons including beautification, tribal identification, and social stature. The development of craniofacial surgery is a more modern practice and its historical evolution is reviewed in the context of techniques and the personalities involved.

  17. 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

  18. Synaptic dysregulation in a human iPS cell model of mental disorders

    PubMed Central

    Wen, Zhexing; Nguyen, Ha Nam; Guo, Ziyuan; Lalli, Matthew A.; Wang, Xinyuan; Su, Yijing; Kim, Nam-Shik; Yoon, Ki-Jun; Shin, Jaehoon; Zhang, Ce; Makri, Georgia; Nauen, David; Yu, Huimei; Guzman, Elmer; Chiang, Cheng-Hsuan; Yoritomo, Nadine; Kaibuchi, Kozo; Zou, Jizhong; Christian, Kimberly M.; Cheng, Linzhao; Ross, Christopher A.; Margolis, Russell L.; Chen, Gong; Kosik, Kenneth S.; Song, Hongjun; Ming, Guo-li

    2015-01-01

    Dysregulated neurodevelopment with altered structural and functional connectivity is believed to underlie many neuropsychiatric disorders1, and ‘a disease of synapses’ is the major hypothesis for the biological basis of schizophrenia2. Although this hypothesis has gained indirect support from human post-mortem brain analyses2–4 and genetic studies5–10, little is known about the pathophysiology of synapses in patient neurons and how susceptibility genes for mental disorders could lead to synaptic deficits in humans. Genetics of most psychiatric disorders are extremely complex due to multiple susceptibility variants with low penetrance and variable phenotypes11. Rare, multiply affected, large families in which a single genetic locus is probably responsible for conferring susceptibility have proven invaluable for the study of complex disorders. Here we generated induced pluripotent stem (iPS) cells from four members of a family in which a frameshift mutation of disrupted in schizophrenia 1 (DISC1) co-segregated with major psychiatric disorders12 and we further produced different isogenic iPS cell lines via gene editing. We showed that mutant DISC1 causes synaptic vesicle release deficits in iPS-cell-derived forebrain neurons. Mutant DISC1 depletes wild-type DISC1 protein and, furthermore, dysregulates expression of many genes related to synapses and psychiatric disorders in human forebrain neurons. Our study reveals that a psychiatric disorder relevant mutation causes synapse deficits and transcriptional dysregulation in human neurons and our findings provide new insight into the molecular and synaptic etiopathology of psychiatric disorders. PMID:25132547

  19. Craniofacial birth defects: The role of neural crest cells in the etiology and pathogenesis of Treacher Collins syndrome and the potential for prevention.

    PubMed

    Trainor, Paul A

    2010-12-01

    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.

  20. 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

  1. 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.

  2. 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

  3. 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

  4. 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

  5. Genetic variations of human neuropsin gene and psychiatric disorders: polymorphism screening and possible association with bipolar disorder and cognitive functions.

    PubMed

    Izumi, Aiko; Iijima, Yoshimi; Noguchi, Hiroko; Numakawa, Tadahiro; Okada, Takeya; Hori, Hiroaki; Kato, Tadafumi; Tatsumi, Masahiko; Kosuga, Asako; Kamijima, Kunitoshi; Asada, Takashi; Arima, Kunimasa; Saitoh, Osamu; Shiosaka, Sadao; Kunugi, Hiroshi

    2008-12-01

    Human neuropsin (NP) (hNP) has been implicated in the progressive change of cognitive abilities during primate evolution. The hNP gene maps to chromosome 19q13, a region reportedly linked to schizophrenia and bipolar disorder. Therefore, hNP is a functional and positional candidate gene for association with schizophrenia, mood disorders, and cognitive ability. Polymorphism screening was performed for the entire hNP gene. The core promoter region was determined and whether or not transcriptional activity alters in an allele-dependent manner was examined by using the dual-luciferase system. Allelic and genotypic distributions of five single-nucleotide polymorphisms (SNPs) were compared between patients with schizophrenia (n=439), major depression (n=409), bipolar disorder (n=207), and controls (n=727). A possible association of the hNP genotype with memory index (assessed with Wechsler Memory Scale, revised, WMS-R) and intelligence quotient (IQ assessed with Wechsler Adult Intelligence Scale, revised; WAIS-R) was examined in healthy controls (n=166). A total of 28 SNPs, including nine novel SNPs, were identified. No significant effects on transcriptional activity were observed for SNPs in the promoter region. A significant allelic association was found between several SNPs and bipolar disorder (for SNP23 at the 3' regulatory region; odds ratio 1.48, 95% confidential interval 1.16-1.88, P=0.0015). However, such an association was not detected for schizophrenia or depression. Significant differences were observed between SNP23 and attention/concentration sub-scale score of WMS-R (P=0.016) and verbal IQ (P<0.001). Genetic variation of the hNP gene may contribute to molecular mechanisms of bipolar disorder and some aspects of memory and intelligence.

  6. 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.

  7. 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

  8. Why bother using non-human primate models of cognitive disorders in translational research?

    PubMed

    Camus, Sandrine; Ko, Wai Kin D; Pioli, Elsa; Bezard, Erwan

    2015-10-01

    Although everyone would agree that successful translation of therapeutic candidates for central nervous disorders should involve non-human primate (nhp) models of cognitive disorders, we are left with the paucity of publications reporting either the target validation or the actual preclinical testing in heuristic nhp models. In this review, we discuss the importance of nhps in translational research, highlighting the advances in technological/methodological approaches for 'bridging the gap' between preclinical and clinical experiments. In this process, we acknowledge that nhps remain a vital tool for the investigation of complex cognitive functions, given their resemblance to humans in aspects of behaviour, anatomy and physiology. The recent improvements made for a suitable nhp model in cognitive research, including new surrogates of disease and application of innovative methodological approaches, are continuous strides for reaching efficient translation for human benefit. This will ultimately aid the development of innovative treatments against the current and future threat of neurological and psychiatric disorders to the global population.

  9. Trigeminal branch stimulation for the treatment of intractable craniofacial pain.

    PubMed

    Ellis, Jason A; Mejia Munne, Juan C; Winfree, Christopher J

    2015-07-01

    OBJECT Trigeminal branch stimulation has been used in the treatment of craniofacial pain syndromes. The risks and benefits of such an approach have not been clearly delineated in large studies, however. The authors report their experience in treating craniofacial pain with trigeminal branch stimulation and share the lessons they have learned after 93 consecutive electrode placements. METHODS A retrospective review of all patients who underwent trigeminal branch electrode placement by the senior author (C.J.W.) for the treatment of craniofacial pain was performed. RESULTS Thirty-five patients underwent implantation of a total of 93 trial and permanent electrodes between 2006 and 2013. Fifteen patients who experienced improved pain control after trial stimulation underwent implantation of permanent stimulators and were followed for an average of 15 months. At last follow-up 73% of patients had improvement in pain control, whereas only 27% of patients had no pain improvement. No serious complications were seen during the course of this study. CONCLUSIONS Trigeminal branch stimulation is a safe and effective treatment for a subset of patients with intractable craniofacial pain.

  10. 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.

  11. 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.

  12. 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

  13. Differential protein import deficiencies in human peroxisome assembly disorders

    PubMed Central

    1994-01-01

    Two peroxisome targeting signals (PTSs) for matrix proteins have been well defined to date. PTS1 comprises a COOH-terminal tripeptide, SKL, and has been found in several matrix proteins, whereas PTS2 has been found only in peroxisomal thiolase and is contained within an NH2- terminal cleavable presequence. We have investigated the functional integrity of the import routes for PTS1 and PTS2 in fibroblasts from patients suffering from peroxisome assembly disorders. Three of the five complementation groups tested showed a general loss of PTS1 and PTS2 import. Two complementation groups showed a differential loss of peroxisomal protein import: group I cells were able to import a PTS1- but not a PTS2- containing reporter protein into their peroxisomes, and group IV cells were able to import the PTS2 but not the PTS1 reporter into aberrant, peroxisomal ghostlike structures. The observation that the PTS2 import pathway is intact only in group IV cells is supported by the protection of endogenous thiolase from protease degradation in group IV cells and its sensitivity in the remaining complementation groups, including the partialized disorder of group I. The functionality of the PTS2 import pathway and colocalization of endogenous thiolase with the peroxisomal membranes in group IV cells was substantiated further using immunofluorescence, subcellular fractionation, and immunoelectron microscopy. The phenotypes of group I and IV cells provide the first evidence for differential import deficiencies in higher eukaryotes. These phenotypes are analogous to those found in Saccharomyces cerevisiae peroxisome assembly mutants. PMID:7910611

  14. Craniofacial pain and jaw-muscle activity during sleep.

    PubMed

    Yachida, W; Castrillon, E E; Baad-Hansen, L; Jensen, R; Arima, T; Tomonaga, A; Ohata, N; Svensson, P

    2012-06-01

    This study compared the jaw-muscle electromyographic (EMG) activity during sleep in patients with craniofacial pain (n = 63) or no painful conditions (n = 52) and between patients with tension-type headache (TTH: n = 30) and healthy control individuals (n = 30). All participants used a portable single-channel EMG device (Medotech A/S) for four nights. There was no significant difference in EMG activity between craniofacial pain (24.5 ± 17.9 events/hr) and no painful conditions (19.7 ± 14.5), or between TTH (20.8 ± 15.0) and healthy control individuals (15.2 ± 11.6, p >.050). There were positive correlations between EMG activity and number of painful muscles (r = 0.188; p = 0.044), characteristic pain intensity (r = 0.187; p = 0.046), McGill Pain Questionnaire (r = 0.251; p = 0.008), and depression scores (r = 0.291; p = 0.002). Patients with painful conditions had significantly higher night-to-night variability compared with pain-free individuals (p < 0.050). This short-term observational study suggests that there are no major differences between patients with different craniofacial pain conditions and pain-free individuals in terms of jaw-muscle EMG activity recorded with a single-channel EMG device during sleep. However, some associations may exist between the level of EMG activity and various parameters of craniofacial pain. Longitudinal studies are warranted to further explore the relationship between sleep bruxism and craniofacial pain.

  15. Managing obstructive sleep apnoea in children: the role of craniofacial morphology.

    PubMed

    Bozzini, Maria Fernanda Rabelo; Di Francesco, Renata Cantisani

    2016-11-01

    Obstructive sleep apnoea syndrome is a type of sleep-disordered breathing that affects 1 to 5% of all children. Pharyngeal and palatine tonsil hypertrophy is the main predisposing factor. Various abnormalities are predisposing factors for obstructive sleep apnoea, such as decreased mandibular and maxillary lengths, skeletal retrusion, increased lower facial height and, consequently, increased total anterior facial height, a larger cranio-cervical angle, small posterior airway space and an inferiorly positioned hyoid bone. The diagnosis is based on the clinical history, a physical examination and tests confirming the presence and severity of upper airway obstruction. The gold standard test for diagnosis is overnight polysomnography. Attention must be paid to identify the craniofacial characteristics. When necessary, children should be referred to orthodontists and/or sleep medicine specialists for adequate treatment in addition to undergoing an adenotonsillectomy.

  16. Managing obstructive sleep apnoea in children: the role of craniofacial morphology

    PubMed Central

    Bozzini, Maria Fernanda Rabelo; Di Francesco, Renata Cantisani

    2016-01-01

    Obstructive sleep apnoea syndrome is a type of sleep-disordered breathing that affects 1 to 5% of all children. Pharyngeal and palatine tonsil hypertrophy is the main predisposing factor. Various abnormalities are predisposing factors for obstructive sleep apnoea, such as decreased mandibular and maxillary lengths, skeletal retrusion, increased lower facial height and, consequently, increased total anterior facial height, a larger cranio-cervical angle, small posterior airway space and an inferiorly positioned hyoid bone. The diagnosis is based on the clinical history, a physical examination and tests confirming the presence and severity of upper airway obstruction. The gold standard test for diagnosis is overnight polysomnography. Attention must be paid to identify the craniofacial characteristics. When necessary, children should be referred to orthodontists and/or sleep medicine specialists for adequate treatment in addition to undergoing an adenotonsillectomy. PMID:27982168

  17. 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…

  18. Mutations in Hedgehog acyltransferase (Hhat) perturb Hedgehog signaling, resulting in severe acrania-holoprosencephaly-agnathia craniofacial defects.

    PubMed

    Dennis, Jennifer F; Kurosaka, Hiroshi; Iulianella, Angelo; Pace, Jennifer; Thomas, Nancy; Beckham, Sharon; Williams, Trevor; Trainor, Paul A

    2012-01-01

    Holoprosencephaly (HPE) is a failure of the forebrain to bifurcate and is the most common structural malformation of the embryonic brain. Mutations in SHH underlie most familial (17%) cases of HPE; and, consistent with this, Shh is expressed in midline embryonic cells and tissues and their derivatives that are affected in HPE. It has long been recognized that a graded series of facial anomalies occurs within the clinical spectrum of HPE, as HPE is often found in patients together with other malformations such as acrania, anencephaly, and agnathia. However, it is not known if these phenotypes arise through a common etiology and pathogenesis. Here we demonstrate for the first time using mouse models that Hedgehog acyltransferase (Hhat) loss-of-function leads to holoprosencephaly together with acrania and agnathia, which mimics the severe condition observed in humans. Hhat is required for post-translational palmitoylation of Hedgehog (Hh) proteins; and, in the absence of Hhat, Hh secretion from producing cells is diminished. We show through downregulation of the Hh receptor Ptch1 that loss of Hhat perturbs long-range Hh signaling, which in turn disrupts Fgf, Bmp and Erk signaling. Collectively, this leads to abnormal patterning and extensive apoptosis within the craniofacial primordial, together with defects in cartilage and bone differentiation. Therefore our work shows that Hhat loss-of-function underscrores HPE; but more importantly it provides a mechanism for the co-occurrence of acrania, holoprosencephaly, and agnathia. Future genetic studies should include HHAT as a potential candidate in the etiology and pathogenesis of HPE and its associated disorders.

  19. Human Mendelian pain disorders: a key to discovery and validation of novel analgesics.

    PubMed

    Goldberg, Y P; Pimstone, S N; Namdari, R; Price, N; Cohen, C; Sherrington, R P; Hayden, M R

    2012-10-01

    We have utilized a novel application of human genetics, illuminating the important role that rare genetic disorders can play in the development of novel drugs that may be of relevance for the treatment of both rare and common diseases. By studying a very rare Mendelian disorder of absent pain perception, congenital indifference to pain, we have defined Nav1.7 (endocded by SCN9A) as a critical and novel target for analgesic development. Strong human validation has emerged with SCN9A gain-of-function mutations causing inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder, both Mendelian disorder of spontaneous or easily evoked pain. Furthermore, variations in the Nav1.7 channel also modulate pain perception in healthy subjects as well as in painful conditions such as osteoarthritis and Parkinson disease. On the basis of this, we have developed a novel compound (XEN402) that exhibits potent, voltage-dependent block of Nav1.7. In a small pilot study, we showed that XEN402 blocks Nav1.7 mediated pain associated with IEM thereby demonstrating the use of rare genetic disorders with mutant target channels as a novel approach to rapid proof-of-concept. Our approach underscores the critical role that human genetics can play by illuminating novel and critical pathways pertinent for drug discovery.

  20. Transduction of human recombinant proteins into mitochondria as a protein therapeutic approach for mitochondrial disorders.

    PubMed

    Papadopoulou, Lefkothea C; Tsiftsoglou, Asterios S

    2011-11-01

    Protein therapy is considered an alternative approach to gene therapy for treatment of genetic-metabolic disorders. Human protein therapeutics (PTs), developed via recombinant DNA technology and used for the treatment of these illnesses, act upon membrane-bound receptors to achieve their pharmacological response. On the contrary, proteins that normally act inside the cells cannot be developed as PTs in the conventional way, since they are not able to "cross" the plasma membrane. Furthermore, in mitochondrial disorders, attributed either to depleted or malfunctioned mitochondrial proteins, PTs should also have to reach the subcellular mitochondria to exert their therapeutic potential. Nowadays, there is no effective therapy for mitochondrial disorders. The development of PTs, however, via the Protein Transduction Domain (PTD) technology offered new opportunities for the deliberate delivery of human recombinant proteins inside eukaryotic subcellular organelles. To this end, mitochondrial disorders could be clinically encountered with the delivery of human mitochondrial proteins (engineered via recombinant DNA and PTD technologies) at specific intramitochondrial sites to exert their function. Overall, PTD-mediated Protein Replacement Therapy emerges as a suitable model system for the therapeutic approach for mitochondrial disorders.

  1. The role of genomic imprinting in human developmental disorders: lessons from Prader-Willi syndrome.

    PubMed

    Hanel, M L; Wevrick, R

    2001-03-01

    Normal human development involves a delicate interplay of gene expression in specific tissues at narrow windows of time. Temporally and spatially regulated gene expression is controlled both by gene-specific factors and chromatin-specific factors. Genomic imprinting is the expression of specific genes primarily from only one allele at particular times during development, and is one mechanism implicated in the intricate control of gene expression. Two human genetic disorders, Prader-Willi syndrome (PWS, MIM 176270) and Angelman syndrome (AS, MIM 105830), result from rearrangements of chromosome 15q11-q13, an imprinted region of the human genome. Despite their rarity, disorders such as PWS and AS can give focused insight into the role of genomic imprinting and imprinted genes in human development.

  2. Membrane-associated immunoglobulins of human lymphocytes in immunologic disorders

    PubMed Central

    Nicod, Isabelle; Girard, J. P.; Cruchaud, A.

    1973-01-01

    Membrane-associated immunoglobulins of peripheral blood lymphocytes were studied by indirect immunofluorescence for γ, α, μ, κ and λ chains in healthy subjects and patients with immunologic disease. In healthy subjects, heavy chains were found on 30·7% of lymphocytes (γ 15·3%, α 7·2% and μ 8·2%) and light chains on 32·8% of cells (κ 20·4% and λ 12·4%). Patients with humoral immune deficiencies had fewer immunoglobulin-bearing cells; sarcoidosis or thymectomy patients had normal or decreased immunoglobulin-bearing lymphocytes; cells with light chains were fewer than those with heavy chains on their lymphocytes. In some cases, normal levels of serum immunoglobulins were found in the absence of the corresponding immunoglobulin-bearing cells, and in others normal immunoglobulin-bearing lymphocytes were present in the absence of the corresponding serum immunoglobulins. These data suggest that (1) immunoglobulin-bearing lymphocytes in blood do not reflect the condition of immunoglobulin-synthesizing cells in peripheral lymphoid tissues, and (2) in certain immunologic disorders, either some B-lymphocytes do not synthesize immunoglobulins, or immunoglobulins are in such a situation that the whole molecule or part of the molecule is not visualized by current methods. PMID:4587505

  3. 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

  4. The contribution of intrinsically disordered regions to protein function, cellular complexity, and human disease

    PubMed Central

    Babu, M. Madan

    2016-01-01

    In the 1960s, Christian Anfinsen postulated that the unique three-dimensional structure of a protein is determined by its amino acid sequence. This work laid the foundation for the sequence–structure–function paradigm, which states that the sequence of a protein determines its structure, and structure determines function. However, a class of polypeptide segments called intrinsically disordered regions does not conform to this postulate. In this review, I will first describe established and emerging ideas about how disordered regions contribute to protein function. I will then discuss molecular principles by which regulatory mechanisms, such as alternative splicing and asymmetric localization of transcripts that encode disordered regions, can increase the functional versatility of proteins. Finally, I will discuss how disordered regions contribute to human disease and the emergence of cellular complexity during organismal evolution. PMID:27911701

  5. Angiogenic and Osteogenic Potential of Bone Repair Cells for Craniofacial Regeneration

    PubMed Central

    Pagni, Giorgio; Park, Chan-Ho; Tarle, Susan A.; Bartel, Ronnda L.; Giannobile, William V.

    2010-01-01

    There has been increased interest in the therapeutic potential of bone marrow derived cells for tissue engineering applications. Bone repair cells (BRCs) represent a unique cell population generated via an ex vivo, closed-system, automated cell expansion process, to drive the propagation of highly osteogenic and angiogenic cells for bone engineering applications. The aims of this study were (1) to evaluate the in vitro osteogenic and angiogenic potential of BRCs, and (2) to evaluate the bone and vascular regenerative potential of BRCs in a craniofacial clinical application. BRCs were produced from bone marrow aspirates and their phenotypes and multipotent potential characterized. Flow cytometry demonstrated that BRCs were enriched for mesenchymal and vascular phenotypes. Alkaline phosphatase and von Kossa staining were performed to assess osteogenic differentiation, and reverse transcriptase–polymerase chain reaction was used to determine the expression levels of bone specific factors. Angiogenic differentiation was determined through in vitro formation of tube-like structures and fluorescent labeling of endothelial cells. Finally, 6 weeks after BRC transplantation into a human jawbone defect, a biopsy of the regenerated site revealed highly vascularized, mineralized bone tissue formation. Taken together, these data provide evidence for the multilineage and clinical potential of BRCs for craniofacial regeneration. PMID:20412009

  6. Scaling Behavior of Human Locomotor Activity Amplitude: Association with Bipolar Disorder

    PubMed Central

    Indic, Premananda; Salvatore, Paola; Maggini, Carlo; Ghidini, Stefano; Ferraro, Gabriella; Baldessarini, Ross J.; Murray, Greg

    2011-01-01

    Scale invariance is a feature of complex biological systems, and abnormality of multi-scale behaviour may serve as an indicator of pathology. The hypothalamic suprachiasmatic nucleus (SCN) is a major node in central neural networks responsible for regulating multi-scale behaviour in measures of human locomotor activity. SCN also is implicated in the pathophysiology of bipolar disorder (BD) or manic-depressive illness, a severe, episodic disorder of mood, cognition and behaviour. Here, we investigated scaling behaviour in actigraphically recorded human motility data for potential indicators of BD, particularly its manic phase. A proposed index of scaling behaviour (Vulnerability Index [VI]) derived from such data distinguished between: [i] healthy subjects at high versus low risk of mood disorders; [ii] currently clinically stable BD patients versus matched controls; and [iii] among clinical states in BD patients. PMID:21655197

  7. 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

  8. Fear Generalization in Humans: Systematic Review and Implications for Anxiety Disorder Research.

    PubMed

    Dymond, Simon; Dunsmoor, Joseph E; Vervliet, Bram; Roche, Bryan; Hermans, Dirk

    2015-09-01

    Fear generalization, in which conditioned fear responses generalize or spread to related stimuli, is a defining feature of anxiety disorders. The behavioral consequences of maladaptive fear generalization are that aversive experiences with one stimulus or event may lead one to regard other cues or situations as potential threats that should be avoided, despite variations in physical form. Theoretical and empirical interest in the generalization of conditioned learning dates to the earliest research on classical conditioning in nonhumans. Recently, there has been renewed focus on fear generalization in humans due in part to its explanatory power in characterizing disorders of fear and anxiety. Here, we review existing behavioral and neuroimaging empirical research on the perceptual and non-perceptual (conceptual and symbolic) generalization of fear and avoidance in healthy humans and patients with anxiety disorders. The clinical implications of this research for understanding the etiology and treatment of anxiety is considered and directions for future research described.

  9. Basonuclin 2 has a function in the multiplication of embryonic craniofacial mesenchymal cells and is orthologous to disco proteins

    PubMed Central

    Vanhoutteghem, Amandine; Maciejewski-Duval, Anna; Bouche, Cyril; Delhomme, Brigitte; Hervé, Françoise; Daubigney, Fabrice; Soubigou, Guillaume; Araki, Masatake; Araki, Kimi; Yamamura, Ken-ichi; Djian, Philippe

    2009-01-01

    Basonuclin 2 is a recently discovered zinc finger protein of unknown function. Its paralog, basonuclin 1, is associated with the ability of keratinocytes to multiply. The basonuclin zinc fingers are closely related to those of the Drosophila proteins disco and discorelated, but the relation between disco proteins and basonuclins has remained elusive because the function of the disco proteins in larval head development seems to have no relation to that of basonuclin 1 and because the amino acid sequence of disco, apart from the zinc fingers, also has no similarity to that of the basonuclins. We have generated mice lacking basonuclin 2. These mice die within 24 h of birth with a cleft palate and abnormalities of craniofacial bones and tongue. In the embryonic head, expression of the basonuclin 2 gene is restricted to mesenchymal cells in the palate, at the periphery of the tongue, and in the mesenchymal sheaths that surround the brain and the osteocartilagineous structures. In late embryos, the rate of multiplication of these mesenchymal cells is greatly diminished. Therefore, basonuclin 2 is essential for the multiplication of craniofacial mesenchymal cells during embryogenesis. Non-Drosophila insect databases available since 2008 reveal that the basonuclins and the disco proteins share much more extensive sequence and gene structure similarity than noted when only Drosophila sequences were examined. We conclude that basonuclin 2 is both structurally and functionally the vertebrate ortholog of the disco proteins. We also note the possibility that some human craniofacial abnormalities are due to a lack of basonuclin 2. PMID:19706529

  10. 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.

  11. Effects of tongue volume reduction on craniofacial growth

    PubMed Central

    Liu, Zi-Jun; Shcherbatyy, Volodymyr; Gu, Gaoman; Perkins, Jonathan A.

    2008-01-01

    The interaction between tongue size/volume and craniofacial skeletal growth is essential for understanding the mechanism of specific types of malocclusion and objectively measuring outcomes of various surgical and/or orthodontic treatments. Currently available information on this interaction is limited. This study was designed to examine how tongue body volume reduction affects craniofacial skeleton and dental arch formation during the rapid growth period in five 12-week-old Yucatan minipig sibling pairs. One of each pair received a standardized reduction glossectomy to reduce tongue volume by 15-17% (reduction group), and the other had the reduction glossectomy incisions without tissue removal (sham group). Before surgery, five stainless steel screws were implanted into standardized craniofacial skeletal locations. A series of cephalograms, lateral and axial, were obtained longitudinally at 1 week preoperative, and 2 and 4 weeks postoperative. These images were traced using superimposition, and linear and angular variables were measured digitally. Upon euthanasia, direct osteometric measurements were obtained from harvested skulls. Five en-bloc bone pieces were further cut for bone mineral examination by dual photon/energy X-ray absorptiometry (DEXA). The results indicate that: (1) while daily food consumption and weekly body weight were not significantly affected, tongue volume reduction showed an overall negative effect on the linear expansion of craniofacial skeletons; (2) premaxilla and mandibular symphysis lengths, and anterior dental arch width were significantly less in reduction than sham animals at 2 and/or 4 weeks after the surgery; (3) both premaxilla/maxilla and mandible bone mineral density and content were lower in reduction than sham animals, significantly lower in anterior mandible; (4) craniofacial skeletal and dental arch size were significantly smaller in reduction than sham animals, being most significant in the mandibular anterior length and

  12. Risk factors for mental disorders in women survivors of human trafficking: a historical cohort study

    PubMed Central

    2013-01-01

    Background Previous studies have found high levels of symptoms of depression, anxiety, and post-traumatic stress disorder among women survivors of human trafficking. No previous research has described risk factors for diagnosed mental disorders in this population. Methods A historical cohort study of women survivors of trafficked women aged 18 and over who returned to Moldova and registered for assistance with the International Organisation for Migration (IOM). Women were approached by IOM social workers and, if they gave informed consented to participate in the study, interviewed by the research team. At 2–12 months post-return to Moldova, a psychiatrist assessed DSM-IV mental disorders blind to information about women’s pre-trafficking and post-trafficking experiences using the Structured Clinical Interview for DSM-IV (SCID). A backwards stepwise selection procedure was used to create a multivariable regression model of risk factors for DSM-IV mental disorder measured at an average of 6 months post-return. Results 120/176 (68%) eligible women participated. At an average of 6 months post-return, 54% met criteria for any DSM-IV mental disorder: 35.8% of women had PTSD (alone or co-morbid), 12.5% had depression without PTSD and 5.8% had another anxiety disorder. Multivariable regression analysis found that childhood sexual abuse (Adjusted Odds Ratio [AOR] 4.68, 95% CI 1.04-20.92), increased number of post-trafficking unmet needs (AOR 1.80; 95% CI 1.28-2.52) and post-trafficking social support (AOR 0.64; 95% CI 0.52-0.79) were independent risk factors for mental disorder, and that duration of trafficking showed a borderline association with mental disorder (AOR 1.12, 95% CI 0.98-1.29). Conclusions Assessment for mental disorders should be part of re-integration follow-up care for women survivors of human trafficking. Mental disorders at that time, most commonly PTSD and depression, are likely to be influenced by a range of predisposing, precipitating and

  13. 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.

  14. Craniofacial morphology in children with cystic fibrosis.

    PubMed

    Hellsing, E; Brattström, V; Strandvik, B

    1992-04-01

    Cystic fibrosis (CF) is a hereditary metabolic disorder with clinical symptoms of abnormal mucus production. This blocks the airways, gives pancreatic insufficiency, and increases sweat electrolytes. The progressive respiratory disease often leads to respiratory insufficiency and cor pulmonale. The aim of the present investigation was to examine the facial morphology in children with cystic fibrosis. The sample comprised 11 children with cystic fibrosis, who were divided in two groups, one with gastrointestinal disorders and the other with predominantly respiratory insufficiency. Eleven healthy children with normal occlusions were selected as controls. Lateral skull radiographs obtained in natural head posture were digitized, and linear and angular variables for the different groups calculated and compared statistically. The cystic fibrosis group showed open bite, decreased posterior facial height, increased mandibular and craniocervical inclination. Additionally, within the CF-group, the children with respiratory insufficiency differed more from the controls than the children with gastrointestinal disorders. Despite the small number of subjects, the facial morphology of the CF children showed a similar pattern to that of children with nasal respiratory obstruction due to enlarged adenoids or tonsils.

  15. 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

  16. Both dog and human faces are explored abnormally by young children with autism spectrum disorders.

    PubMed

    Guillon, Quentin; Hadjikhani, Nouchine; Baduel, Sophie; Kruck, Jeanne; Arnaud, Mado; Rogé, Bernadette

    2014-10-22

    When looking at faces, typical individuals tend to have a right hemispheric bias manifested by a tendency to look first toward the left visual hemifield. Here, we tested for the presence of this bias in young children with autism spectrum disorders (ASD) for both human and dog faces. We show that children with ASD do not show a left visual hemifield (right hemispheric) bias for human faces. In addition, we show that this effect extends to faces of dogs, suggesting that the absence of bias is not specific to human faces, but applies to all faces with the first-order configuration, pointing to an anomaly at an early stage of visual analysis of faces. The lack of right hemispheric dominance for face processing may reflect a more general disorder of cerebral specialization of social functions in ASD.

  17. Craniofacial features of children with spinal deformities

    PubMed Central

    Segatto, Emil; Lippold, Carsten; Végh, András

    2008-01-01

    Background The objective of this epidemiological study is to map the dentofacial anomalies that can be correlated to the two most frequent spinal diseases responsible for postural abnormalities and that can be clinically identified by the orthodontic examination. Methods Twenty-three children with Scheuermann's disease participated in the study (mean age: 14Y8M; SD: 1Y8M), 28 with Scoliosis (mean age: 14Y7M; SD: 2Y3M) and a control group of 68 orthopedically healthy children (mean age: 14Y8M; SD: 0Y11M). Standardized orthodontic screening protocols were used to map the occlusal relations in the sagittal, vertical, and transversal dimensions, space relations of the maxillary and mandibular frontal segment, and the TMJ status and function. The examinations for the children with orthopedic disorders were supplemented by the evaluation of routine orthodontic radiograms – lateral cephalograms and panoramic X-rays. Results The majority of the dentofacial features examined revealed more and greater abnormalities among patients in the Scheuermann's disease group than in the scoliosis group. In the latter group the proportion of the TMJ symptoms and the consecutive functional deviations were greater. When comparing the values of the two spinal-disorder groups and the control group, statistically significant differences (p < .05) occurred for the following measurements: frequency of unilateral Cl.II. molar occlusion, overjet and extreme overjet mean value (Scheuermann's disease group), as well as the frequency of TMJ pathological symptoms (scoliosis group). The evaluation of the panoramic X-rays showed significant differences among the mandibular measurements of the two spinal-disorder groups. Within the framework of the evaluation of the cephalograms significant differences (p < .05) were found only in the case of dental relations. However, several values differed significantly from the Ricketts' norms, none of the indices strictly characterized any of the groups with

  18. Immune globulin subcutaneous (human) 20%: in primary immunodeficiency disorders.

    PubMed

    McCormack, Paul L

    2012-05-28

    Immune globulin subcutaneous 20% is a new high-concentration (200 g/L) solution of highly purified human IgG (≥98%) indicated in the EU and the US for antibody replacement therapy in patients with primary immunodeficiency with antibody deficiency, and in the EU for replacement therapy in humoral immunodeficiency secondary to myeloma or chronic lymphocytic leukaemia. Immune globulin subcutaneous 20% is formulated with L-proline, which imparts long-term stability at room temperature and a relatively low viscosity. In two pivotal phase III trials in stably treated patients with primary immunodeficiency, immune globulin subcutaneous 20% at weekly subcutaneous dosages either equivalent to each patient's previous intravenous or subcutaneous replacement therapy, or providing equivalent systemic exposure to previous intravenous therapy, produced mean serum IgG trough levels equal to or greater than pre-study levels. In each trial, there were no serious bacterial infections during treatment throughout the 28-week or 12-month efficacy periods. The rates of infectious episodes, days missed from work/school, days hospitalized or days with antibiotics were low. Immune globulin subcutaneous 20% was generally well tolerated. A high proportion of patients experienced local infusion-site reactions, but infusion-related systemic adverse events were relatively infrequent. Most adverse events were of mild or moderate intensity and did not interfere with therapy.

  19. Fibrous dysplasia of bone: craniofacial and dental implications.

    PubMed

    Burke, A B; Collins, M T; Boyce, A M

    2016-08-05

    Fibrous dysplasia (FD) is a rare bone disease caused by postzygotic somatic activating mutations in the GNAS gene, which lead to constitutive activation of adenylyl cyclase and elevated levels of cyclic AMP, which act on downstream signaling pathways and cause normal bone to be replaced with fibrous tissue and abnormal (woven) bone. The bone disease may occur in one bone (monostotic), multiple bones (polyostotic), or in combination with hyperfunctioning endocrinopathies and hyperpigmented skin lesions (in the setting of McCune-Albright Syndrome). FD is common in the craniofacial skeleton, causing significant dysmorphic features, bone pain, and dental anomalies. This review summarizes the pathophysiology, clinical findings, and treatment of FD, with an emphasis on the craniofacial and oral manifestations of the disease.

  20. 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.

  1. Coordinate systems integration for development of malaysian craniofacial database.

    PubMed

    Rajion, Zainul; Suwardhi, Deni; Setan, Halim; Chong, Albert; Majid, Zulkepli; Ahmad, Anuar; Rani Samsudin, Ab; Aziz, Izhar; Wan Harun, W A R

    2005-01-01

    This study presents a data registration method for craniofacial spatial data of different modalities. The data consists of three dimensional (3D) vector and raster data models. The data is stored in object relational database. The data capture devices are Laser scanner, CT (Computed Tomography) scan and CR (Close Range) Photogrammetry. The objective of the registration is to transform the data from various coordinate systems into a single 3-D Cartesian coordinate system. The standard error of the registration obtained from multimodal imaging devices using 3D affine transformation is in the ranged of 1-2 mm. This study is a step forward for storing the spatial craniofacial data in one reference system in database.

  2. Craniofacial abnormalities in Hutchinson-Gilford progeria syndrome.

    PubMed

    Ullrich, N J; Silvera, V M; Campbell, S E; Gordon, L B

    2012-09-01

    HGPS is a rare syndrome of segmental premature aging. Our goal was to expand the scope of structural bone and soft-tissue craniofacial abnormalities in HGPS through CT or MR imaging. Using The Progeria Research Foundation Medical and Research Database, 98 imaging studies on 25 patients, birth to 14.1 years of age, were comprehensively reviewed. Eight newly identified abnormalities involving the calvaria, skull base, and soft tissues of the face and orbits were present with prevalences between 43% and 100%. These included J-shaped sellas, a mottled appearance and increased vascular markings of the calvaria, abnormally configured mandibular condyles, hypoplastic articular eminences, small zygomatic arches, prominent parotid glands, and optic nerve kinking. This expanded craniofacial characterization helps link disease features and improves our ability to evaluate how underlying genetic and cellular abnormalities culminate in a disease phenotype.

  3. Neurodevelopmental disorders involving genomic imprinting at human chromosome 15q11-q13.

    PubMed

    Chamberlain, Stormy J; Lalande, Marc

    2010-07-01

    Human chromosome 15q11-q13 is subject to regulation by genomic imprinting, an epigenetic process by which genes are expressed in a parent-of-origin specific manner. Three neurodevelopmental disorders, Prader-Willi syndrome, Angelman syndrome, and 15q duplication syndrome, result from aberrant expression of imprinted genes in this region. Here, we review the current literature pertaining to mouse models and recently identified patients with atypical deletions, which shed light on the epigenetic regulation of the chromosome 15q11-q13 subregion and the genes that are responsible for the phenotypic outcomes of these disorders.

  4. Craniofacial Deviations in the Children With Nasal Obstruction.

    PubMed

    Ant, Ayca; Kemaloglu, Yusuf Kemal; Yilmaz, Metin; Dilci, Alper

    2017-01-20

    Nasal obstruction mainly caused by adenoid hypertrophy in children affects the craniofacial growth and development process, and the craniofacial deviations and/or differences reported in the children are very similar to those in the adults with obstructive sleep apnea syndrome (OSAS). The authors aimed to look for relationships of the linear craniofacial dimensions in the children suffering from nasal obstruction with age, degree of clinical nasal obstruction score (CNOS), and relative size of the adenoid mass within the nasopharynx in their study.Fifty-five children suffering from nasal obstruction were retrospectively enrolled, and clinical data was used to calculate CNOS. On the lateral cephalometric radiographies, 9 linear variables were measured and adenoidal-nasopharyngeal ratio (ANR) was calculated.The data presented that, not CNOS, but ANR shown decrease by age, while many skeletal variables with exception of the nasopharyngeal and adenoidal postero-anterior dimensions were increased by age. Further, it was found that while CNOS were negatively correlated with the anterior cranial base length, anterior-superior facial height, and maxillary depth, ANR disclosed significant correlation only with the anteriorsuperior facial height. The authors' results support that nasal obstruction in the children was related not only to the adenoidal hypertrophy. Although relative size of the adenoidal mass in relation to the nasopharynx decreased by age, nasal obstruction was still present. Further, these results support that craniofacial deviations and/or differences in the children with nasal obstruction is similar to the adult OSAS patients. Smaller dimensions related to the naso-maxillary complex in the children with more severe nasal obstruction appear to be continuous by age. Hence, it could be said that narrow naso-maxillary complex could contribute to proceed nasal obstruction by age, which may contribute to OSAS in the adults.

  5. Sagittal back contour and craniofacial morphology in preadolescents.

    PubMed

    Lippold, Carsten; Segatto, Emil; Végh, András; Drerup, Burkhard; Moiseenko, Tatjana; Danesh, Gholamreza

    2010-03-01

    The aim of this study was to analyze the correlation ratios between the sagittal back contour (flèche cervicale and lombaire, trunk inclination) and selected parameters of craniofacial morphology in children. The patient sample consisted of 66 healthy children with a mean age of 11.2 years (SD 1.6 years), of which 34 were male (mean age 11.5 years, SD 1.3 years) and 32 were females (mean age 10.9 years, SD 1.9 years). The children were recruited during the preparation of the initial orthodontic treatment records. Craniofacial morphology was analyzed by six angular measurements: facial axis, mandibular plane angle, inner gonial angle, lower facial height, facial depth and maxilla position. Rasterstereography was used for reconstruction of the spinal back sagittal profile. From the profile flèche cervicale, flèche lombaire and trunk inclination were determined and the correlations with the craniofacial morphology were calculated (Pearson and Mann-Whitney U test). Significant correlations were found with respect to the inner gonial angle and the flèche cervicale, the mandibular plane angle and the flèche lombaire, the inner gonial angle and the flèche lombaire, and the angular lower facial height and the flèche lombaire, as well as the inner gonial angle and the trunk inclination. The craniofacial vertical growth pattern, presented by mandibular plane angle, inner gonial angle and the angular lower facial height, and the correlation to flèche cervicale and lombaire as well as trunk inclination reveal correlations between growth pattern and sagittal back contour.

  6. Sagittal back contour and craniofacial morphology in preadolescents

    PubMed Central

    Lippold, Carsten; Végh, András; Drerup, Burkhard; Moiseenko, Tatjana; Danesh, Gholamreza

    2009-01-01

    The aim of this study was to analyze the correlation ratios between the sagittal back contour (flèche cervicale and lombaire, trunk inclination) and selected parameters of craniofacial morphology in children. The patient sample consisted of 66 healthy children with a mean age of 11.2 years (SD 1.6 years), of which 34 were male (mean age 11.5 years, SD 1.3 years) and 32 were females (mean age 10.9 years, SD 1.9 years). The children were recruited during the preparation of the initial orthodontic treatment records. Craniofacial morphology was analyzed by six angular measurements: facial axis, mandibular plane angle, inner gonial angle, lower facial height, facial depth and maxilla position. Rasterstereography was used for reconstruction of the spinal back sagittal profile. From the profile flèche cervicale, flèche lombaire and trunk inclination were determined and the correlations with the craniofacial morphology were calculated (Pearson and Mann–Whitney U test). Significant correlations were found with respect to the inner gonial angle and the flèche cervicale, the mandibular plane angle and the flèche lombaire, the inner gonial angle and the flèche lombaire, and the angular lower facial height and the flèche lombaire, as well as the inner gonial angle and the trunk inclination. The craniofacial vertical growth pattern, presented by mandibular plane angle, inner gonial angle and the angular lower facial height, and the correlation to flèche cervicale and lombaire as well as trunk inclination reveal correlations between growth pattern and sagittal back contour. PMID:19946733

  7. Multimodality imaging for precise localization of craniofacial osteomyelitis.

    PubMed

    Strumas, Nick; Antonyshyn, Oleh; Caldwell, Curtis B; Mainprize, James

    2003-03-01

    Functional imaging identifies areas of abnormal bone turnover, providing a useful adjunct in the treatment of osteomyelitis and bone tumors. The low resolution and lack of anatomical detail limit the application of bone scans in craniofacial surgery, however. Multimodality image registration addresses this problem by fusing functional images (single photon emission computed tomography [SPECT]) to high-resolution structural images (computed tomography [CT]) for precise anatomical delineation of bone activity. This article describes a technique for spatial registration of CT and SPECT images to provide precise anatomical delineation of abnormal bone turnover, thereby guiding the extent of resection in the management of craniofacial osteomyelitis. Standard CT and SPECT imaging protocols were used in imaging the skull from the vertex to the mentum. Image data were imported into Analyze (Biomedical Imaging Resource; Mayo Foundation, Rochester, MN) on a dedicated Windows NT (Microsoft Corporation, Redmond, WA) workstation. Using the CT data, the craniofacial skeleton, osteotomy segments, and bone grafts were interactively mapped out. Consecutive axial slices were then reconstructed to form a three-dimensional volume of interest. The CT-derived volume of interest was registered to the technetium Tc 99m-methylene diphosphonate SPECT scan using the Analyze program to provide a fused multimodality image. The imaging technique was used to localize osteomyelitis in a complex craniofacial reconstruction. The fused images guided the extent of resection during surgery, and postoperative microbiological and histological testing confirmed the diagnosis. Multimodality image registration provides a readily available method to relate facial skeletal anatomy and physiology. This technique is valuable in planning and monitoring therapeutic interventions in clinical conditions in which bone turnover is abnormal.

  8. 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

  9. Association of Endogenous Retroviruses and Long Terminal Repeats with Human Disorders

    PubMed Central

    Katoh, Iyoko; Kurata, Shun-ichi

    2013-01-01

    Since the human genome sequences became available in 2001, our knowledge about the human transposable elements which comprise ∼40% of the total nucleotides has been expanding. Non-long terminal repeat (non-LTR) retrotransposons are actively transposing in the present-day human genome, and have been found to cause ∼100 identified clinical cases of varied disorders. In contrast, almost all of the human endogenous retroviruses (HERVs) originating from ancient infectious retroviruses lost their infectivity and transposing activity at various times before the human-chimpanzee speciation (∼6 million years ago), and no known HERV is presently infectious. Insertion of HERVs and mammalian apparent LTR retrotransposons (MaLRs) into the chromosomal DNA influenced a number of host genes in various modes during human evolution. Apart from the aspect of genome evolution, HERVs and solitary LTRs being suppressed in normal biological processes can potentially act as extra transcriptional apparatuses of cellular genes by re-activation in individuals. There has been a reasonable prediction that aberrant LTR activation could trigger malignant disorders and autoimmune responses if epigenetic changes including DNA hypomethylation occur in somatic cells. Evidence supporting this hypothesis has begun to emerge only recently: a MaLR family LTR activation in the pathogenesis of Hodgkin’s lymphoma and a HERV-E antigen expression in an anti-renal cell carcinoma immune response. This mini review addresses the impacts of the remnant-form LTR retrotransposons on human pathogenesis. PMID:24062987

  10. Injection of adjuvant but not acidic saline into craniofacial muscle evokes nociceptive behaviors and neuropeptide expression.

    PubMed

    Ambalavanar, R; Yallampalli, C; Yallampalli, U; Dessem, D

    2007-11-09

    Craniofacial muscle pain including muscular temporomandibular disorders accounts for a substantial portion of all pain perceived in the head and neck region. In spite of its high clinical prevalence, the mechanisms of chronic craniofacial muscle pain are not well understood. Injection of acidic saline into rodent hindlimb muscles produces pathologies which resemble muscular pathologies in chronic pain patients. Here we investigated whether analogous transformations occur following repeated injections of acidic saline into the rat masseter muscle. Injection of acidic saline (pH 4) into the masseter muscle transiently lowered i.m. pH to levels comparable to those reported for rodent hindlimb muscles. Nevertheless, repeated unilateral or bilateral injections of acidic saline (pH 4) into the masseter muscle failed to alter nociceptive behavioral responses as occurs in the hindlimb. Changing the pH of injected saline to pH 3.0 or 5.0 also did not evoke nocifensive behavior. Acid sensing ion channel 3 receptors, which are implicated in transformations following acidification of hindlimb muscles, were found on trigeminal ganglion muscle afferent neurons via combined neuronal tracing and immunocytochemistry. In contrast to the acidic saline, injection of complete Freund's adjuvant (CFA) into the masseter muscle induced mechanical allodynia for 3 weeks, thermal hyperalgesia for 1 week and an increase in the number of calcitonin gene-related peptide (CGRP)-immunoreactive muscle afferent neurons in the trigeminal ganglion. Although pH may alter CGRP release in primary afferent neurons, the number of CGRP-muscle afferent neurons did not change following i.m. injection of acidic saline. Further, there was no change in ganglionic iCGRP levels at 1, 4 or 12 days after i.m. injection of acidic saline. While these findings extend our earlier reports that CFA-induced muscle inflammation results in behavioral and neuropeptide changes they further suggest that i.m. acidification in

  11. Effect of prenatal alcohol exposure on bony craniofacial development: a mouse MicroCT study.

    PubMed

    Shen, Li; Ai, Huisi; Liang, Yun; Ren, Xiaowei; Anthony, Charles Bruce; Goodlett, Charles R; Ward, Richard; Zhou, Feng C

    2013-08-01

    Craniofacial bone dysmorphology is an important but under-explored potential diagnostic feature of fetal alcohol spectrum disorders. This study used longitudinal MicroCT 3D imaging to examine the effect of prenatal alcohol exposure on craniofacial bone growth in a mouse model. C57BL/6J dams were divided into 3 groups: alcohol 4.2% v/v in PMI® liquid diet (ALC), 2 weeks prior to and during pregnancy from embryonic (E) days 7-E16; pair-fed controls (PF), isocalorically matched to the ALC group; chow controls (CHOW), given ad libitum chow and water. The MicroCT scans were performed on pups on postnatal days 7 (P7) and P21. The volumes of the neurocranium (volume encased by the frontal, parietal, and occipital bones) and the viscerocranium (volume encased by the mandible and nasal bone), along with total skull bone volume, head size, and head circumference were evaluated using general linear models and discriminant analyses. The pups in the alcohol-treated group, when compared to the chow-fed controls (ALC vs CHOW) and the isocaloric-fed controls (ALC vs PF), showed differences in head size and circumference at P7 and P21, the total skull volume and parietal bone volume at P7, and volume of all the tested bones except nasal at P21. There was a growth trend of ALC < CHOW and ALC < PF. While covarying for gender and head size or circumference, the treatment affected the total skull and mandible at P7 (ALC > CHOW), and the total skull, parietal bone, and occipital bone at P21 (ALC < CHOW, ALC < PF). While covarying for the P7 measures, the treatment affected only the 3 neurocranial bones at P21 (ALC < CHOW, ALC < PF). Discriminant analysis sensitively selected between ALC and CHOW (AUC = 0.967), between ALC and PF (AUC = 0.995), and between PF and CHOW (AUC = 0.805). These results supported our hypothesis that craniofacial bones might be a reliable and sensitive indicator for the diagnosis of prenatal alcohol exposure. Significantly, we found that the neurocranium (upper

  12. 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.

  13. Endoscopic delivery of calcium phosphate cement for secondary craniofacial reconstruction.

    PubMed

    Francis, Cameron S; Wong, Ryan K; Cohen, Steven R

    2012-11-01

    Contour defects are common following primary craniofacial procedures including cranial vault remodeling, fronto-orbital and midface advancements, and complex posttraumatic reconstructions. When onlayed as fast-setting pastes, calcium phosphate cements (CPCs) have been used to effectively correct contour defects in open secondary reconstruction procedures. Here, we describe an endoscopic procedure using an injectable CPC and compare surgical outcomes with the open technique. A retrospective review was conducted for 36 consecutive patients aged 3.0-28.9 years (mean, 10.1 years) who underwent secondary craniofacial reconstruction over a 3-year period. Patients were stratified into endoscopic or open groups depending on the surgical approach utilized. Mean operative time was significantly shorter (P < 0.001) for the endoscopic group (64 minutes) than for the open group (131 minutes). Similarly, hospital stay was significantly shorter (P = 0.005) in the endoscopic group than in the open group. There was also a significant difference with respect to cost (P < 0.001), with the endoscopic approach resulting in a per-patient cost savings of $2208.05. In conclusion, endoscopic delivery of CPC appears to be a safe, efficacious, and cost-effective method of performing secondary craniofacial reconstruction, with the additional benefits of decreased operative time and shorter postoperative hospital stay when compared with an open procedure.

  14. Craniofacial sexual dimorphism patterns and allometry among extant hominids.

    PubMed

    Schaefer, Katrin; Mitteroecker, Philipp; Gunz, Philipp; Bernhard, Markus; Bookstein, Fred L

    2004-12-01

    Craniofacial sexual dimorphism in primates varies in both magnitude and pattern among species. In the past two decades, there has been an increasing emphasis in exploring the correlations of these patterns with taxonomy and the variation in patterns within and among the craniofacial regions. Scrutinising these relationships for hominids, we decompose the craniofacial morphology in five taxa: Homo sapiens, Pan paniscus, Pan troglodytes, Gorilla gorilla and Pongo pygmaeus. 3D coordinates of 35 traditional landmarks and 61 semilandmarks, covering five ridge curves, are measured for each of 268 adult and sub-adult specimens and analysed using geometric morphometric methods. A multivariate analysis in size-shape space shows that ontogenetic scaling contributes to the development of sexual dimorphism in all five taxa, but to a varying extent. In absolute as well as in relative terms P. pygmaeus shows the greatest allometric component, followed by G. gorilla. Homo is intermediate, while in Pan the non-allometric constituent part contributes a large fraction to the actual sexual dimorphism, most markedly in the pygmy chimpanzee. An eigendecomposition of the five vectors of sexual dimorphism reveals two dimensions independent of allometry. One separates orang-utan sexual dimorphism from the African apes and Homo, and the other differentiates between the great apes and Homo with Pan mediating. We discuss these patterns and speculate on their use as characters for taxonomic analysis in the fossil record.

  15. 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.

  16. 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.

  17. 78 FR 39740 - National Institute of Dental & Craniofacial Research; Notice of Closed Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-07-02

    ... applications. Place: National Institutes of Health, One Democracy Plaza, 6701 Democracy Boulevard, Bethesda, MD..., Scientific Review Branch, National Institute of Dental and Craniofacial Research, 6701 Democracy Blvd.,...

  18. Exploring the Underlying Genetics of Craniofacial Morphology through Various Sources of Knowledge

    PubMed Central

    Roosenboom, Jasmien; Hens, Greet; Mattern, Brooke C.; Shriver, Mark D.

    2016-01-01

    The craniofacial complex is the billboard of sorts containing information about sex, health, ancestry, kinship, genes, and environment. A thorough knowledge of the genes underlying craniofacial morphology is fundamental to understanding craniofacial biology and evolution. These genes can also provide an important foundation for practical efforts like predicting faces from DNA and phenotype-based facial diagnostics. In this work, we focus on the various sources of knowledge regarding the genes that affect patterns of craniofacial development. Although tremendous successes recently have been made using these sources in both methodology and biology, many challenges remain. Primary among these are precise phenotyping techniques and efficient modeling methods. PMID:28053980

  19. 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.

  20. Using human-induced pluripotent stem cells to model monogenic metabolic disorders of the liver.

    PubMed

    Ordonez, Maria Paulina; Goldstein, Lawrence S B

    2012-11-01

    A crucial problem in liver disease biology and a major obstacle to the development of new therapies is the inability to conduct mechanistic studies of live human hepatocytes. Liver tissue from patients is difficult to obtain and only reveals the disease aftermath, while animal models lack the significant genetic diversity of humans. Monogenic metabolic disorders of the liver are an ideal platform to explore the complex gene-environment interactions and the role of genetic variation in the onset and progression of liver disease. Human induced pluripotent stem cell (hIPSC) technology provides an unprecedented opportunity to generate live cellular models of disease for therapeutic candidate discovery and cell replacement therapy. In this review, we discuss the potential of hIPSC to increase our understanding of human disease with a focus on the current efforts to model metabolic diseases of the liver and to generate suitable populations of human hepatocytes for cell transplantation.

  1. 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

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

    PubMed Central

    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.

    2014-01-01

    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-Rag1null IL2rγnull 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

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

    PubMed

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

    2015-10-27

    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.

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

    PubMed

    Sabbagh, Ubadah; 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.

  5. 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

  6. Comprehensive DNA methylation and hydroxymethylation analysis in the human brain and its implication in mental disorders.

    PubMed

    Kato, Tadafumi; Iwamoto, Kazuya

    2014-05-01

    Covalent modifications of nucleotides, such as methylation or hydroxymethylation of cytosine, regulate gene expression. Early environmental risk factors play a role in mental disorders in adulthood. This may be in part mediated by epigenetic DNA modifications. Methods for comprehensive analysis of DNA methylation and hydroxymethylation include DNA modification methods such as bisulfite sequencing, or collection of methylated, hydroxymethylated, or unmethylated DNA by specific binding proteins, antibodies, or restriction enzymes, followed by sequencing or microarray analysis. Results from these experiments should be interpreted with caution because each method gives different result. Cytosine hydroxymethylation has different effects on gene expression than cytosine methylation; methylation of CpG islands is associated with lower gene expression, whereas hydroxymethylation in intragenic regions is associated with higher gene expression. The role of hydroxymethylcytosine is of particular interest in mental disorders because the modification is enriched in the brain and synapse related genes, and it exhibits dynamic regulation during development. Many DNA methylation patterns are conserved across species, but there are also human specific signatures. Comprehensive analysis of DNA methylation shows characteristic changes associated with tissues, brain regions, cell types, and developmental states. Thus, differences in DNA methylation status between tissues, brain regions, cell types, and developmental stages should be considered when the role of DNA methylation in mental disorders is studied. Several disease-associated changes in methylation have been reported: hypermethylation of SOX10 in schizophrenia, hypomethylation of HCG9 (HLA complex group 9) in bipolar disorder, hypermethylation of PRIMA1, hypermethylation of SLC6A4 (serotonin transporter) in bipolar disorder, and hypomethylation of ST6GALNAC1 in bipolar disorder. These findings need to be replicated in

  7. Progress and challenges in using human stem cells for biological and therapeutics discovery: neuropsychiatric disorders

    PubMed Central

    Panchision, David M.

    2016-01-01

    In facing the daunting challenge of using human embryonic and induced pluripotent stem cells (hESCs, hiPSCs) to study complex neural circuit disorders such as schizophrenia (SCZ), mood and anxiety disorders and autism spectrum disorders (ASDs), 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. PMID:26840228

  8. Current Applications of Chromatographic Methods in the Study of Human Body Fluids for Diagnosing Disorders.

    PubMed

    Jóźwik, Jagoda; Kałużna-Czaplińska, Joanna

    2016-01-01

    Currently, analysis of various human body fluids is one of the most essential and promising approaches to enable the discovery of biomarkers or pathophysiological mechanisms for disorders and diseases. Analysis of these fluids is challenging due to their complex composition and unique characteristics. Development of new analytical methods in this field has made it possible to analyze body fluids with higher selectivity, sensitivity, and precision. The composition and concentration of analytes in body fluids are most often determined by chromatography-based techniques. There is no doubt that proper use of knowledge that comes from a better understanding of the role of body fluids requires the cooperation of scientists of diverse specializations, including analytical chemists, biologists, and physicians. This article summarizes current knowledge about the application of different chromatographic methods in analyses of a wide range of compounds in human body fluids in order to diagnose certain diseases and disorders.

  9. Epigenetic regulation of UBE3A and roles in human neurodevelopmental disorders

    PubMed Central

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

    2015-01-01

    The E3 ubiquitin ligase 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

  10. 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.

  11. 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.

  12. Regional isolation in the Balkan region: an analysis of craniofacial variation.

    PubMed

    Ross, Ann H

    2004-05-01

    Biological variation is investigated among contemporary Croatians, Bosnians, American whites, and other multitemporal Balkan populations (World War II Croatians, Macedonians, and Greeks) via multivariate statistics and distance measures of the craniofacial complex. This study demonstrates that there is considerable variation among groups of European ancestry. Bosnians and Croatians who are thought to be relatively homogenous and historically to originate from the same Slav ancestry show local variations. While environmental plasticity has been used to explain cranial changes among human groups, it does not adequately explain the variation observed between Bosnians and Croatians. It is an oversimplification to exclusively attribute the vast range of variability observed among local as well as geographic populations to environmental adaptations.

  13. In vitro quantification of strain patterns in the craniofacial skeleton due to masseter and temporalis activities.

    PubMed

    Maloul, Asmaa; Regev, Eran; Whyne, Cari M; Beek, Marteen; Fialkov, Jeffrey A

    2012-09-01

    Many complications in craniofacial surgery can be attributed to a lack of characterization of facial skeletal strain patterns. This study aimed to delineate human midfacial strain patterns under uniform muscle loading. The left sides of 5 fresh-frozen human cadaveric heads were dissected of all soft tissues except the temporalis and masseter muscles. Tensile forces were applied to the free mandibular ends of the muscles. Maxillary alveolar arches were used to restrain the skulls. Eight strain gauges were bonded to the surface of the midface to measure the strain under single muscle loading conditions (100 N). Maxillary strain gauges revealed a biaxial load state for both muscles. Thin antral bone experienced high maximum principal tensile strains (maximum of 685.5 με) and high minimum principal compressive strains (maximum of -722.44 με). Similar biaxial patterns of lower magnitude were measured on the zygoma (maximum of 208.59 με for maximum principal strains and -78.11 με for minimum principal strains). Results, consistent for all specimens and counter to previously accepted concepts of biomechanical behavior of the midface under masticatory muscle loading, included high strain in the thin maxillary antral wall, rotational bending through the maxilla and zygoma, and a previously underestimated contribution of the temporalis muscle. This experimental model produced repeatable strain patterns quantifying the mechanics of the facial skeleton. These new counterintuitive findings underscore the need for accurate characterization of craniofacial strain patterns to address problems in the current treatment methods and develop robust design criteria.

  14. 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

  15. 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

  16. Psychological profile and self-administered relaxation in patients with craniofacial pain: a prospective in-office study

    PubMed Central

    2013-01-01

    Introduction The objective of this study was to evaluate the psychological profile of craniofacial pain sufferers and the impact of patient subtype classification on the short-time effectiveness of a self-administered relaxation training. Methods One hundred unselected in-office patients (67% females) suffering from chronic facial pain and/or headache with the presumptive diagnose of temporo-mandibular disorder (TMD) completed a questionnaire battery comprising craniofacial pain perception, somatic complaints, irrational beliefs, and pain behavior and were classified into subtypes using cluster analysis. They underwent a self-administered progressive relaxation training and were re-evaluated for pain perception after 3 months. Results Pain was mild to moderate in the majority of patients. Symptom domains comprised parafunctional activities, temporo-mandibular pain and dysfunction, fronto-temporal headache, head/neck and neck/back pain. Three patient subtypes were identified regarding symptom/dysfunction level: (i) low burden (mild/moderate), (ii) psychosocial dysfunction (moderate/high), (iii) adaptive coping (moderate/mild). Self-rated adherence to the recommended relaxation training was moderate throughout the sample, but self-rated relief was significantly different between clusters. At follow-up, pain intensity was significantly decreased in all patients, whereas pain-related interference was improved only in dysfunctional and adaptive patients. Improvement of symptom domains varied between clusters and was most comprehensive in adaptive patients. Conclusions In conclusion, craniofacial pain sufferers can be divided in meaningful subtypes based on their pain perception, irrational beliefs, and pain behaviour. A self-administered relaxation training generally yielded positive effects on pain perception, however the benefit may be greater in patients with more marked symptom impact (both dysfunctional and adaptive). PMID:24382096

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

    PubMed Central

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

    2015-01-01

    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

  18. 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.

  19. 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

  20. Coexistence of 9p Deletion Syndrome and Autism Spectrum Disorder

    ERIC Educational Resources Information Center

    Günes, Serkan; Ekinci, Özalp; Ekinci, Nuran; Toros, Fevziye

    2017-01-01

    Deletion or duplication of the short arm of chromosome 9 may lead to a variety of clinical conditions including craniofacial and limb abnormalities, skeletal malformations, mental retardation, and autism spectrum disorder. Here, we present a case report of 5-year-old boy with 9p deletion syndrome and autism spectrum disorder.

  1. Efficient and versatile CRISPR engineering of human neurons in culture to model neurological disorders.

    PubMed

    Shah, Ruth R; Cholewa-Waclaw, Justyna; Davies, Faith C J; Paton, Katie M; Chaligne, Ronan; Heard, Edith; Abbott, Catherine M; Bird, Adrian P

    2016-11-15

    The recent identification of multiple new genetic causes of neurological disorders highlights the need for model systems that give experimental access to the underlying biology. In particular, the ability to couple disease-causing mutations with human neuronal differentiation systems would be beneficial. Gene targeting is a well-known approach for dissecting gene function, but low rates of homologous recombination in somatic cells (including neuronal cells) have traditionally impeded the development of robust cellular models of neurological disorders. Recently, however, CRISPR/Cas9 gene editing technologies have expanded the number of systems within which gene targeting is possible. Here we adopt as a model system LUHMES cells, a commercially available diploid human female mesencephalic cell line that differentiates into homogeneous mature neurons in 1-2 weeks. We describe optimised methods for transfection and selection of neuronal progenitor cells carrying targeted genomic alterations using CRISPR/Cas9 technology. By targeting the endogenous X-linked MECP2 locus, we introduced four independent missense mutations that cause the autism spectrum disorder Rett syndrome and observed the desired genetic structure in 3-26% of selected clones, including gene targeting of the inactive X chromosome. Similar efficiencies were achieved by introducing neurodevelopmental disorder-causing mutations at the autosomal EEF1A2 locus on chromosome 20. Our results indicate that efficiency of genetic "knock-in" is determined by the location of the mutation within the donor DNA molecule. Furthermore, we successfully introduced an mCherry tag at the MECP2 locus to yield a fusion protein, demonstrating that larger insertions are also straightforward in this system. We suggest that our optimised methods for altering the genome of LUHMES cells make them an attractive model for the study of neurogenetic disorders.

  2. Efficient and versatile CRISPR engineering of human neurons in culture to model neurological disorders

    PubMed Central

    2016-01-01

    The recent identification of multiple new genetic causes of neurological disorders highlights the need for model systems that give experimental access to the underlying biology. In particular, the ability to couple disease-causing mutations with human neuronal differentiation systems would be beneficial. Gene targeting is a well-known approach for dissecting gene function, but low rates of homologous recombination in somatic cells (including neuronal cells) have traditionally impeded the development of robust cellular models of neurological disorders. Recently, however, CRISPR/Cas9 gene editing technologies have expanded the number of systems within which gene targeting is possible. Here we adopt as a model system LUHMES cells, a commercially available diploid human female mesencephalic cell line that differentiates into homogeneous mature neurons in 1-2 weeks. We describe optimised methods for transfection and selection of neuronal progenitor cells carrying targeted genomic alterations using CRISPR/Cas9 technology. By targeting the endogenous X-linked MECP2 locus, we introduced four independent missense mutations that cause the autism spectrum disorder Rett syndrome and observed the desired genetic structure in 3-26% of selected clones, including gene targeting of the inactive X chromosome. Similar efficiencies were achieved by introducing neurodevelopmental disorder-causing mutations at the autosomal EEF1A2 locus on chromosome 20. Our results indicate that efficiency of genetic “knock-in” is determined by the location of the mutation within the donor DNA molecule. Furthermore, we successfully introduced an mCherry tag at the MECP2 locus to yield a fusion protein, demonstrating that larger insertions are also straightforward in this system. We suggest that our optimised methods for altering the genome of LUHMES cells make them an attractive model for the study of neurogenetic disorders. PMID:27976757

  3. 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.

  4. Genomic Regions Associated With Interspecies Communication in Dogs Contain Genes Related to Human Social Disorders

    PubMed Central

    Persson, Mia E.; Wright, Dominic; Roth, Lina S. V.; Batakis, Petros; Jensen, Per

    2016-01-01

    Unlike their wolf ancestors, dogs have unique social skills for communicating and cooperating with humans. Previously, significant heritabilities for human-directed social behaviors have been found in laboratory beagles. Here, a Genome-Wide Association Study identified two genomic regions associated with dog’s human-directed social behaviors. We recorded the propensity of laboratory beagles, bred, kept and handled under standardized conditions, to initiate physical interactions with a human during an unsolvable problem-task, and 190 individuals were genotyped with an HD Canine SNP-chip. One genetic marker on chromosome 26 within the SEZ6L gene was significantly associated with time spent close to, and in physical contact with, the human. Two suggestive markers on chromosome 26, located within the ARVCF gene, were also associated with human contact seeking. Strikingly, four additional genes present in the same linkage blocks affect social abilities in humans, e.g., SEZ6L has been associated with autism and COMT affects aggression in adolescents with ADHD. This is, to our knowledge, the first genome-wide study presenting candidate genomic regions for dog sociability and inter-species communication. These results advance our understanding of dog domestication and raise the use of the dog as a novel model system for human social disorders. PMID:27685260

  5. Genomic Regions Associated With Interspecies Communication in Dogs Contain Genes Related to Human Social Disorders.

    PubMed

    Persson, Mia E; Wright, Dominic; Roth, Lina S V; Batakis, Petros; Jensen, Per

    2016-09-29

    Unlike their wolf ancestors, dogs have unique social skills for communicating and cooperating with humans. Previously, significant heritabilities for human-directed social behaviors have been found in laboratory beagles. Here, a Genome-Wide Association Study identified two genomic regions associated with dog's human-directed social behaviors. We recorded the propensity of laboratory beagles, bred, kept and handled under standardized conditions, to initiate physical interactions with a human during an unsolvable problem-task, and 190 individuals were genotyped with an HD Canine SNP-chip. One genetic marker on chromosome 26 within the SEZ6L gene was significantly associated with time spent close to, and in physical contact with, the human. Two suggestive markers on chromosome 26, located within the ARVCF gene, were also associated with human contact seeking. Strikingly, four additional genes present in the same linkage blocks affect social abilities in humans, e.g., SEZ6L has been associated with autism and COMT affects aggression in adolescents with ADHD. This is, to our knowledge, the first genome-wide study presenting candidate genomic regions for dog sociability and inter-species communication. These results advance our understanding of dog domestication and raise the use of the dog as a novel model system for human social disorders.

  6. 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

  7. Defective Craniofacial Development and Brain Function in a Mouse Model for Depletion of Intracellular Inositol Synthesis*

    PubMed Central

    Ohnishi, Tetsuo; Murata, Takuya; Watanabe, Akiko; Hida, Akiko; Ohba, Hisako; Iwayama, Yoshimi; Mishima, Kazuo; Gondo, Yoichi; Yoshikawa, Takeo

    2014-01-01

    myo-Inositol is an essential biomolecule that is synthesized by myo-inositol monophosphatase (IMPase) from inositol monophosphate species. The enzymatic activity of IMPase is inhibited by lithium, a drug used for the treatment of mood swings seen in bipolar disorder. Therefore, myo-inositol is thought to have an important role in the mechanism of bipolar disorder, although the details remain elusive. We screened an ethyl nitrosourea mutant mouse library for IMPase gene (Impa) mutations and identified an Impa1 T95K missense mutation. The mutant protein possessed undetectable enzymatic activity. Homozygotes died perinatally, and E18.5 embryos exhibited striking developmental defects, including hypoplasia of the mandible and asymmetric fusion of ribs to the sternum. Perinatal lethality and morphological defects in homozygotes were rescued by dietary myo-inositol. Rescued homozygotes raised on normal drinking water after weaning exhibited a hyper-locomotive trait and prolonged circadian periods, as reported in rodents treated with lithium. Our mice should be advantageous, compared with those generated by the conventional gene knock-out strategy, because they carry minimal genomic damage, e.g. a point mutation. In conclusion, our results reveal critical roles for intracellular myo-inositol synthesis in craniofacial development and the maintenance of proper brain function. Furthermore, this mouse model for cellular inositol depletion could be beneficial for understanding the molecular mechanisms underlying the clinical effect of lithium and myo-inositol-mediated skeletal development. PMID:24554717

  8. 75 FR 26762 - National Institute of Dental & Craniofacial Research; Notice of Closed Meetings

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-05-12

    ... Institute of Dental & Craniofacial Research; Notice of Closed Meetings Pursuant to section 10(d) of the... disclose confidential trade secrets or commercial property such as patentable material, and personal... Institute of Dental and Craniofacial Research Special Emphasis Panel; RFA (DE-10-003). Date: June 7,...

  9. The serotonergic anatomy of the developing human medulla oblongata: implications for pediatric disorders of homeostasis.

    PubMed

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

    2011-07-01

    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.

  10. The pathological consequences of impaired genome integrity in humans; disorders of the DNA replication machinery.

    PubMed

    O'Driscoll, Mark

    2017-01-01

    Accurate and efficient replication of the human genome occurs in the context of an array of constitutional barriers, including regional topological constraints imposed by chromatin architecture and processes such as transcription, catenation of the helical polymer and spontaneously generated DNA lesions, including base modifications and strand breaks. DNA replication is fundamentally important for tissue development and homeostasis; differentiation programmes are intimately linked with stem cell division. Unsurprisingly, impairments of the DNA replication machinery can have catastrophic consequences for genome stability and cell division. Functional impacts on DNA replication and genome stability have long been known to play roles in malignant transformation through a variety of complex mechanisms, and significant further insights have been gained from studying model organisms in this context. Congenital hypomorphic defects in components of the DNA replication machinery have been and continue to be identified in humans. These disorders present with a wide range of clinical features. Indeed, in some instances, different mutations in the same gene underlie different clinical presentations. Understanding the origin and molecular basis of these features opens a window onto the range of developmental impacts of suboptimal DNA replication and genome instability in humans. Here, I will briefly overview the basic steps involved in DNA replication and the key concepts that have emerged from this area of research, before switching emphasis to the pathological consequences of defects within the DNA replication network; the human disorders. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  11. 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

  12. 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

  13. Blepharocheilodontic (BCD) syndrome: New insights on craniofacial and dental features.

    PubMed

    Awadh, Wael; Kiukkonen, Anu; Nieminen, Pekka; Arte, Sirpa; Hurmerinta, Kirsti; Rice, David P

    2017-04-01

    Blepharocheilodontic (BCD) syndrome is a rare condition characterized by bilateral cleft lip and palate (BCLP), eyelid abnormalities, and oligodontia. Despite orofacial clefting and oligodontia being central features of the condition, detailed reports of dental and craniofacial characteristics are scarce. The aim of this study was to analyze the dental and craniofacial features in a group of patients with BCD syndrome (three of which were related). Cephalometric radiographic analyses were performed on BCD syndrome patients (all radiographs taken at age 8 years) and compared to 40 randomly selected age-matched controls (20 non-syndromic BCLP, 20 non-cleft). Also, we assessed clinical records, photographs, dental study casts, and dental radiographs to determine the extent and pattern of tooth agenesis, dental morphology and malocclusion. BCD syndrome patients showed a very severe skeletal III malocclusion (maxillary-mandibular sagittal discrepancy) and reduced anterior lower face measurement compared to non-syndromic BCLP and non-cleft controls (P = 0.001, P = 0.027). All patients exhibited oligodontia (mean number of missing permanent teeth 13.7, range 7-17). All patients exhibited missing upper central and lateral incisor, upper canine and premolar teeth. Variations in dental morphology included taurodontism, conical-shaped teeth, and notching of the incisal edges. All patients had a short and narrow maxilla which translated into anterior and posterior cross bites. We conclude that, in our BCD syndrome group, the craniofacial skeletal defects are more severe than patients with BCLP. The pattern of tooth agenesis is unusual as it included teeth that are normally highly resistant to agenesis, namely upper central incisor and canine teeth. © 2017 Wiley Periodicals, Inc.

  14. 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

  15. 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

  16. Dopamine Transporter Gene Variant Affecting Expression in Human Brain is Associated with Bipolar Disorder

    PubMed Central

    Pinsonneault, Julia K; Han, Dawn D; Burdick, Katherine E; Kataki, Maria; Bertolino, Alessandro; Malhotra, Anil K; Gu, Howard H; Sadee, Wolfgang

    2011-01-01

    The gene encoding the dopamine transporter (DAT) has been implicated in CNS disorders, but the responsible polymorphisms remain uncertain. To search for regulatory polymorphisms, we measured allelic DAT mRNA expression in substantia nigra of human autopsy brain tissues, using two marker SNPs (rs6347 in exon 9 and rs27072 in the 3′-UTR). Allelic mRNA expression imbalance (AEI), an indicator of cis-acting regulatory polymorphisms, was observed in all tissues heterozygous for either of the two marker SNPs. SNP scanning of the DAT locus with AEI ratios as the phenotype, followed by in vitro molecular genetics studies, demonstrated that rs27072 C>T affects mRNA expression and translation. Expression of the minor T allele was dynamically regulated in transfected cell cultures, possibly involving microRNA interactions. Both rs6347 and rs3836790 (intron8 5/6 VNTR) also seemed to affect DAT expression, but not the commonly tested 9/10 VNTR in the 3′UTR (rs28363170). All four polymorphisms (rs6347, intron8 5/6 VNTR, rs27072 and 3′UTR 9/10 VNTR) were genotyped in clinical cohorts, representing schizophrenia, bipolar disorder, depression, and controls. Only rs27072 was significantly associated with bipolar disorder (OR=2.1, p=0.03). This result was replicated in a second bipolar/control population (OR=1.65, p=0.01), supporting a critical role for DAT regulation in bipolar disorder. PMID:21525861

  17. 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

  18. 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.

  19. Genome engineering of isogenic human ES cells to model autism disorders

    PubMed Central

    Martinez, Refugio A.; Stein, Jason L.; Krostag, Anne-Rachel F.; Nelson, Angelique M.; Marken, John S.; Menon, Vilas; May, Ryan C.; Yao, Zizhen; Kaykas, Ajamete; Geschwind, Daniel H.; Grimley, Joshua S.

    2015-01-01

    Isogenic pluripotent stem cells are critical tools for studying human neurological diseases by allowing one to study the effects of a mutation in a fixed genetic background. Of particular interest are the spectrum of autism disorders, some of which are monogenic such as Timothy syndrome (TS); others are multigenic such as the microdeletion and microduplication syndromes of the 16p11.2 chromosomal locus. Here, we report engineered human embryonic stem cell (hESC) lines for modeling these two disorders using locus-specific endonucleases to increase the efficiency of homology-directed repair (HDR). We developed a system to: (1) computationally identify unique transcription activator-like effector nuclease (TALEN) binding sites in the genome using a new software program, TALENSeek, (2) assemble the TALEN genes by combining golden gate cloning with modified constructs from the FLASH protocol, and (3) test the TALEN pairs in an amplification-based HDR assay that is more sensitive than the typical non-homologous end joining assay. We applied these methods to identify, construct, and test TALENs that were used with HDR donors in hESCs to generate an isogenic TS cell line in a scarless manner and to model the 16p11.2 copy number disorder without modifying genomic loci with high sequence similarity. PMID:25765640

  20. 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

  1. 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.

  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. Midfacial and Dental Changes Associated with Nasal Positive Airway Pressure in Children with Obstructive Sleep Apnea and Craniofacial Conditions

    PubMed Central

    Roberts, Soleil D.; Kapadia, Hitesh; Greenlee, Geoff; Chen, Maida L.

    2016-01-01

    Study Objectives: Nasal positive airway pressure (nPAP) for treatment of pediatric obstructive sleep apnea (OSA) is a widespread therapy that currently lacks longitudinal data describing how mask pressure impacts the developing facial skeleton. This retrospective cohort study compared midfacial growth in pediatric patients with underlying craniofacial conditions diagnosed with OSA who were compliant vs. noncompliant with nPAP therapy, and explored correlations between demographic, medical, and sleep variables with annual rate of facial change. Methods: Records from Seattle Children's Hospital's Craniofacial Center and Sleep Disorders Center were reviewed to identify patients prescribed nPAP for OSA with serial cephalographic images obtained during routine clinical care for concomitant craniofacial diagnosis. Lateral cephalometric analysis was used to determine mean annual change in midfacial structures from T1 (pre-nPAP) to T2 (post-nPAP) in compliant vs. noncompliant subjects. Compliance was indicated by nPAP usage of > 20 h/week for > 6 months. Results: 50 subjects were compliant with nPAP therapy (mean age 10.42 years) for an average of 2.57 years, and 50 subjects were noncompliant (mean age 8.53 years). Compliant subjects experienced negative mean annual change (retrusion) of the midface compared to forward growth seen in noncompliant subjects (SNA: −0.57° vs. 0.56°), counterclockwise rotation of palatal plane (SN-PP: −1.15° vs. 0.09°), and upper incisor flaring (U1-SN: 2.41° vs. −0.51°). Conclusions: Pressure to the midface from compliant nPAP use may alter normal facial growth. Cephalometric findings indicate a greater need for collaboration between sleep medicine physicians and orthodontists to monitor midfacial growth during nPAP treatment. Citation: Roberts SD, Kapadia H, Greenlee G, Chen ML. Midfacial and dental changes associated with nasal positive airway pressure in children with obstructive sleep apnea and craniofacial conditions. J Clin

  4. The Future in Craniofacial Surgery: Computer-Assisted Planning

    PubMed Central

    Schendel, Stephen A.; Hazan-Molina, Hagai; Rachmiel, Adi; Aizenbud, Dror

    2012-01-01

    Advancements in computers, prototyping, and imaging, especially over the last 10 years, have permitted the adoption of three-dimensional imaging protocols in the health care field. In this article, the authors present an integrated simulation system for craniofacial surgical planning and treatment. Image fusion technology, which involves combining different imaging modalities, was utilized to create a realistic prototype and virtual image that can be manipulated in real time. The resultant data can then be shared over the Internet with distantly located practitioners. PMID:23908836

  5. A Tbx1-Six1/Eya1-Fgf8 genetic pathway controls mammalian cardiovascular and craniofacial morphogenesis.

    PubMed

    Guo, Chaoshe; Sun, Ye; Zhou, Bin; Adam, Rosalyn M; Li, XiaoKun; Pu, William T; Morrow, Bernice E; Moon, Anne; Li, Xue

    2011-04-01

    Shared molecular programs govern the formation of heart and head during mammalian embryogenesis. Development of both structures is disrupted in human chromosomal microdeletion of 22q11.2 (del22q11), which causes DiGeorge syndrome (DGS) and velo-cardio-facial syndrome (VCFS). Here, we have identified a genetic pathway involving the Six1/Eya1 transcription complex that regulates cardiovascular and craniofacial development. We demonstrate that murine mutation of both Six1 and Eya1 recapitulated most features of human del22q11 syndromes, including craniofacial, cardiac outflow tract, and aortic arch malformations. The mutant phenotypes were attributable in part to a reduction of fibroblast growth factor 8 (Fgf8), which was shown to be a direct downstream effector of Six1 and Eya1. Furthermore, we showed that Six1 and Eya1 genetically interacted with Fgf8 and the critical del22q11 gene T-box transcription factor 1 (Tbx1) in mice. Together, these findings reveal a Tbx1-Six1/Eya1-Fgf8 genetic pathway that is crucial for mammalian cardiocraniofacial morphogenesis and provide insights into the pathogenesis of human del22q11 syndromes.

  6. Skeletal dysplasia with craniofacial deformity and disproportionate dwarfism in hair sheep of northeastern Brazil.

    PubMed

    Dantas, F P M; Medeiros, G X; Figueiredo, A P M; Thompson, K; Riet-Correa, F

    2014-01-01

    This paper reports a newly described form of skeletal dysplasia affecting Brazilian hair sheep of the Cabugi breed. This breed is characterized by having a short head and in some cases the animals are smaller and more compact than sheep of similar breeds. Lambs born with craniofacial abnormalities and dwarfism that die at 2-6 months of age are frequent in this breed. In a flock of 68 ewes and three rams of the Cabugi breed, 134 lambs were born over a 4-year period. Of these, 14 (10.4%) had marked cranial abnormalities and dwarfism and died or were humanely destroyed, 43 (32%) had a normal face and 77 (57.5%) had the short face characteristic of the breed. Dwarf lambs were much smaller than normal, with short legs, a domed head with retruded muzzle and protruded mandible, sternal deformities and exophthalmic eyes situated more laterally in the face than normal. Microscopical examination of long bones of the limbs, bones of the base of the skull and vertebrae showed no lesions. Bones from four affected lambs and one control lamb were macerated for morphometric examination. Although the length of the spinal cord was similar, there was disproportionate shortening of the appendicular bones, particularly the distal segments. Thus the disease was defined as a skeletal dysplasia characterized by craniofacial deformity and disproportionate dwarfism. It is suggested that the disease is inherited as an incomplete dominant trait. The shortened face, which is a feature of the Cabugi breed, may represent the heterozygous state and the more severe, often lethal, dwarfism may occur in homozygotes.

  7. 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

  8. 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.

  9. 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.

  10. Shape-based classification of 3D facial data to support 22q11.2DS craniofacial research.

    PubMed

    Wilamowska, Katarzyna; Wu, Jia; Heike, Carrie; Shapiro, Linda

    2012-06-01

    3D imaging systems are used to construct high-resolution meshes of patient's heads that can be analyzed by computer algorithms. Our work starts with such 3D head meshes and produces both global and local descriptors of 3D shape. Since these descriptors are numeric feature vectors, they can be used in both classification and quantification of various different abnormalities. In this paper, we define these descriptors, describe our methodology for constructing them from 3D head meshes, and show through a set of classification experiments involving cases and controls for a genetic disorder called 22q11.2 deletion syndrome that they are suitable for use in craniofacial research studies. The main contributions of this work include: automatic generation of novel global and local data representations, robust automatic placement of anthropometric landmarks, generation of local descriptors for nasal and oral facial features from landmarks, use of local descriptors for predicting various local facial features, and use of global features for 22q11.2DS classification, showing their potential use as descriptors in craniofacial research.

  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. 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

  14. 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

  15. 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.

  16. Craniofacial and dental phenotype of Smith-Magenis syndrome.

    PubMed

    Tomona, Natalia; Smith, Ann C M; Guadagnini, Jean Pierre; Hart, Thomas C

    2006-12-01

    The aim of this study was to assess and characterize dental and craniofacial findings in individuals with a confirmed diagnosis of Smith-Magenis syndrome (SMS). Extraoral and intraoral examination including dental and craniofacial radiographs and three-dimensional facial photoimaging were performed for 15 cases between ages 4 and 19 years old. Tooth agenesis (13/15 cases) affecting primarily the mandibular second premolars and taurodontism (13/15 cases) were common findings. Dilaceration of the tooth roots was present in one-third of the cases. At least one dental anomaly was present in each case. These findings occur with greater frequency than in the general population (P < 0.001). An age-related increase in decayed and restored teeth was found. Poorer oral hygiene, increased dental plaque, and increased gingival inflammation progressed from childhood to teenage years. Radiographic findings suggest the prognathic appearance is not caused by excessive mandibular growth. Other findings including protrusion of the mandibular anterior teeth, increased bony chin size, and macroglossia were noted, which may contribute to the prognathic appearance. The high prevalence of dental anomalies (>90%) further expands the phenotype and indicates that dental evaluation may aid in the diagnosis of SMS.

  17. 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

  18. Craniofacial morphologic parameters in a Persian population: an anthropometric study.

    PubMed

    Amini, Fariborz; Mashayekhi, Ziba; Rahimi, Hajir; Morad, Golnaz

    2014-09-01

    Limited data are available regarding the reference ranges of facial proportions of the Persian population in Iran. This study aimed to establish the reference range of craniofacial anthropometric measurements in an adult Iranian population. On 100 individuals (men = women), aged 18 to 30 years with normal faces and occlusions, 34 linear and 7 angular measurements as well as 24 indices were calculated. The difference of measurements between men and women were evaluated by paired t-test. The data were compared with the norms of North American whites using 1-sample t-test. The subjects belonged to 5 ethnic groups (57% from Fars, 14% from Kord, 11% from Azari, 10% from Gilaki-Mazani, and 2% from Lor). All head measurements were greater in men except for the head index and the head height. The subjects had leptoprosopic faces. The intercanthal width was almost one third of the biocular width and greater than the eye fissure length. Although the nose width of women was significantly smaller, both sexes had leptorrhine noses. The chin height and lower chin height were greater in men. In comparison with North American whites, considerable differences were found regarding head height and width, biocular width, nose height, face height, mouth width, and upper chin height. In conclusion, the reference range of craniofacial anthropometric measurements established for the Iranian population might be efficiently used for esthetic treatments.

  19. 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.

  20. Craniofacial development in marsupial mammals: developmental origins of evolutionary change.

    PubMed

    Smith, Kathleen K

    2006-05-01

    Biologists have long studied the evolutionary consequences of the differences in reproductive and life history strategies of marsupial and eutherian mammals. Over the past few decades, the impact of these strategies on the development of the marsupial embryo and neonate has received attention. In this review, the differences in development in the craniofacial region in marsupial and eutherian mammals will be discussed. The review will highlight differences at the organogenic and cellular levels, and discuss hypotheses for shifts in the expression of important regulatory genes. The major difference in the organogenic period is a whole-scale shift in the relative timing of central nervous system structures, in particular those of the forebrain, which are delayed in marsupials, relative to the structures of the oral-facial apparatus. Correlated with the delay in development of nervous system structures, the ossification of the bones of the neurocranium are delayed, while those of the face are accelerated. This study will also review work showing that the neural crest, which provides much of the cellular material to the facial skeleton and may also carry important patterning information, is notably accelerated in its development in marsupials. Potential consequences of these observations for hypotheses on constraint, evolutionary integration, and the existence of developmental modules is discussed. Finally, the implications of these results for hypotheses on the genetic modulation of craniofacial patterning are presented.

  1. 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.

  2. SHOT, a SHOX-related homeobox gene, is implicated in craniofacial, brain, heart, and limb development.

    PubMed

    Blaschke, R J; Monaghan, A P; Schiller, S; Schechinger, B; Rao, E; Padilla-Nash, H; Ried, T; Rappold, G A

    1998-03-03

    Deletion of the SHOX region on the human sex chromosomes has been shown to result in idiopathic short stature and proposed to play a role in the short stature associated with Turner syndrome. We have identified a human paired-related homeobox gene, SHOT, by virtue of its homology to the human SHOX and mouse OG-12 genes. Two different isoforms were isolated, SHOTa and SHOTb, which have identical homeodomains and share a C-terminal 14-amino acid residue motif characteristic for craniofacially expressed homeodomain proteins. Differences between SHOTa and b reside within the N termini and an alternatively spliced exon in the C termini. In situ hybridization of the mouse equivalent, OG-12, on sections from staged mouse embryos detected highly restricted transcripts in the developing sinus venosus (aorta), female genitalia, diencephalon, mes- and myelencephalon, nasal capsula, palate, eyelid, and in the limbs. SHOT was mapped to human chromosome 3q25-q26 and OG-12 within a syntenic region on chromosome 3. Based on the localization and expression pattern of its mouse homologue during embryonic development, SHOT represents a candidate for the Cornelia de Lange syndrome.

  3. Targeting drug sensitivity predictors: New potential strategies to improve pharmacotherapy of human brain disorders.

    PubMed

    Kalueff, Allan V; Stewart, Adam Michael; Nguyen, Michael; Song, Cai; Gottesman, Irving I

    2015-12-03

    One of the main challenges in medicine is the lack of efficient drug therapies for common human disorders. For example, although depressed patients receive powerful antidepressants, many often remain resistant to psychopharmacotherapy. The growing recognition of complex interplay between the drug targets and the predictors of drug sensitivity requires an improved understanding of these two key aspects of drug action and their potentially shared molecular networks. Here, we apply the concept of endophenotypes and their interplay to drug action and sensitivity. Based on these analyses, we postulate that novel drugs may be developed by targeting specific molecular pathways that integrate drug targets with drug sensitivity predictors.

  4. 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.

  5. Functional and Genomic Features of Human Genes Mutated in Neuropsychiatric Disorders

    PubMed Central

    Forero, Diego A.; Prada, Carlos F.; Perry, George

    2016-01-01

    Background: In recent years, a large number of studies around the world have led to the identification of causal genes for hereditary types of common and rare neurological and psychiatric disorders. Objective: To explore the functional and genomic features of known human genes mutated in neuropsychiatric disorders. Methods: A systematic search was used to develop a comprehensive catalog of genes mutated in neuropsychiatric disorders (NPD). Functional enrichment and protein-protein interaction analyses were carried out. A false discovery rate approach was used for correction for multiple testing. Results: We found several functional categories that are enriched among NPD genes, such as gene ontologies, protein domains, tissue expression, signaling pathways and regulation by brain-expressed miRNAs and transcription factors. Sixty six of those NPD genes are known to be druggable. Several topographic parameters of protein-protein interaction networks and the degree of conservation between orthologous genes were identified as significant among NPD genes. Conclusion: These results represent one of the first analyses of enrichment of functional categories of genes known to harbor mutations for NPD. These findings could be useful for a future creation of computational tools for prioritization of novel candidate genes for NPD. PMID:27990183

  6. BCL11B expression in intramembranous osteogenesis during murine craniofacial suture development.

    PubMed

    Holmes, Greg; van Bakel, Harm; Zhou, Xueyan; Losic, Bojan; Jabs, Ethylin Wang

    2015-01-01

    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.

  7. 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

  8. The hubs of the human connectome are generally implicated in the anatomy of brain disorders.

    PubMed

    Crossley, Nicolas A; Mechelli, Andrea; Scott, Jessica; Carletti, Francesco; Fox, Peter T; McGuire, Philip; Bullmore, Edward T

    2014-08-01

    more than 1500 task-related functional neuroimaging studies of healthy volunteers to create a normative functional co-activation network. We conclude that the high cost/high value hubs of human brain networks are more likely to be anatomically abnormal than non-hubs in many (if not all) brain disorders.

  9. The hubs of the human connectome are generally implicated in the anatomy of brain disorders

    PubMed Central

    Mechelli, Andrea; Scott, Jessica; Carletti, Francesco; Fox, Peter T.; McGuire, Philip; Bullmore, Edward T.

    2014-01-01

    -analysis of more than 1500 task-related functional neuroimaging studies of healthy volunteers to create a normative functional co-activation network. We conclude that the high cost/high value hubs of human brain networks are more likely to be anatomically abnormal than non-hubs in many (if not all) brain disorders. PMID:25057133

  10. Immortalized pathological human myoblasts: towards a universal tool for the study of neuromuscular disorders

    PubMed Central

    2011-01-01

    Background Investigations into both the pathophysiology and therapeutic targets in muscle dystrophies have been hampered by the limited proliferative capacity of human myoblasts. Isolation of reliable and stable immortalized cell lines from patient biopsies is a powerful tool for investigating pathological mechanisms, including those associated with muscle aging, and for developing innovative gene-based, cell-based or pharmacological biotherapies. Methods Using transduction with both telomerase-expressing and cyclin-dependent kinase 4-expressing vectors, we were able to generate a battery of immortalized human muscle stem-cell lines from patients with various neuromuscular disorders. Results The immortalized human cell lines from patients with Duchenne muscular dystrophy, facioscapulohumeral muscular dystrophy, oculopharyngeal muscular dystrophy, congenital muscular dystrophy, and limb-girdle muscular dystrophy type 2B had greatly increased proliferative capacity, and maintained their potential to differentiate both in vitro and in vivo after transplantation into regenerating muscle of immunodeficient mice. Conclusions Dystrophic cellular models are required as a supplement to animal models to assess cellular mechanisms, such as signaling defects, or to perform high-throughput screening for therapeutic molecules. These investigations have been conducted for many years on cells derived from animals, and would greatly benefit from having human cell models with prolonged proliferative capacity. Furthermore, the possibility to assess in vivo the regenerative capacity of these cells extends their potential use. The innovative cellular tools derived from several different neuromuscular diseases as described in this report will allow investigation of the pathophysiology of these disorders and assessment of new therapeutic strategies. PMID:22040608

  11. 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

  12. 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

  13. The human BDNF gene: peripheral gene expression and protein levels as biomarkers for psychiatric disorders

    PubMed Central

    Cattaneo, A; Cattane, N; Begni, V; Pariante, C M; Riva, M A

    2016-01-01

    Brain-derived neurotrophic factor (BDNF) regulates the survival and growth of neurons, and influences synaptic efficiency and plasticity. The human BDNF gene consists of 11 exons, and distinct BDNF transcripts are produced through the use of alternative promoters and splicing events. The majority of the BDNF transcripts can be detected not only in the brain but also in the blood cells, although no study has yet investigated the differential expression of BDNF transcripts at the peripheral level. This review provides a description of the human BDNF gene structure as well as a summary of clinical and preclinical evidence supporting the role of BDNF in the pathogenesis of psychiatric disorders. We will discuss several mechanisms as possibly underlying BDNF modulation, including epigenetic mechanisms. We will also discuss the potential use of peripheral BDNF as a biomarker for psychiatric disorders, focusing on the factors that can influence BDNF gene expression and protein levels. Within this context, we have also characterized, for we believe the first time, the expression of BDNF transcripts in the blood, with the aim to provide novel insights into the molecular mechanisms and signaling that may regulate peripheral BDNF gene expression levels. PMID:27874848

  14. 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.

  15. Gene identification using exon amplification on human chromosome 18q21: implications for bipolar disorder.

    PubMed

    Chen, H; Huo, Y; Patel, S; Zhu, X; Swift-Scanlan, T; Reeves, R H; DePaulo, R; Ross, C A; McInnis, M G

    2000-09-01

    We previously reported linkage between bipolar disorder and a region on human chromosome (HC) 18q21. To identify genes in this region, exon trapping was performed on cosmids isolated from an HC18-specific cosmid library (LL18NC02) using 47 sequence tagged site (STS) markers from 18q21 as hybridization probes. A total of 285 unique sequences (exons) were obtained from 850 sequenced clones. Homology searching of the databases using NCBI's BLAST algorithms revealed that 31 exons have identity to known genes and/or ESTs, seven are identical to regions of finished genomic sequences in the 18q21 region, 20 have significant similarity (>30% sequence identity) to genes from human and/or other species, 19 were repetitive sequences, and 208 sequences (72%) are novel. Seventy per cent of the trapped sequences were predicted to be derived from genes using library screening and RT-PCR analyses. This represents an initial stage in characterizing genes in a susceptibility region for further study in bipolar disorder or other diseases that map to this region.

  16. Fishing for Fetal Alcohol Spectrum Disorders: Zebrafish as a Model for Ethanol Teratogenesis.

    PubMed

    Lovely, Charles Ben; Fernandes, Yohaan; Eberhart, Johann K

    2016-10-01

    Fetal Alcohol Spectrum Disorders (FASD) describes a wide array of ethanol-induced developmental defects, including craniofacial dysmorphology and cognitive impairments. It affects ∼1 in 100 children born in the United States each year. Due to the pleiotropic effects of ethanol, animal models have proven critical in characterizing the mechanisms of ethanol teratogenesis. In this review, we focus on the utility of zebrafish in characterizing ethanol-induced developmental defects. A growing number of laboratories have focused on using zebrafish to examine ethanol-induced defects in craniofacial, cardiac, ocular, and neural development, as well as cognitive and behavioral impairments. Growing evidence supports that genetic predisposition plays a role in these ethanol-induced defects, yet little is understood about these gene-ethanol interactions. With a high degree of genetic amenability, zebrafish is at the forefront of identifying and characterizing the gene-ethanol interactions that underlie FASD. Because of the conservation of gene function between zebrafish and humans, these studies will directly translate to studies of candidate genes in human populations and allow for better diagnosis and treatment of FASD.

  17. Genome-wide approaches (GWA) in oral and craniofacial diseases research

    PubMed Central

    Kim, H; Gordon, S; Dionne, R

    2012-01-01

    Underlying molecular genetic mechanisms of diseases can be deciphered with unbiased strategies using recently developed technologies enabling genome-wide scale investigations. These technologies have been applied in scanning for genetic variations, gene expression profiles, and epigenetic changes for oral and craniofacial diseases. However, these approaches as applied to oral and craniofacial conditions are in the initial stages, and challenges remain to be overcome, including analysis of high throughput data and their interpretation. Here, we review methodology and studies using genome-wide approaches in oral and craniofacial diseases and suggest future directions. PMID:22913301

  18. COLEC10 is mutated in 3MC patients and regulates early craniofacial development

    PubMed Central

    Munye, Mustafa M.; Diaz-Font, Anna; Ocaka, Louise; Henriksen, Maiken L.; Brady, Angela; Jenkins, Dagan; Morton, Jenny; Hansen, Soren W.; Bacchelli, Chiara; Beales, Philip L.

    2017-01-01

    3MC syndrome is an autosomal recessive heterogeneous disorder with features linked to developmental abnormalities. The main features include facial dysmorphism, craniosynostosis and cleft lip/palate; skeletal structures derived from cranial neural crest cells (cNCC). We previously reported that lectin complement pathway genes COLEC11 and MASP1/3 are mutated in 3MC syndrome patients. Here we define a new gene, COLEC10, also mutated in 3MC families and present novel mutations in COLEC11 and MASP1/3 genes in a further five families. The protein products of COLEC11 and COLEC10, CL-K1 and CL-L1 respectively, form heteromeric complexes. We show COLEC10 is expressed in the base membrane of the palate during murine embryo development. We demonstrate how mutations in COLEC10 (c.25C>T; p.Arg9Ter, c.226delA; p.Gly77Glufs*66 and c.528C>G p.Cys176Trp) impair the expression and/or secretion of CL-L1 highlighting their pathogenicity. Together, these findings provide further evidence linking the lectin complement pathway and complement factors COLEC11 and COLEC10 to morphogenesis of craniofacial structures and 3MC etiology. PMID:28301481

  19. COLEC10 is mutated in 3MC patients and regulates early craniofacial development.

    PubMed

    Munye, Mustafa M; Diaz-Font, Anna; Ocaka, Louise; Henriksen, Maiken L; Lees, Melissa; Brady, Angela; Jenkins, Dagan; Morton, Jenny; Hansen, Soren W; Bacchelli, Chiara; Beales, Philip L; Hernandez-Hernandez, Victor

    2017-03-16

    3MC syndrome is an autosomal recessive heterogeneous disorder with features linked to developmental abnormalities. The main features include facial dysmorphism, craniosynostosis and cleft lip/palate; skeletal structures derived from cranial neural crest cells (cNCC). We previously reported that lectin complement pathway genes COLEC11 and MASP1/3 are mutated in 3MC syndrome patients. Here we define a new gene, COLEC10, also mutated in 3MC families and present novel mutations in COLEC11 and MASP1/3 genes in a further five families. The protein products of COLEC11 and COLEC10, CL-K1 and CL-L1 respectively, form heteromeric complexes. We show COLEC10 is expressed in the base membrane of the palate during murine embryo development. We demonstrate how mutations in COLEC10 (c.25C>T; p.Arg9Ter, c.226delA; p.Gly77Glufs*66 and c.528C>G p.Cys176Trp) impair the expression and/or secretion of CL-L1 highlighting their pathogenicity. Together, these findings provide further evidence linking the lectin complement pathway and complement factors COLEC11 and COLEC10 to morphogenesis of craniofacial structures and 3MC etiology.

  20. How Relevant Are Imaging Findings in Animal Models of Movement Disorders to Human Disease?

    PubMed

    Bannon, Darryl; Landau, Anne M; Doudet, Doris J

    2015-08-01

    The combination of novel imaging techniques with the use of small animal models of disease is often used in attempt to understand disease mechanisms, design potential clinical biomarkers and therapeutic interventions, and develop novel methods with translatability to human clinical conditions. However, it is clear that most animal models are deficient when compared to the complexity of human diseases: they cannot sufficiently replicate all the features of multisystem disorders. Furthermore, some practical differences may affect the use or interpretation of animal imaging to model human conditions such as the use of anesthesia, various species differences, and limitations of methodological tools. Nevertheless, imaging animal models allows us to dissect, in interpretable bits, the effects of one system upon another, the consequences of variable neuronal losses or overactive systems, the results of experimental treatments, and we can develop and validate new methods. In this review, we focus on imaging modalities that are easily used in both human subjects and animal models such as positron emission and magnetic resonance imaging and discuss aging and Parkinson's disease as prototypical examples of preclinical imaging studies.

  1. "False" migration of rigid fixation appliances in pediatric craniofacial surgery.

    PubMed

    Papay, F A; Hardy, S; Morales, L; Walker, M; Enlow, D

    1995-07-01

    Osseous fixation techniques have been widely used to provide rigid stabilization in the craniofacial skeleton. Reported sequelae of its usage has been limited to palpation of the screw-plate system and radiological imaging artifacts. Over the past 3 years we have identified miniplates, microplates, and wire sutures on the inner cranial table of the growing child. The observation of "false" migration of these appliances has provided the impetus to review these patients in more detail. Twenty patients underwent secondary cranial remodeling within a two-year period; 7 of these patients were seen to have "false" migration. There were no untoward sequelae in removal of these appliances, and no adverse neurological symptoms were seen.

  2. 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

  3. 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

  4. Functional coupling constrains craniofacial diversification in Lake Tanganyika cichlids

    PubMed Central

    Tsuboi, Masahito; Gonzalez-Voyer, Alejandro; Kolm, Niclas

    2015-01-01

    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

  5. 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.

  6. 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

  7. Use of a natural hybrid zone for genomewide association mapping of craniofacial traits in the house mouse.

    PubMed

    Pallares, Luisa F; Harr, Bettina; Turner, Leslie M; Tautz, Diethard

    2014-12-01

    The identification of the genes involved in morphological variation in nature is still a major challenge. Here, we explore a new approach: we combine 178 samples from a natural hybrid zone between two subspecies of the house mouse (Mus musculus domesticus and Mus musculus musculus), and high coverage of the genome (~ 145K SNPs) to identify loci underlying craniofacial shape variation. Due to the long history of recombination in the hybrid zone, high mapping resolution is anticipated. The combination of genomes from subspecies allows the mapping of both, variation within subspecies and inter-subspecific differences, thereby increasing the overall amount of causal genetic variation that can be detected. Skull and mandible shape were measured using 3D landmarks and geometric morphometrics. Using principal component axes as phenotypes, and a linear mixed model accounting for genetic relatedness in the mapping populations, we identified nine genomic regions associated with skull shape and 10 with mandible shape. High mapping resolution (median size of significant regions = 148 kb) enabled identification of single or few candidate genes in most cases. Some of the genes act as regulators or modifiers of signalling pathways relevant for morphological development and bone formation, including several with known craniofacial phenotypes in mice and humans. The significant associations combined explain 13% and 7% of the skull and mandible shape variation, respectively. In addition, a positive correlation was found between chromosomal length and proportion of variation explained. Our results suggest a complex genetic architecture for shape traits and support a polygenic model.

  8. Craniocervical postural relations and craniofacial morphology in 30 blind subjects.

    PubMed

    Fjellvang, H; Solow, B

    1986-10-01

    Previous studies have shown that head posture is dependent on vision. The head posture of blind persons therefore can be expected to differ from that of normal subjects. This is of interest in the current analyses of the relation between head posture and craniofacial morphology. The purpose of the present investigation was to describe the posture of the head and cervical column and the craniofacial morphology in a group of blind subjects, and to compare the findings with those previously found in male and female groups of normal subjects. The sample comprised 30 blind subjects--18 men and 12 women, aged 15 to 35 years, all of whom had been without perception of light since birth. The control group comprised 120 male dental students in the age range 22 to 30 years and 51 female dental students in the age range 22 to 27 years. The analysis of head posture showed that the intra-and interindividual variabilities of the craniovertical angles were significantly larger than those of the craniocervical angles in the blind group. The interindividual variabilities of the craniovertical angles were significantly larger in the blind than in the control group, but the variabilities of the craniocervical angles were similar in both groups. Craniovertical relations thus were more variable in the blind subjects, whereas craniocervical relations showed the same variability as normal subjects. On the average, the head was carried in a 4.3 degrees lower position in the neck was 4.5 degrees more forward inclined in the blind group. No differences were found in the position of the head in relation to the cervical column between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

  9. Sella turcica-Its importance in orthodontics and craniofacial morphology

    PubMed Central

    Sathyanarayana, Haritha Pottipalli; Kailasam, Vignesh; Chitharanjan, Arun B

    2013-01-01

    The sella turcica is a structure which can be readily seen on lateral cephalometric radiographs and sella point is routinely traced for various cephalometric analyses. The search was carried out using the following key words (sella turcica, bridging of sella, size, shape of sella turcica) and with the following search engine (Pubmed, Cochrane, Google scholar). The morphology is very important for the cephalometric position of the reference point sella, not only for evaluating craniofacial morphology, but also when growth changes and orthodontic treatment results are to be evaluated. This makes it a good source of additional diagnostic information related to pathology of the pituitary gland, or to various syndromes that affect the craniofacial region. Clinicians should be familiar with the normal radiographic anatomy and morphologic variability of this area, in order to recognize and investigate deviations that may reflect pathological situations, even before these become clinically apparent. During embryological development, the sella turcica area is the key point for the migration of the neural crest cells to the frontonasal and maxillary developmental fields. The neural crest cells are involved in the formation and development of sella turcica and teeth. The size of sella turcica ranges from 4 to 12 mm for the vertical and 5 to 16 mm for the anteroposterior dimension. There are many classification systems regarding the shape of sella turcica. Majority of the studies show that about 67% of the subjects had normal appearance and about 33% showed variations. The prevalence of sella turcica bridging is high in class III malocclusions and dental anomalies. PMID:24348611

  10. [Innovation in craniofacial surgery: From Tessier to future prospects. According to testimonies of F. Ortiz-Monasterio, D. Marchac, F. Firmin and T. Wolfe].

    PubMed

    Arnaud, É

    2010-10-01

    Innovation is one of the founding values of plastic surgery. By its fundamental innovations, Paul Tessier (1917-2008) created craniofacial surgery in the sixties. The exploration of the new field, which has modified the boundaries of knowledge, has been evoked by Fernando Ortiz Monasterio, Daniel Marchac, Françoise Firmin and Tony Wolfe. This work defined the human qualities leading to creative breakthrough: (1) rigourous work and passion; (2) withdrawal from the current educative dogmas; (3) maintainance of the excellence of reconstructive and aesthetic practice; (4) progressive complexity of the procedures with concomitant validation by peers; (5) humility and continuous self criticizing maintained in one's own results. The main focus of those evolutions in craniofacial care at the forefront include among others: (1) functional imaging in order to help for mental prognosis assessment; (2) sophistication of biomaterials in order to limit morbidity; (3) ultimate developments of osteogenic distraction techniques; (4) genetic evaluation and counselling toward genetic therapies; (5) antenatal diagnosis toward in utero treatment. The necessity of well recognized reference centers for treatment of craniofacial anomalies is currently one of the healthcare priorities in Europe among the management of all are rare diseases (less than one out of 2000 living births).

  11. Identifying craniofacial features associated with prenatal exposure to androgens and testing their relationship with brain development.

    PubMed

    Marečková, Klára; Chakravarty, Mallar M; Lawrence, Claire; Leonard, Gabriel; Perusse, Daniel; Perron, Michel; Pike, Bruce G; Richer, Louis; Veillette, Suzanne; Pausova, Zdenka; Paus, Tomáš

    2015-11-01

    We used magnetic resonance (MR) images obtained in same-sex and opposite-sex dizygotic twins (n = 119, 8 years of age) to study possible effects of prenatal androgens on craniofacial features. Using a principal component analysis of 19 craniofacial landmarks placed on the MR images, we identified a principal component capturing craniofacial features that distinguished females with a presumed differential exposure to prenatal androgens by virtue of having a male (vs. a female) co-twin (Cohen's d = 0.76). Subsequently, we tested the possibility that this craniofacial "signature" of prenatal exposure to androgens predicts brain size, a known sexually dimorphic trait. In an independent sample of female adolescents (singletons; n = 462), we found that the facial signature predicts up to 8% of variance in brain size. These findings are consistent with the organizational effects of androgens on brain development and suggest that the facial signature derived in this study could complement other indirect measures of prenatal exposure to androgens.

  12. The influence of incompetent lip seal on the growth and development of craniofacial complex.

    PubMed

    Drevensek, Martina; Stefanac-Papić, Jadranka; Farcnik, Franc

    2005-12-01

    Abnormal orofacial functions in the period of growth and development can cause morphological anomalies of the craniofacial complex. The aim of this study was to determine the correlation between open mouth posture and morphology of craniofacial complex. The shape, size and relationships of skeletal parts of craniofacial complex were determined by analysis of lateral cephalograms in the sample of 84 children--45 girls and 39 boys (aged 8.96 +/- 0.66 years). The sample was divided into two groups--lip competence and lip incompetence group. Differences in cephalometric values between observed groups were found. The values of inclination of lower central incisors (angle ILi/NB), interbasal angle (NL/NSL), angle between occlusal and mandibular plane and anterior lower facial height were significantly higher in the group with open mouth posture. It can be concluded that lip incompetence plays an important role in growth and development of craniofacial complex.

  13. 76 FR 20693 - National Institute of Dental & Craniofacial Research; Notice of Closed Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-13

    ... Emphasis Panel; Review RFA-DE-12-001, NIDCR Behavioral or Social Intervention Planning and Pilot Data Grant..., National Institute of Dental and Craniofacial Research, One Democracy Plaza, Room 670, Bethesda, MD...

  14. 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...

  15. Alx3-deficient mice exhibit folic acid-resistant craniofacial midline and neural tube closure defects.

    PubMed

    Lakhwani, Sita; García-Sanz, Patricia; Vallejo, Mario

    2010-08-15

    Neural tube closure defects are among the most frequent congenital malformations in humans. Supplemental maternal intake of folic acid before and during pregnancy reduces their incidence significantly, but the mechanism underlying this preventive effect is unknown. As a number of genes that cause neural tube closure defects encode transcriptional regulators in mice, one possibility is that folic acid could induce the expression of transcription factors to compensate for the primary genetic defect. We report that folic acid is required in mouse embryos for the specific expression of the homeodomain gene Alx3 in the head mesenchyme, an important tissue for cranial neural tube closure. Alx3-deficient mice exhibit increased failure of cranial neural tube closure and increased cell death in the craniofacial region, two effects that are also observed in wild type embryos developing in the absence of folic acid. Folic acid cannot prevent these defects in Alx3-deficient embryos, indicating that one mechanism of folic acid action is through induced expression of Alx3. Thus, Alx3 emerges as a candidate gene for human neural tube defects and reveals the existence of induced transcription factor gene expression as a previously unknown mechanism by which folic acid prevents neural tube closure defects.

  16. Investigation of genes important in neurodevelopment disorders in adult human brain.

    PubMed

    Maussion, Gilles; Diallo, Alpha B; Gigek, Carolina O; Chen, Elizabeth S; Crapper, Liam; Théroux, Jean-Francois; Chen, Gary G; Vasuta, Cristina; Ernst, Carl

    2015-10-01

    Several neurodevelopmental disorders (NDDs) are caused by mutations in genes expressed in fetal brain, but little is known about these same genes in adult human brain. Here, we test the hypothesis that genes associated with NDDs continue to have a role in adult human brain to explore the idea that NDD symptoms may be partially a result of their adult function rather than just their neurodevelopmental function. To demonstrate adult brain function, we performed expression analyses and ChIPseq in human neural stem cell(NSC) lines at different developmental stages and adult human brain, targeting two genes associated with NDDs, SATB2 and EHMT1, and the WNT signaling gene TCF7L2, which has not been associated with NDDs. Analysis of DNA interaction sites in neural stem cells reveals high (40-50 %) overlap between proliferating and differentiating cells for each gene in temporal space. Studies in adult brain demonstrate that consensus sites are similar to NSCs but occur at different genomic locations. We also performed expression analyses using BrainSpan data for NDD-associated genes SATB2, EHMT1, FMR1, MECP2, MBD5, CTNND2, RAI1, CHD8, GRIN2A, GRIN2B, TCF4, SCN2A, and DYRK1A and find high expression of these genes in adult brain, at least comparable to developing human brain, confirming that genes associated with NDDs likely have a role in adult tissue. Adult function of genes associated with NDDs might be important in clinical disease presentation and may be suitable targets for therapeutic intervention.

  17. 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

  18. Online Mendelian Inheritance in Man (OMIM), a knowledgebase of human genes and genetic disorders.

    PubMed

    Hamosh, Ada; Scott, Alan F; Amberger, Joanna S; Bocchini, Carol A; McKusick, Victor A

    2005-01-01

    Online Mendelian Inheritance in Man (OMIM) is a comprehensive, authoritative and timely knowledgebase of human genes and genetic disorders compiled to support human genetics research and education and the practice of clinical genetics. Started by Dr Victor A. McKusick as the definitive reference Mendelian Inheritance in Man, OMIM (http://www.ncbi.nlm.nih.gov/omim/) is now distributed electronically by the National Center for Biotechnology Information, where it is integrated with the Entrez suite of databases. Derived from the biomedical literature, OMIM is written and edited at Johns Hopkins University with input from scientists and physicians around the world. Each OMIM entry has a full-text summary of a genetically determined phenotype and/or gene and has numerous links to other genetic databases such as DNA and protein sequence, PubMed references, general and locus-specific mutation databases, HUGO nomenclature, MapViewer, GeneTests, patient support groups and many others. OMIM is an easy and straightforward portal to the burgeoning information in human genetics.

  19. A novel disorder reveals clathrin heavy chain-22 is essential for human pain and touch development.

    PubMed

    Nahorski, Michael S; 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; Woods, C Geoffrey

    2015-08-01

    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.

  20. Affinity purification of human m-calpain through an intrinsically disordered inhibitor, calpastatin

    PubMed Central

    Nguyen, Hung Huy; Varadi, Mihaly; Tompa, Peter

    2017-01-01

    Calpains are calcium-activated proteases that have biomedical and biotechnological potential. Their activity is tightly regulated by their endogenous inhibitor, calpastatin that binds to the enzyme only in the presence of calcium. Conventional approaches to purify calpain comprise multiple chromatographic steps, and are labor-intensive, leading to low yields. Here we report a new purification procedure for the human m-calpain based on its reversible calcium-mediated interaction with the intrinsically disordered calpastatin. We exploit the specific binding properties of human calpastatin domain 1 (hCSD1) to physically capture human m-calpain from a complex biological mixture. The dissociation of the complex is mediated by chelating calcium, upon which heterodimeric calpain elutes while hCSD1 remains immobilized onto the stationary phase. This novel affinity-based purification was compared to the conventional multistep purification strategy and we find that it is robust, it yields a homogeneous preparation, it can be scaled up easily and it rests on a non-disruptive step that maintains close to physiological conditions that allow further biophysical and functional studies. PMID:28319173

  1. The role of distraction osteogenesis in the management of craniofacial syndromes

    PubMed Central

    Heggie, Andrew A.; Kumar, Ricky; Shand, Jocelyn M.

    2013-01-01

    Distraction osteogenesis (DO) has been established as a useful technique in the correction of skeletal anomalies of the long bones for several decades. However, the use of DO in the management of craniofacial deformities has been evolving over the past 20 years, with initial experience in the mandible, followed by the mid-face and subsequently, the cranium. This review aims to provide an overview of the current role of DO in the treatment of patients with craniofacial anomalies. PMID:23662252

  2. The extracellular matrix of muscle--implications for manipulation of the craniofacial musculature.

    PubMed

    Lewis, M P; Machell, J R; Hunt, N P; Sinanan, A C; Tippett, H L

    2001-08-01

    Successful adaptation of craniofacial skeletal muscle is dependent upon the connective tissue component of the muscle. This is exemplified by procedures such as distraction histo/osteogenesis. The mechanisms underlying remodelling of intramuscular connective tissue are complex and multifactorial and involve extracellular matrix (ECM) molecules, receptors for the ECM (integrins) and enzymes that remodel the ECM (MMPs). This review discusses the current state of knowledge and clinical implications of connective tissue biology as applied to craniofacial skeletal muscle.

  3. An Atypical Presentation of Multiple Central Osteomas Mimicking Craniofacial Fibrous Dysplasia – A Pictorial Essay

    PubMed Central

    Mhapuskar, Amit A; Hebbale, Manjula; Tepan, Meenal; Ayushee

    2016-01-01

    Osteoma is benign neoplasm with slow growth characterized by deposition of compact lamellar cortical or cancellous bone creating a tumour mass. It is still unclear whether osteomas are benign neoplasms or hamartomas. They have typical clinical presentations and are easily diagnosed with the help of radiographs. We present a rare case of non-syndromic multiple osteomas in the craniofacial region which are typically restricted to the midline and presents radiographically as craniofacial fibrous dysplasia causing a diagnostic dilemma. PMID:28050513

  4. Two cases of orbital dystopia: Tessier III cleft and craniofacial osteomas.

    PubMed

    Furnas, D W; Achauer, B M

    1981-01-01

    Two cases of orbital dystopia are reported. One was caused by a Tessier III cleft and was treated by cranio-facial osteotomies of three walls of the orbit, allowing the left to be moved upward. The second involved multiple craniofacial osteomas and was treated by extractional osteotomies of four walls of the orbit including a transverse split of the roof. These osteotomies were entirely extramucosal.

  5. Human imprinting anomalies in fetal and childhood growth disorders: clinical implications and molecular mechanisms.

    PubMed

    Azzi, Salah; Brioude, Fréderic; Le Bouc, Yves; Netchine, Irène

    2014-01-01

    Genomic imprinting is among the most important epigenetic mechanisms whereby expression of a subset of genes is restricted to a single parental allele. Loss of imprinting (LOI) through hypo or hyper methylation is involved in various human syndromes. These LOI occur early during development and usually impair growth. Some imprinting syndromes are the consequences of genetic anomalies, such as uniparental disomies (UPD) or copy number variations (deletion or duplications) involving the imprinted domains; others are due to LOI at the imprinting control regions (ICR) regulating each domain. Imprinting disorders are phenotypically heterogeneous, although some share various common clinical features such that diagnosis may be difficult. Multilocus imprinting defects associated with several syndromes have been increasingly reported in recent years, although there are no obvious clinical differences between monolocus and multilocus LOI patients. Subsequently, some rare mutations of transacting factors have been identified in patients with multilocus imprinting defects but they do not explain the majority of the cases; this therefore implies that other factors are involved. By contrast, no mutation of a transacting factor has yet been identified in monolocus LOI. The effect of the environment on the regulation of imprinting is clearly illustrated by studies of assisted reproductive technology (ART). The regulation of imprinting is complex and involves a huge range of genetic and environmental factors; the identification of these factors will undoubtedly help to elucidate the regulation of imprinting and contribute to the understanding of imprinting disorders. This would be beneficial for diagnostics, clinical follow up and the development of treatment guidelines.

  6. Immunohistochemical expression of doublecortin in the human cerebrum: comparison of normal development and neuronal migration disorders.

    PubMed

    Qin, J; Mizuguchi, M; Itoh, M; Takashima, S

    2000-04-28

    Immunohistochemical expression of the doublecortin (DCX) gene product was investigated in cerebral cortices from 33 normal developing human, aged 9 gestational weeks (GW) to 29 years, and from 26 patients with various neuronal migration disorders, aged 19 GW to 34 years. DCX immunoreactivity was detected predominantly in the fetal cerebral cortex. The neurons in the cortical plate (CP) exhibited positive labeling at 9 GW. Staining was the most marked intense at 12-20 GW, and gradually decreased thereafter, only relatively weak immunoreactivity remaining in pyramidal cells. Comparison of the immunohistochemical characteristics of DCX and those of nestin and vimentin indicated the early expression of DCX in neuroepithelial stem cells of the subventricular germinal layer, as well as in neurons of the CP. The most marked intense expression in the period of neuronal migration strongly indicated its role in neuronal migration. The abnormal distribution of DCX immunolabeling in the cerebral cortex was associated with a neuronal disarrangement in some migration disorders, such as Miller-Dieker syndrome and Fukuyama congenital muscular dystrophy. Decreased DCX immunolabeling was demonstrated in fetuses and infants with Zellweger syndrome, implicating DCX in the neuronal migration abnormality in this syndrome.

  7. The Role of Serotonin Transporter in Human Lung Development and in Neonatal Lung Disorders

    PubMed Central

    Sen, P.; Parks, W. T.; Langston, C.

    2017-01-01

    Introduction. Failure of the vascular pulmonary remodeling at birth often manifests as pulmonary hypertension (PHT) and is associated with a variety of neonatal lung disorders including a uniformly fatal developmental disorder known as alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV). Serum serotonin regulation has been linked to pulmonary vascular function and disease, and serotonin transporter (SERT) is thought to be one of the key regulators in these processes. We sought to find evidence of a role that SERT plays in the neonatal respiratory adaptation process and in the pathomechanism of ACD/MPV. Methods. We used histology and immunohistochemistry to determine the timetable of SERT protein expression in normal human fetal and postnatal lungs and in cases of newborn and childhood PHT of varied etiology. In addition, we tested for a SERT gene promoter defect in ACD/MPV patients. Results. We found that SERT protein expression begins at 30 weeks of gestation, increases to term, and stays high postnatally. ACD/MPV patients had diminished SERT expression without SERT promoter alteration. Conclusion. We concluded that SERT/serotonin pathway is crucial in the process of pulmonary vascular remodeling/adaptation at birth and plays a key role in the pathobiology of ACD/MPV. PMID:28316463

  8. Catalytic ferrous iron in amniotic fluid as a predictive marker of human maternal-fetal disorders.

    PubMed

    Hattori, Yuka; Mukaide, Takahiro; Jiang, Li; Kotani, Tomomi; Tsuda, Hiroyuki; Mano, Yukio; Sumigama, Seiji; Hirayama, Tasuku; Nagasawa, Hideko; Kikkawa, Fumitaka; Toyokuni, Shinya

    2015-01-01

    Amniotic fluid contains numerous biomolecules derived from fetus and mother, thus providing precious information on pregnancy. Here, we evaluated oxidative stress of human amniotic fluid and measured the concentration of catalytic Fe(II). Amniotic fluid samples were collected with consent from a total of 89 subjects in Nagoya University Hospital, under necessary medical interventions: normal pregnancy at term, normal pregnancy at the 2nd trimester, preterm delivery with maternal disorders but without fetal disorders, congenital diaphragmatic hernia, fetal growth restriction, pregnancy-induced hypertension, gestational diabetes mellitus, Down syndrome and trisomy 18. Catalytic Fe(II) and oxidative stress markers (8-hydroxy-2'-deoxyguanosine, 8-OHdG; dityrosine) were determined with RhoNox-1 and specific antibodies, respectively, using plate assays. Levels of 8-OHdG and dityrosine were higher in the 3rd trimester compared with the 2nd trimester in normal subjects, and the abnormal groups generally showed lower levels than the controls, thus suggesting that they represent fetal metabolic activities. In contrast, catalytic Fe(II) was higher in the 2nd trimester than the 3rd trimester in the normal subjects, and overall the abnormal groups showed higher levels than the controls, suggesting that high catalytic Fe(II) at late gestation reflects fetal pathologic alterations. Notably, products of H2O2 and catalytic Fe(II) remained almost constant in amniotic fluid.

  9. 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.

  10. Genotyping for human platelet alloantigen polymorphisms: applications in the diagnosis of alloimmune platelet disorders.

    PubMed

    Curtis, Brian R

    2008-09-01

    Molecular typing for platelet allelic polymorphisms was first made possible by discovery of the HPA-1a/1b single nucleotide polymorphism in 1989. Since then, six other biallelic human platelet antigen (HPA) systems have been determined and can be typed using genomic DNA. The introduction of polymerase chain reaction enabled development of several different assays including polymerase chain reaction-sequence-specific primer, melting curve analysis by LightCycler, and 5'-nuclease assays. More recently, multiplex polymerase chain reaction has allowed for the development of high-throughput assays for genotyping large numbers of patients and blood donors for not only platelet gene polymorphisms but also for those of other blood cell genes. Platelet genotyping is a valuable tool in confirming platelet antigen specificities of alloantibodies detected in patient sera to complement the clinical history in the diagnosis of alloimmune platelet disorders such as fetal and neonatal alloimmune thrombocytopenia (FNAIT), posttransfusion purpura, and multiplatelet transfusion refractoriness. In addition, it has made possible prenatal platelet typing of the fetus in suspected cases of FNAIT and large-scale blood donor typing for provision of antigen-negative platelets to transfuse highly alloimmunized patients. Platelet genotyping may also someday prove important as an aid in determining the relative risk of patients for various thrombotic disorders.

  11. Alcohol use disorder and its impact on chronic hepatitis C virus and human immunodeficiency virus infections

    PubMed Central

    Fuster, Daniel; Sanvisens, Arantza; Bolao, Ferran; Rivas, Inmaculada; Tor, Jordi; Muga, Robert

    2016-01-01

    Alcohol use disorder (AUD) and hepatitis C virus (HCV) infection frequently co-occur. AUD is associated with greater exposure to HCV infection, increased HCV infection persistence, and more extensive liver damage due to interactions between AUD and HCV on immune responses, cytotoxicity, and oxidative stress. Although AUD and HCV infection are associated with increased morbidity and mortality, HCV antiviral therapy is less commonly prescribed in individuals with both conditions. AUD is also common in human immunodeficiency virus (HIV) infection, which negatively impacts proper HIV care and adherence to antiretroviral therapy, and liver disease. In addition, AUD and HCV infection are also frequent within a proportion of patients with HIV infection, which negatively impacts liver disease. This review summarizes the current knowledge regarding pathological interactions of AUD with hepatitis C infection, HIV infection, and HCV/HIV co-infection, as well as relating to AUD treatment interventions in these individuals. PMID:27872681

  12. Partial craniofacial duplication: a review of the literature and case report.

    PubMed

    Costa, Melinda A; Borzabadi-Farahani, Ali; Lara-Sanchez, Pedro A; Schweitzer, Daniela; Jacobson, Lia; Clarke, Noreen; Hammoudeh, Jeffery; Urata, Mark M; Magee, William P

    2014-06-01

    Diprosopus (Greek; di-, "two" + prosopon, "face"), or craniofacial duplication, is a rare craniofacial anomaly referring to the complete duplication of facial structures. Partial craniofacial duplication describes a broad spectrum of congenital anomalies, including duplications of the oral cavity. This paper describes a 15 month-old female with a duplicated oral cavity, mandible, and maxilla. A Tessier type 7 cleft, midline meningocele, and duplicated hypophysis were also present. The preoperative evaluation, surgical approach, postoperative results, and a review of the literature are presented. The surgical approach was designed to preserve facial nerve innervation to the reconstructed cheek and mouth. The duplicated mandible and maxilla were excised and the remaining left maxilla was bone grafted. Soft tissue repair included closure of the Tessier type VII cleft. Craniofacial duplication remains a rare entity that is more common in females. The pathophysiology remains incompletely characterized, but is postulated to be due to duplication of the notochord, as well as duplication of mandibular growth centres. While diprosopus is a severe deformity often associated with anencephaly, patients with partial duplication typically benefit from surgical treatment. Managing craniofacial duplication requires a detailed preoperative evaluation as well as a comprehensive, staged treatment plan. Long-term follow up is needed appropriately to address ongoing craniofacial deformity.

  13. 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…

  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. Reasons for rarity of Th17 cells in inflammatory sites of human disorders.

    PubMed

    Annunziato, Francesco; Santarlasci, Veronica; Maggi, Laura; Cosmi, Lorenzo; Liotta, Francesco; Romagnani, Sergio

    2013-11-15

    T helper 17 (Th17) cells have been reported to be responsible for several chronic inflammatory diseases. However, a peculiar feature of human Th17 cells is that they are very rare in the inflammatory sites in comparison with Th1 cells. The first reason for this rarity is the existence of some self-regulatory mechanisms that limit their expansion. The limited expansion of human Th17 cells is related to the retinoic acid orphan (ROR)C-dependent up-regulation of the interleukin (IL)-4 induced gene 1 (IL4I1), which encodes for a l-phenylalanine oxidase, that has been shown to down-regulate CD3ζ expression in T cells. This results in abnormalities of the molecular pathway which is responsible for the impairment of IL-2 production and therefore for the lack of cell proliferation in response to T-cell receptor (TCR) signalling. IL4I1 up-regulation also associates with the increased expression of Tob1, a member of the Tob/BTG anti-proliferative protein family, which is involved in cell cycle arrest. A second reason for the rarity of human Th17 cells in the inflammatory sites is their rapid shifting into the Th1 phenotype, which is mainly related to the activity of IL-12 and TNF-α. We have named these Th17-derived Th1 cells as non-classic because they differ from classic Th1 cells for the expression of molecules specific for Th17 cells, such as RORC, CD161, CCR6, IL4I1, and IL-17 receptor E. This distinction may be important for defining the respective pathogenic role of Th17, non-classic Th1 and classic Th1 cells in many human inflammatory disorders.

  16. Orthodontic treatment in children to prevent sleep-disordered breathing in adulthood.

    PubMed

    Kikuchi, Makoto

    2005-12-01

    The purpose of this article is to review human craniofacial growth and development, especially the growth of the mandible, to clarify the relationship between obstructive sleep apnea (OSA) syndrome and craniofacial abnormality, and finally, to propose the hypothesis that negative pressure produced in the chest of the OSA child inhibits the growth of the mandible. Recently, the development of diagnosis and treatment of OSA syndrome has progressed rapidly; however, the prevention of OSA syndrome was merely seen. Craniofacial abnormality is reported as one of the causes of OSA syndrome. If craniofacial abnormality is determined only by genetics, it is difficult to manage the craniofacial skeleton to prevent OSA syndrome. The role of epigenetic factors on craniofacial growth and development is still controversial. However, if we stand on the functional matrix hypothesis, we can manage not only growth of the mandible but also the craniofacial skeleton as a whole. The author proposes the hypothesis that the negative pressure produced in the chest prohibits the growth of the mandible even if the patients have a capacity for growth and development; therefore, if this negative pressure disappears because of the removal of the tonsil and/or adenoids or by an orthodontic treatment to make a patency of the airway, the mandible may grow normally, and we can prevent or reduce a number of OSA syndromes in the future.

  17. 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.

  18. Metabolic implications for the mechanism of mitochondrial endosymbiosis and human hereditary disorders.

    PubMed

    de Bivort, Benjamin Lovegren; Chen, Chun-Chung; Perretti, Fabrizio; Negro, Giacomo; Philip, Thomas M; Bar-Yam, Yaneer

    2007-09-07

    The endosymbiosis of proto-mitochondrial prokaryotes (PMP) into proto-eukaryotic host-cells was a major advance in eukaryotic evolution. The nature of the initial relationship remains the subject of controversy. Various conceptual models have been proposed, but none has definitive support. We construct a model of inter-species interactions based upon well-established respiratory pathways, describing the respective energy gain of host-cell and PMP resulting from varying levels of cooperation. The model demonstrates conflicting evolutionary strategies ("Prisoner's Dilemmas") in the interspecies molecular transfers. Nevertheless, we show that coercion and iterated, multilevel selection on both species encourage endosymbiosis. Mutualism is favored if host-cells are significantly more effective than PMPs at gathering food. Otherwise, an unambiguous asymmetry between host-cell and PMP benefits implies that the initial relationship consisted of the host-cell deriving a reproductive advantage at the PMPs' expense-a cellular version of farming. Other initial relationships such as oxygen-detoxification mutualism and parasitism are not strongly supported by the model. We compare the model behavior with experiments on mutant human mitochondria and find the model predicts proliferation rates consistent with that data. We derive from the evolutionary dynamics counter-intuitive therapeutic targets for two human hereditary mitochondrial disorders that reflect the ongoing effect of short-term selection at the mitochondrial level.

  19. The difficult relationship between occlusal interferences and temporomandibular disorder - insights from animal and human experimental studies.

    PubMed

    Xie, Q; Li, X; Xu, X

    2013-04-01

    The aetiology of temporomandibular disorder (TMD) is multifactorial, and numerous studies have addressed that occlusion may be of great importance. However, whether occlusion plays a crucial role in the pathogenesis of TMD remains controversial. Study designs utilising animal models have been used to study the effects of artificial occlusal alterations. Experimental traumatic occlusion affects blood flow in the temporomandibular joint and results in changes in the condylar cartilage, and artificial occlusal interference induces masticatory muscle nociceptive responses that are associated with peripheral sensitisation and lead to central sensitisation, which maintains masticatory muscle hyperalgesia. The possibility that occlusal interference results in TMD has been investigated in humans using a double-blind randomised design. Subjects without a history of TMD show fairly good adaptation to interferences. In contrast, subjects with a history of TMD develop a significant increase in clinical signs and self-report stronger symptoms (occlusal discomfort and chewing difficulties) in response to interferences. Meanwhile, psychological factors appear meaningful for symptomatic responses to artificial interferences in subjects with a history of TMD. Thus, individual differences in vulnerability to occlusal interferences do exist. Although there are advantages and disadvantages to using human and animal occlusal interference models, these approaches are indispensable for discovering the role of occlusion in TMD pathogenesis.

  20. Contributions of endocannabinoid signaling to psychiatric disorders in humans: Genetic and biochemical evidence

    PubMed Central

    Hillard, Cecilia J.; Weinlander, Kenneth M.; Stuhr, Kara L.

    2011-01-01

    The endocannabinoid signaling system is a widespread, neuromodulatory system in brain and is also widely utilized in the periphery to modulate metabolic functions and the immune system. Preclinical data demonstrate that endocannabinoid signaling is an important stress buffer and modulates emotional and cognitive functions. These data suggest the hypothesis that endocannabinoid signaling could be dysfunctional in a number of mental disorders. Genetic polymorphisms in the human genes for two important proteins of the endocannabinoid signaling system, the CB1 cannabinoid receptor (CB1R) and fatty acid amide hydrolase (FAAH), have been explored in the context of normal and pathological conditions. In the case the gene for FAAH, the mechanistic relationships among the common genetic polymorphism, the expression of the FAAH protein and its likely impact on endocannabinoid signaling are understood. However, multiple polymorphisms in the gene for the CB1R occur and are associated with human phenotypic differences without an understanding of the functional relationships among the gene, mRNA, protein and protein function. The endocannabinoid ligands are found in the circulation and several studies have identified changes in their concentrations under various conditions. These data are reviewed for the purpose of generating hypotheses and to encourage further studies in this very interesting and important area. PMID:22123166

  1. Mutations in sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders.

    PubMed

    Drenth, Joost P H; Waxman, Stephen G

    2007-12-01

    The voltage-gated sodium-channel type IX alpha subunit, known as Na(v)1.7 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 Na(v)1.7 dysfunction in three different human pain disorders. Gain-of-function missense mutations in Na(v)1.7 have been shown to cause primary erythermalgia and paroxysmal extreme pain disorder, while nonsense mutations in Na(v)1.7 result in loss of Na(v)1.7 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 Na(v)1.7 in pain sensation in humans.

  2. Localization of human T-cell lymphotropic virus-1 gag proviral sequences in dermato-immunological disorders with eosinophilia.

    PubMed

    Nagy, K; Marschalkó, Márta; Kemény, B; Horváth, A

    2005-01-01

    The mechanisms leading to the development of eosinophilia were investigated in 65 patients with immunodermatological disorders, including the role of eosinophilotactic cytokines and the possible involvement of human T-cell leukemia virus, HTLV. HTLV-1 gag proviral sequences were revealed in two cases of lymphoproliferative disorders such as angiolymphoid hyperplasia with eosinophilia (ALHE) and CD4+ cutaneous lymphoma, respectively. Increased level of GM-CSF was detected in 33% of disorders studied. Elevated level of IL-5 and eotaxin was detected in 27% and 30%, respectively, of patients with bullous diseases. Elevated level of GM-CSF and eotaxin was found in 33% and 46%, respectively, of patients with inflammatory diseases. Neither of the four cytokines, however proved to be responsible alone or together for the induction of eosinophilia. The possible indirect role of human retroviruses through induction of eosinophilic chemotactic cytokines is hypothesized.

  3. Infection and characterization of Toxoplasma gondii in human induced neurons from patients with brain disorders and healthy controls

    PubMed Central

    Passeri, Eleonora; Jones-Brando, Lorraine; Bordón, Claudia; Sengupta, Srona; Wilson, Ashley M; Primerano, Amedeo; Rapoport, Judith L; Ishikuza, Koko; Kano, Shin-ichi; Yolken, Robert H; Sawa, Akira

    2016-01-01

    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

  4. 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.

  5. 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

    Gao, Li; Guo, Hao; Ye, Nan; 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.

  6. The gene for Crouzon craniofacial dysostosis maps to a 7 centiMorgan region on chromosome 10q in three unrelated kindreds

    SciTech Connect

    Ehrlich, G.D.; Preston, R.A.; Aston, C.A.

    1994-09-01

    Crouzon craniofacial dysostosis (CFD, M.I.M. number 123500) is an autosomal dominant disorder of craniofacial development with complete penetrance and variable expressivity that is characterized by premature craniosynostosis, maxilary hypoplasia, and shallow orbits. We recently mapped CFD to a 21 centiMorgan (cM) region of chromosome 10q25-q26 in two unrelated families from North America. We now report the confirmation of this locus using a third large CFD kindred from South America and describe a refinement of the CFD gene map position. A recombination was observed in two members of the Argentinean kindred at marker D10S209, thereby redefining the centromeric limit of the CFD locus. In addition, a newly available Genethon microsatellite marker, D10S587, which maps between D10S216 and D10S209, proved to be informative for the original family and a recombination was observed at this marker in an unaffected family member, redefining the telomeric limit of the Crouzon syndrome locus. The finding of these obligate recombinants reduces the candidate region for the CFD gene locus to 7 cM. Multipoint linkage analysis (LINKAGE (ver 5.1)) carried out on the three pedigrees produced a maximal LOD score of 12.33 at a locus approximately 2 cM telomeric to D10S209. These findings suggest that CFD is a genetically homogeneous disorder caused by mutations in a gene located on chromosome 10q.

  7. 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

  8. 11,000 years of craniofacial and mandibular variation in Lower Nubia.

    PubMed

    Galland, Manon; Van Gerven, Denis P; Von Cramon-Taubadel, Noreen; Pinhasi, Ron

    2016-08-09

    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.

  9. 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,…

  10. 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…

  11. [Balance disorders in the elderly].

    PubMed

    Bracchi, E; Rizzo, S; Longari, F; Bernardini, M; Bizzotti, C; Frenguelli, A

    2002-10-01

    In the elderly patient, instability is a syndrome in which a loss of balance, during ambulation or while standing, can give rise to falls, with consequent disability and morbidity. Maintaining the correct static and dynamic balance is known to be the result of the synergetic functioning of different systems. In old age, however, the efficiency of these mechanisms is impaired because of the physiological process of aging, which affects all of the organs and systems of the human body. Besides that, different concomitant causes such as cardiovascular and dysmetabolic pathologies, chronic pharmacological therapies etc. contribute to the aging of our organism. The object of this study was to evaluate 40 subjects, 21 males and 19 females, aged between 70 and 86, who were referred to us with craniofacial trauma consequent to a fall. Upon hospitalization, all of the patients were asked to fill in a questionnaire evaluating the incidence of the vertigo symptom as a possible cause of the falls. All of the subjects underwent the following clinicoinstrumental examinations: standard audiometric evaluation, vestibular tests, neurological and ophthalmic examination. Careful appraisal of the results obtained enabled us to conclude that balance disorders in the elderly patient are due to the synergetic action of three factors: aging, concomitant diseases and environmental factors. In conclusion, we can affirm that balance disorders giving rise to a fall in the elderly are attributable to the concomitance of different factors that determine a clinical state of imbalance, defined by some Authors with the term "presbivertigo". It follows that a suitable diagnostic protocol must be employed, comprising a detailed medical, pharmacological and functional history, a study both of the environmental conditions in which the patient lives and the modalities according to which the traumatic event occurred. It is, last of all, indispensable that steps be taken to improve these environmental

  12. A mouse model of a human congenital disorder of glycosylation caused by loss of PMM2

    PubMed Central

    Chan, Barden; Clasquin, Michelle; Smolen, Gromoslaw A.; Histen, Gavin; Powe, Josh; Chen, Yue; Lin, Zhizhong; Lu, Chenming; Liu, Yan; Cang, Yong; Yan, Zhonghua; Xia, Yuanfeng; Thompson, Ryan; Singleton, Chris; Dorsch, Marion; Silverman, Lee; Su, Shin-San Michael; Freeze, Hudson H.; Jin, Shengfang

    2016-01-01

    The most common congenital disorder of glycosylation (CDG), phosphomannomutase 2 (PMM2)-CDG, is caused by mutations in PMM2 that limit availability of mannose precursors required for protein N-glycosylation. The disorder has no therapy and there are no models to test new treatments. We generated compound heterozygous mice with the R137H and F115L mutations in Pmm2 that correspond to the most prevalent alleles found in patients with PMM2-CDG. Many Pmm2R137H/F115L mice died prenatally, while survivors had significantly stunted growth. These animals and cells derived from them showed protein glycosylation deficiencies similar to those found in patients with PMM2-CDG. Growth-related glycoproteins insulin-like growth factor (IGF) 1, IGF binding protein-3 and acid-labile subunit, along with antithrombin III, were all deficient in Pmm2R137H/F115L mice, but their levels in heterozygous mice were comparable to wild-type (WT) littermates. These imbalances, resulting from defective glycosylation, are likely the cause of the stunted growth seen both in our model and in PMM2-CDG patients. Both Pmm2R137H/F115L mouse and PMM2-CDG patient-derived fibroblasts displayed reductions in PMM activity, guanosine diphosphate mannose, lipid-linked oligosaccharide precursor and total cellular protein glycosylation, along with hypoglycosylation of a new endogenous biomarker, glycoprotein 130 (gp130). Over-expression of WT-PMM2 in patient-derived fibroblasts rescued all these defects, showing that restoration of mutant PMM2 activity is a viable therapeutic strategy. This functional mouse model of PMM2-CDG, in vitro assays and identification of the novel gp130 biomarker all shed light on the human disease, and moreover, provide the essential tools to test potential therapeutics for this untreatable disease. PMID:27053713

  13. 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

  14. Molecular characteristics of Human Endogenous Retrovirus type-W in schizophrenia and bipolar disorder.

    PubMed

    Perron, H; Hamdani, N; Faucard, R; Lajnef, M; Jamain, S; Daban-Huard, C; Sarrazin, S; LeGuen, E; Houenou, J; Delavest, M; Moins-Teisserenc, H; Moins-Teiserenc, H; Bengoufa, D; Yolken, R; Madeira, A; Garcia-Montojo, M; Gehin, N; Burgelin, I; Ollagnier, G; Bernard, C; Dumaine, A; Henrion, A; Gombert, A; Le Dudal, K; Charron, D; Krishnamoorthy, R; Tamouza, R; Leboyer, M

    2012-12-04

    Epidemiological and genome-wide association studies of severe psychiatric disorders such as schizophrenia (SZ) and bipolar disorder (BD), suggest complex interactions between multiple genetic elements and environmental factors. The involvement of genetic elements such as Human Endogenous Retroviruses type 'W' family (HERV-W) has consistently been associated with SZ. HERV-W envelope gene (env) is activated by environmental factors and encodes a protein displaying inflammation and neurotoxicity. The present study addressed the molecular characteristics of HERV-W env in SZ and BD. Hundred and thirty-six patients, 91 with BD, 45 with SZ and 73 healthy controls (HC) were included. HERV-W env transcription was found to be elevated in BD (P<10-4) and in SZ (P=0.012) as compared with HC, but with higher values in BD than in SZ group (P<0.01). The corresponding DNA copy number was paradoxically lower in the genome of patients with BD (P=0.0016) or SZ (P<0.0003) than in HC. Differences in nucleotide sequence of HERV-W env were found between patients with SZ and BD as compared with HC, as well as between SZ and BD. The molecular characteristics of HERV-W env also differ from what was observed in Multiple Sclerosis (MS) and may represent distinct features of the genome of patients with BD and SZ. The seroprevalence for Toxoplasma gondii yielded low but significant association with HERV-W transcriptional level in a subgroup of BD and SZ, suggesting a potential role in particular patients. A global hypothesis of mechanisms inducing such major psychoses is discussed, placing HERV-W at the crossroads between environmental, genetic and immunological factors. Thus, particular infections would act as activators of HERV-W elements in earliest life, resulting in the production of an HERV-W envelope protein, which then stimulates pro-inflammatory and neurotoxic cascades. This hypothesis needs to be further explored as it may yield major changes in our understanding and treatment of

  15. [Genes, forces and forms: mechanical aspects of prenatal craniofacial development].

    PubMed

    Radlanski, Ralf J; Renz, Herbert

    2007-12-01

    Current knowledge of molecular signaling during craniofacial development is advancing rapidly. We know that cells can respond to mechanical stimuli by biochemical signaling. Thus, the link between mechanical stimuli and gene expression has become a new and important area of the morphological sciences. This field of research seems to be a revival of the old approach of developmental mechanics, which goes back to the embryologists His [36], Carey [13, 14], and Blechschmidt [5]. These researchers argued that forces play a fundamental role in tissue differentiation and morphogenesis. They understood morphogenesis as a closed system with living cells as the active part and biological, chemical, and physical laws as the rules. This review reports on linking mechanical aspects of developmental biology with the contemporary knowledge of tissue differentiation. We focus on the formation of cartilage (in relation to pressure), bone (in relation to shearing forces), and muscles (in relation to dilation forces). The cascade of molecules may be triggered by forces, which arise during physical cell and tissue interaction. Detailed morphological knowledge is mandatory to elucidate the exact location and timing of the regions where forces are exerted. Because this finding also holds true for the exact timing and location of signals, more 3D images of the developmental processes are required. Further research is also required to create methods for measuring forces within a tissue. The molecules whose presence and indispensability we are investigating appear to be mediators rather than creators of form.

  16. Genes, forces, and forms: mechanical aspects of prenatal craniofacial development.

    PubMed

    Radlanski, Ralf J; Renz, Herbert

    2006-05-01

    Current knowledge of molecular signaling during craniofacial development is advancing rapidly. We know that cells can respond to mechanical stimuli by biochemical signaling. Thus, the link between mechanical stimuli and gene expression has become a new and important area of the morphological sciences. This field of research seems to be a revival of the old approach of developmental mechanics, which goes back to the embryologists His (1874), Carey (1920), and Blechschmidt (1948). These researchers argued that forces play a fundamental role in tissue differentiation and morphogenesis. They understood morphogenesis as a closed system with living cells as the active part and biological, chemical, and physical laws as the rules. This review reports on linking mechanical aspects of developmental biology with the contemporary knowledge of tissue differentiation. We focus on the formation of cartilage (in relation to pressure), bone (in relation to shearing forces), and muscles (in relation to dilation forces). The cascade of molecules may be triggered by forces, which arise during physical cell and tissue interaction. Detailed morphological knowledge is mandatory to elucidate the exact location and timing of the regions where forces are exerted. Because this finding also holds true for the exact timing and location of signals, more 3D images of the developmental processes are required. Further research is also required to create methods for measuring forces within a tissue. The molecules whose presence and indispensability we are investigating appear to be mediators rather than creators of form.

  17. 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

  18. Assessment of Stability of Craniofacial Implants by Resonant Frequency Analysis.

    PubMed

    Ivanjac, Filip; Konstantinović, Vitomir S; Lazić, Vojkan; Dordević, Igor; Ihde, Stefan

    2016-03-01

    Implant stability is a principal precondition for the success of implant therapy. Extraoral implants (EO) are mainly used for anchoring of maxillofacial epithesis. However, assessment of implant stability is mostly based on principles derived from oral implants. The aim of this study was to investigate clinical stability of EO craniofacial disk implants (single, double, and triple) by resonance frequency analysis at different stages of the bone's healing. Twenty patients with orbital (11), nasal (5), and auricular (4) defects with 50 EO implants placed for epithesis anchorage were included. Implant stability was measured 3 times; after implant placement, at 3 months and at least after 6 months. A significant increase in implant stability values was noted between all of the measurements, except for triple-disk implants between third and sixth months, and screw implants between 0 and third months. Disk implants showed lower implant stability quotient (ISQ) values compared with screw implants. Triple-disk implants showed better stability compared with single and double-disk implants. Based on resonance frequency analysis values, disk implants could be safely loaded when their ISQ values are 38 (single disks), 47 (double disks), and 48 (triple disks). According to resonance frequency analysis, disk implant stability increased over time, which showed good osseointegration and increasing mineralization. Although EO screw implants showed higher ISQ values than disk implants, disk-type implants can be safely loaded even if lower values of stability are measured.

  19. 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.

  20. Independence of biomechanical forces and craniofacial pneumatization in Cebus.

    PubMed

    Rae, Todd C; Koppe, Thomas

    2008-11-01

    Several different factors have been hypothesized as explanations of variation in primate paranasal sinus size. Biomechanical forces, particularly those associated with mastication, are frequently evoked to account for differences in primate craniofacial pneumatization. To test whether masticatory stresses are responsible for maxillary sinus volume diversity, two platyrrhine species of the genus Cebus (C. apella and C. albifrons) were examined. The former has been identified as a hard object feeder, and many morphological differences between the two species are attributable to differences in the mechanical properties of their respective diets. Sinus volumes were derived from serial coronal CT scans of the crania of adults. Several external cranial measurements were used to scale sinus volume relative to the size of the face. Relative measures of maxillary sinus volume were compared using standard statistical techniques. In all comparisons, the two capuchin species do not differ from one another significantly at P < 0.05. Thus, this "natural experiment" fails to support the interpretation that biomechanical forces acting on the facial skeleton substantially affect the degree of paranasal pneumatization in primates. This result suggests that it is unlikely that the maxillary sinus performs any function in relation to masticatory stress; other factors must be responsible for the variation in sinus volume among primates.

  1. 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

  2. Scanning Electron Microscopy And Data Digitization Of Craniofacial Growth

    NASA Astrophysics Data System (ADS)

    Rice, Robert W.; Oyen, Ordean J.; Walker, Alan C.

    1980-07-01

    The scanning electron microscope (SEM), combining high resolution and large depth of focus, affords detailed observation of surface microstructure in a three-dimensional perspective. It also allows large specimen dimensions and avoids the processing and sectioning limitations of light and transmission electron microscopic procedures. For these reasons the SEM is ideally suited for analyses of bone, a rigid tissue whose surface topography and internal architecture accurately reflect the developmental, metabolic and mechanical influences exerted upon it. Furthermore, SEM photomicrographs are compatible with devices for quantification, mathematical manipulation and graphic reconstruction of the image. Features of a photo may be traced with a stylus on the electromagnetically activated surface of a data digitizer, which converts the outlined path to x and y axis coordinates. Interfaced with a programmed calculator these data undergo algebraic and geometrical computation and may be stored for statistical analyses. Alternatively, stereopairs of micrograph transparencies may be utilized in micro-stereophotogrammetric procedures in which x, y and z axis coordinates are generated for selected morphologic points. Our research concerns spatiotemporal interrelationships of primate craniofacial growth as evidenced by changes in the skeletal gross morphology and microanatomy of the orbital region, jaws and teeth during their growth and development. Applications of SEM and digitization techniques to these studies and an evaluation of the derived data will be presented.

  3. 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

  4. A radioimmunoassay for erythropoietin: serum levels in normal human subjects and patients with hemopoietic disorders

    SciTech Connect

    Rege, A.B.; Brookins, J.; Fisher, J.W.

    1982-12-01

    An RIA for Ep has been developed that is highly sensitive and specific. A homogeneous Ep preparation was labeled with /sup 125/I by the chloramine-T method to a specific activity of 90 to 136 ..mu..Ci/..mu..g and immunoreactivity of 80%. Ep antiserum, which was produced to a human urinary Ep preparation (80 U/mg of protein), was adsorbed with normal human urinary and serum proteins without any loss in sensitivity of the RIA to increase the specificity of the assay. A good correlation was seen between the RIA and the exhypoxic polycythemic mouse assay (corr. coef. 0.967; slope 1.05 and ''y'' intercept 0.75). Ep titers in sera from 175 hematologically normal human subjects exhibited a normal frequency distribution and ranged between 5.8 and 36.6 mU/ml with a mean of 14.9 +/- 4.7 (S.D.) and median of 14.3. Serum Ep titers were markedly elevated in seven patients with aplastic anemia and one patient with pure red cell aplasia (1350 to 20,640 mU/ml) and were lower than normal in two patients with polycythemia vera (8.1 and 9.4 mU/ml). The serum Ep titers in a prenephrectomy patient with chronic glomerulonephritis (31.1 mU/ml) decreased to below normal levels (9.04 mU/ml) after nephrectomy. The cord serum erythropoietin titers in 10 IDM (90.82 +/- 134.1 (S.D.) mu/ml) returned to values within the normal range (13.86 +/- 5.55) on day 3 after birth, suggesting the utility of the RIA in elucidating the role of hypoxia and/or insulin in increased erythropoiesis in IDM. The serum Ep titers in patients with anemias and polycythemias were compared to those of normal human subjects and agreed well with pathophysiologic mechanisms of these hemopoietic disorders, confirming the validity of the RIA.

  5. A radioimmunoassay for erythropoietin: serum levels in normal human subjects and patients with hemopoietic disorders

    SciTech Connect

    Rege, A.B.; Brookins, J.; Fisher, J.W.

    1982-12-01

    An RIA for Ep has been developed that is highly sensitive and specific. A homogeneous Ep preparation was labeled with /sup 125/I by the chloramine-T method to a specific activity of 90 to 136 micro Ci/microgram and immunoreactivity of 80%. Ep antiserum, which was produced to a human urinary Ep preparation (80 U/mg of protein), was adsorbed with normal human urinary and serum proteins without any loss in sensitivity of the RIA to increase the specificity of the assay. A good correlation was seen between the RIA and the exhypoxic polycythemic mouse assay (corr. coef. 0.967; slope 1.05 and y intercept 0.75). Ep titers in sera from 175 hematologically normal human subjects exhibited a normal frequency distribution and ranged between 5.8 and 36.6 mU/ml with a mean of 14.9 +/- 4.7 (S.D.) and median of 14.3 Serum Ep titers were markedly elevated in seven patients with aplastic anemia and one patient with pure red cell aplasia (1350 to 20,640 mU/ml) and were lower than normal in two patients with polycythemia vera (8.1 and 9.4 mU/ml). The serum Ep titers in a prenephrectomy patient with chronic glomerulonephritis (32.1 mU/ml) decreased to below normal levels (9.04 mU/ml) after nephrectomy. The cord serum erythropoietin titers in 10 IDM (90.82 +/- 134.1 (S.D.) mu/ml) returned to values within the normal range (13.86 +/- 5.55) on day 3 after birth, suggesting the utility of the RIA in elucidating the role of hypoxia and/or insulin in increased erythropoiesis in IDM. The serum Ep titers in patients with anemias and polycythemias were compared to those of normal human subjects and agreed well with pathophysiologic mechanisms of these hemopoietic disorders, confirming the validity of the RIA.

  6. The human genome, implications for oral health and diseases, and dental education.

    PubMed

    Slavkin, H C

    2001-05-01

    We are living in an extraordinary time in human history punctuated by the convergence of major scientific and technological progress in the physical, chemical, and biological ways of knowing. Equally extraordinary are the sparkling intellectual developments at the interface between fields of study. One major example of an emerging influence on the future of oral health education is at the interface between the human genome, information technology, and biotechnology with miniaturizations (nanotechnology), suggesting new oral health professional competencies for a new century. A great deal has recently been learned from human and non-human genomics. Genome databases are being "mined" to prompt hypothesis-driven "postgenomic" or functional genomic science in microbial models such as Candida albicans related to oral candidiasis and in human genomics related to biological processes found in craniofacial, oral, and dental diseases and disorders. This growing body of knowledge is already providing the gene content of many oral microbial and human genomes and the knowledge of genetic variants or polymorphisms related to disease, disease progression, and disease response to therapeutics (pharmacogenomics). The knowledge base from human and non-human genomics, functional genomics, biotechnology, and associated information technologies is serving to revolutionize oral health promotion, risk assessment using biomarkers and disease prevention, diagnostics, treatments, and the full range of therapeutics for craniofacial, oral, and dental diseases and disorders. Education, training, and research opportunities are already transforming the curriculum and pedagogy for undergraduate science majors, predoctoral health professional programs, residency and specialty programs, and graduate programs within the health professions. In the words of Bob Dylan, "the times they are a-changing."

  7. 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

  8. 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.

  9. Psychological and Social Factors in Undergoing Reconstructive Surgery Among Individuals With Craniofacial Conditions: An Exploratory Study

    PubMed Central

    Bemmels, Heather; Biesecker, Barbara; Schmidt, Johanna L.; Krokosky, Alyson; Guidotti, Rick; Sutton, Erica J.

    2012-01-01

    Objective Reconstructive surgery to improve psychological well-being is commonly offered to children with craniofacial conditions. Few studies have explored the challenges of reconstructive surgery beyond the physical risks: poor treatment outcomes, infection, brain damage, and death. This qualitative study aims to understand the psychological and social implications such interventions can have for individuals with craniofacial conditions. Design A total of 38 individuals between the ages of 12 and 61 with such craniofacial conditions as Sturge-Weber syndrome, Treacher Collins syndrome, Möbius syndrome, cleft lip and palate, Noonan syndrome, Crouzon syndrome, and amniotic band syndrome participated in semistructured video-recorded interviews. Participants were recruited at conferences, through study flyers, and by word of mouth. Descriptive, thematic analysis was used to identify themes related to reconstructive surgery. Results Dominant themes included undergoing surgery to reduce stigmatization, the psychological and social implications of the interventions, outcome satisfaction, parental involvement in decision making about surgery, and recommendations for parents considering surgery for their children with craniofacial conditions. Experiences with reconstructive surgery varied, with some participants expressing surgical benefits and others, disillusionment. Conclusions The range of participant attitudes and experiences reflect the complexity of reconstructive surgery. Pediatric health care teams involved in the care of children with craniofacial conditions play an important role in advising patients (and their parents) about existing treatment options. The psychological and social implications of reconstructive surgery should be relayed to help families weigh the risks and benefits of surgery in an informed and meaningful way. PMID:22315960

  10. Craniofacial and cervical morphology related to sagittal spinal posture in children and adolescents.

    PubMed

    Segatto, Emil; Segatto, Angyalka; Braunitzer, Gábor; Kirschneck, Christian; Fanghänel, Jochen; Danesh, Gholamreza; Lippold, Carsten

    2014-01-01

    Studies on the relationship between body posture and craniofacial parameters often focus on the cervical spine. Thus, less attention has been paid to the morphology of the vertebra C2 that serves as both a structural and functional link between the craniofacial area and the other part of the spine. The objective of this study was to assess the relation of craniofacial features to certain morphological and positional characteristics of the cervical vertebrae and the spine during growth. We determined body posture indices for 69 children and adolescents by means of a radiation-free method (rasterstereography). The morphological and positional analysis of the craniofacial area and the cervical vertebrae was based on standardized lateral X-ray cephalograms. Medium to strong correlations were found between body posture, C2 morphology, and craniofacial parameters. We found significant correlations between the C2 dens axis height and maxillary indices as well as between the C2 dens axis inclination and cephalometrical values of the mandibular area. Similarly the correlation between the C2 dens axis inclination and the postural index flèche cervicale was highly significant (P < 0.05, r = 0.333). These results suggest that morphological features of the odontoid process may serve as valuable predictive markers in interdisciplinary orthopedic-orthodontic diagnostics.

  11. Craniofacial and Cervical Morphology Related to Sagittal Spinal Posture in Children and Adolescents

    PubMed Central

    Segatto, Angyalka; Braunitzer, Gábor

    2014-01-01

    Studies on the relationship between body posture and craniofacial parameters often focus on the cervical spine. Thus, less attention has been paid to the morphology of the vertebra C2 that serves as both a structural and functional link between the craniofacial area and the other part of the spine. The objective of this study was to assess the relation of craniofacial features to certain morphological and positional characteristics of the cervical vertebrae and the spine during growth. We determined body posture indices for 69 children and adolescents by means of a radiation-free method (rasterstereography). The morphological and positional analysis of the craniofacial area and the cervical vertebrae was based on standardized lateral X-ray cephalograms. Medium to strong correlations were found between body posture, C2 morphology, and craniofacial parameters. We found significant correlations between the C2 dens axis height and maxillary indices as well as between the C2 dens axis inclination and cephalometrical values of the mandibular area. Similarly the correlation between the C2 dens axis inclination and the postural index flèche cervicale was highly significant (P < 0.05, r = 0.333). These results suggest that morphological features of the odontoid process may serve as valuable predictive markers in interdisciplinary orthopedic-orthodontic diagnostics. PMID:25276804

  12. Correlation between maximum bite force and craniofacial morphology of young adults in Indonesia.

    PubMed

    Sondang, P; Kumagai, H; Tanaka, E; Ozaki, H; Nikawa, H; Tanne, K; Hamada, T

    2003-11-01

    The present study was conducted to evaluate the relationship between maximum bite force and craniofacial morphology. Sixty-four Indonesian female dental students aged 19-27 years with normal occlusion served as the subjects. The Dental Prescale System was used to measure the maximum bite force using a pressure sensitive sheets while craniofacial morphology measurements were determined from conventional lateral radiograms. The antero-posterior and right-left position of the occlusal load centre (the OLC) were measured also. Stepwise multiple regression analysis was performed to evaluate the relationship between bite force and craniofacial morphology while correlation analysis was used to evaluate the antero-posterior position of the OLC related to craniofacial morphology. Fifty-five per cent of the bite force could be explained by variations in the posterior facial height, gonial angle, antero-posterior size of the maxilla, and posterior length of the cranial base. The result showed a larger bite force implies a greater posterior facial height, smaller gonial angle, larger maxilla and straighter posterior length of the cranial base. This study suggests that among Indonesians, maximum bite force could be explained by craniofacial morphology as found in Caucasians. In addition, we proposed a clinical standard of the OLC for the comprehensive evaluation of occlusion.

  13. Craniofacial pain can be the sole prodromal symptom of an acute myocardial infarction: an interdisciplinary study.

    PubMed

    Kreiner, Marcelo; Álvarez, Ramón; Michelis, Virginia; Waldenström, Anders; Isberg, Annika

    2016-04-01

    We recently found craniofacial pain to be the sole symptom of an acute myocardial infarction (AMI) in 4% of patients. We hypothesized that this scenario is also true for symptoms of prodromal (pre-infarction) angina. We studied 326 consecutive patients who experienced myocardial ischemia. Intra-individual variability analyses with respect to ECG findings and pain characteristics were performed for those 150 patients who experienced at least one recurrent ischemic episode. AMI patients (n=113) were categorized into two subgroups: "abrupt onset" (n=81) and "prodromal angina" (n=32). Age, gender and risk factor comparisons were performed between groups. Craniofacial pain constituted the sole prodromal symptom of an AMI in 5% of patients. In those who experienced two ischemic episodes, women were more likely than men to experience craniofacial pain in both episodes (p<0.01). There was no statistically significant difference between episodes regarding either ECG findings or the use of the two typical pain quality descriptors "pressure" and "burning". This study is to our knowledge the first to report that craniofacial pain can be the only symptom of a pre-infarction angina. Craniofacial pain constitutes the sole prodromal AMI symptom in one out of 20 AMI patients. Recognition of this atypical symptom presentation is low because research on prodromal AMI symptoms has to date studied only patients with chest pain. To avoid a potentially fatal misdiagnosis, awareness of this clinical presentation needs to be brought to the attention of clinicians, researchers and the general public.

  14. Divergent and conserved roles of Dll1 signaling in development of craniofacial and trunk muscle.

    PubMed

    Czajkowski, Maciej T; Rassek, Claudia; Lenhard, Diana C; Bröhl, Dominique; Birchmeier, Carmen

    2014-11-15

    Craniofacial and trunk skeletal muscles are evolutionarily distinct and derive from cranial and somitic mesoderm, respectively. Different regulatory hierarchies act upstream of myogenic regulatory factors in cranial and somitic mesoderm, but the same core regulatory network - MyoD, Myf5 and Mrf4 - executes the myogenic differentiation program. Notch signaling controls self-renewal of myogenic progenitors as well as satellite cell homing during formation of trunk muscle, but its role in craniofacial muscles has been little investigated. We show here that the pool of myogenic progenitor cells in craniofacial muscle of Dll1(LacZ/Ki) mutant mice is depleted in early fetal development, which is accompanied by a major deficit in muscle growth. At the expense of progenitor cells, supernumerary differentiating myoblasts appear transiently and these express MyoD. The progenitor pool in craniofacial muscle of Dll1(LacZ/Ki) mutants is largely rescued by an additional mutation of MyoD. We conclude from this that Notch exerts its decisive role in craniofacial myogenesis by repression of MyoD. This function is similar to the one previously observed in trunk myogenesis, and is thus conserved in cranial and trunk muscle. However, in cranial mesoderm-derived progenitors, Notch signaling is not required for Pax7 expression and impinges little on the homing of satellite cells. Thus, Dll1 functions in satellite cell homing and Pax7 expression diverge in cranial- and somite-derived muscle.

  15. Customized Polymethyl Methacrylate Implants for the Reconstruction of Craniofacial Osseous Defects

    PubMed Central

    Fernandes da Silva, André Luis; Borba, Alexandre Meireles; Simão, Niverso Rodrigues; Pedro, Fábio Luis Miranda

    2014-01-01

    Craniofacial defects represent alterations in the anatomy and morphology of the cranial vault and the facial bones that potentially affect an individual's psychological and social well-being. Although a variety of techniques and restorative procedures have been described for the reconstruction of the affected area, polymethyl methacrylate (PMMA), a biocompatible and nondegradable acrylic resin-based implant, is the most widely used alloplastic material for such craniomaxillofacial reconstruction. The aim of this study was to describe a technique for aesthetic and functional preoperative customized reconstruction of craniofacial bone defects from a small series of patients offered by the Brazilian public health system. Three adult male patients attended consultation with chief complaints directly related to their individual craniofacial bone defects. With the aid of multislice computed tomography scans and subsequent fabrication of the three-dimensional craniofacial prototype, custom-made PMMA implants were fabricated preoperatively. Under general anesthesia, with access to the craniofacial defects with a coronal approach, the PMMA implants were adapted and fixated to the facial skeleton with titanium plates and screws. Postoperative evaluation demonstrated uneventful recovery and an excellent aesthetic result. Customized prefabricated PMMA implants manufactured over the rapid prototyping models proved to be effective and feasible. PMID:25093139

  16. 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

  17. Radiation-induced craniofacial deformities: a new classification and management algorithm.

    PubMed

    Allam, Karam A; Lim, Alan A; Elsherbiny, Ahmed; Bradley, James P; Kawamoto, Henry K

    2013-08-01

    Little is written about the spectrum of late radiation-induced craniofacial abnormalities and the guidelines for treating these abnormalities. The clinical records of 13 patients (eight males and five females) who received childhood craniofacial radiation between birth and 11 years of age and who subsequently had reconstructive surgery were reviewed. Eleven patients had their irradiation at the age from 1 to 5 years. The other two patients received their treatment at a relatively older age (9 and 11 years). Their deformities ranged from isolated soft-tissue deficiency with no or minimal bony deficiency to cases having osseous deformities with or without soft-tissue deficiency but still the normal or near-normal craniofacial form can be obtained with surgical intervention and the outermost extreme of the deformity is the patients whose normal or near-normal craniofacial form and function cannot be regained even with much sophisticated surgeries. Our new classification is based on two factors: the tissue component of the deformity and the possibility of regaining a normal or near-normal craniofacial form and function with the planned surgical intervention. Based on this classification, a new treatment algorithm was created.

  18. 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

    2016-08-10

    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.

  19. 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.

  20. Exploring the Human Seminal Plasma Proteome: An Unexplored Gold Mine of Biomarker for Male Infertility and Male Reproduction Disorder

    PubMed Central

    Gilany, Kambiz; Minai-Tehrani, Arash; Savadi-Shiraz, Elham; Rezadoost, Hassan; Lakpour, Niknam

    2015-01-01

    Background The human seminal fluid is a complex body fluid. It is not known how many proteins are expressed in the seminal plasma; however in analog with the blood it is possible up to 10,000 proteins are expressed in the seminal plasma. The human seminal fluid is a rich source of potential biomarkers for male infertility and reproduction disorder. Methods In this review, the ongoing list of proteins identified from the human seminal fluid was collected. To date, 4188 redundant proteins of the seminal fluid are identified using different proteomics technology, including 2-DE, SDS-PAGE-LC-MS/MS, MudPIT. However, this was reduced to a database of 2168 non-redundant protein using UniProtKB/Swiss-Prot reviewed database. Results The core concept of proteome were analyzed including pI, MW, Amino Acids, Chromosome and PTM distribution in the human seminal plasma proteome. Additionally, the biological process, molecular function and KEGG pathway were investigated using DAVID software. Finally, the biomarker identified in different male reproductive system disorder was investigated using proteomics platforms so far. Conclusion In this study, an attempt was made to update the human seminal plasma proteome database. Our finding showed that human seminal plasma studies used to date seem to have converged on a set of proteins that are repeatedly identified in many studies and that represent only a small fraction of the entire human seminal plasma proteome. PMID:25927022

  1. 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

  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. Foxc1 Ablated Mice Are Anhidrotic and Recapitulate Features of Human Miliaria Sweat Retention Disorder.

    PubMed

    Cui, Chang-Yi; Ishii, Ryuga; Campbell, Dean P; Michel, Marc; Piao, Yulan; Kume, Tsutomu; Schlessinger, David

    2017-01-01

    Sweat glands are critical for thermoregulation. The single tubular structure of sweat glands has a lower secretory portion and an upper reabsorptive duct leading to the secretory pore in the skin. Genes that determine sweat gland structure and function are largely unidentified. Here we report that a Fox family transcription factor, Foxc1, is obligate for appreciable sweat duct activity in mice. When Foxc1 was specifically ablated in skin, sweat glands appeared mature, but the mice were severely hypohidrotic. Morphologic analysis revealed that sweat ducts were blocked by hyperkeratotic or parakeratotic plugs. Consequently, lumens in ducts and secretory portions were dilated, and blisters and papules formed on the skin surface in the knockout mice. The phenotype was strikingly similar to the human sweat retention disorder miliaria. We further show that Foxc1 deficiency ectopically induces the expression of keratinocyte terminal differentiation markers in the duct luminal cells, which most likely contribute to keratotic plug formation. Among those differentiation markers, we show that Sprr2a transcription is directly repressed by overexpressed Foxc1 in keratinocytes. In summary, Foxc1 regulates sweat duct luminal cell differentiation, and mutant mice mimic miliaria and provide a possible animal model for its study.

  4. The crystal structure of human GlnRS provides basis for the development of neurological disorders

    DOE PAGES

    Ognjenovic, Jana; Wu, Jiang; Matthies, Doreen; ...

    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

  5. Circulating Human Eosinophils Share a Similar Transcriptional Profile in Asthma and Other Hypereosinophilic Disorders.

    PubMed

    Barnig, Cindy; Alsaleh, Ghada; Jung, Nicolas; 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.

  6. Neuropathologic confirmation of definitional criteria for human immunodeficiency virus-associated neurocognitive disorders.

    PubMed

    Cherner, Mariana; Cysique, Lucette; Heaton, Robert K; Marcotte, Thomas D; Ellis, Ronald J; Masliah, Eliezer; Grant, Igor

    2007-01-01

    Research findings have suggested a need for modifications to the original nomenclature for human immunodeficiency virus (HIV)-associated neurocognitive disorders issued in 1991 by the American Academy of Neurology (AAN). The HIV Neurobehavioral Research Center (HNRC) proposed a diagnostic scheme that departs from the AAN 1991 criteria primarily in the inclusion of an asymptomatic neurocognitive impairment (ANI) category that relies on cognitive disturbances as a necessary criterion for diagnosis, without requiring declines in daily functioning, motor, or other behavioral abnormalities. In order to test the predictive validity of these two nomenclatures, the authors compared the correspondence between antemortem neurocognitive diagnoses resulting from AAN and HNRC criteria to a neuropathological diagnosis of HIV encephalitis (HIVE) made at autopsy. Agreement between the two sets of definitional criteria was 79% regarding the classification of cases as either neurocognitively normal or impaired, and 54% with regard to specific neurocognitive diagnoses. When pathological evidence of HIVE was considered as the external indicator of HIV-related brain involvement, 64% of cases were correctly classified by AAN criteria, compared to 72% by HNRC criteria. HNRC criteria had better positive predictive power (95% versus 88%), sensitivity (67% versus 56%), and specificity (92% versus 83%). Three cases with HIVE and were correctly identified by HNRC criteria for ANI but called normal by AAN criteria, supporting inclusion of an asymptomatic neurocognitive condition. The modifications to the AAN 1991 criteria proposed by the HNRC and others in the field have served as a point of departure for a recently revised consensus nomenclature.

  7. The crystal structure of human GlnRS provides basis for the development of neurological disorders

    SciTech Connect

    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 suggest 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

  8. 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.

  9. 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

  10. PDYN, a gene implicated in brain/mental disorders, is targeted by REST in the adult human brain.

    PubMed

    Henriksson, Richard; Bäckman, Cristina M; Harvey, Brandon K; Kadyrova, Helena; Bazov, Igor; Shippenberg, Toni S; Bakalkin, Georgy

    2014-11-01

    The dynorphin κ-opioid receptor system is implicated in mental health and brain/mental disorders. However, despite accumulating evidence that PDYN and/or dynorphin peptide expression is altered in the brain of individuals with brain/mental disorders, little is known about transcriptional control of PDYN in humans. In the present study, we show that PDYN is targeted by the transcription factor REST in human neuroblastoma SH-SY5Y cells and that that interfering with REST activity increases PDYN expression in these cells. We also show that REST binding to PDYN is reduced in the adult human brain compared to SH-SY5Y cells, which coincides with higher PDYN expression. This may be related to MIR-9 mediated down-regulation of REST as suggested by a strong inverse correlation between REST and MIR-9 expression. Our results suggest that REST represses PDYN expression in SH-SY5Y cells and the adult human brain and may have implications for mental health and brain/mental disorders.

  11. 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

  12. Cell replication in craniofacial periosteum: appositional vs. resorptive sites

    PubMed Central

    Ochareon, Pannee; Herring, Susan W

    2011-01-01

    The size and the shape of craniofacial bones results from periosteal activity, which can be either appositional or resorptive. The periosteum is often used as a source of graft material for osteogenesis, but differences in cellular makeup and proliferative capacity may render resorptive regions unsuitable for transplant. This study was undertaken to characterize the cells in appositional and resorptive periosteum, and to assess variation in proliferative activity. Young pigs (n = 9) were injected with bromodeoxyuridine to label replicating cells and killed 3 h later. The mandibular ramus, hard palate and zygomatic arch were examined for patterns of periosteal activity, and replicating cells were quantified in 16 appositional and eight resorptive regions. Sections were also reacted for markers of osteogenic (Runx2) and osteoclastic [CTR (calcitonin receptor), RANK, TRAP, CD14] lineage, and for an endothelial label (lectin). Replicating cells were often associated with the vasculature; most were unreactive for markers of differentiation. Although the fibrous layers of periosteum had fewer replicating cells per unit area than inner layers (P < 0.005), t