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Sample records for previously reported missense

  1. Structural analysis of eight novel and 112 previously reported missense mutations in the interactive FXI mutation database reveals new insight on FXI deficiency.

    Science.gov (United States)

    Saunders, Rebecca E; Shiltagh, Nuha; Gomez, Keith; Mellars, Gillian; Cooper, Carolyn; Perry, David J; Tuddenham, Edward G; Perkins, Stephen J

    2009-08-01

    Factor XI (FXI) functions in blood coagulation. FXI is composed of four apple (Ap) domains and a serine protease (SP) domain. Deficiency of FXI leads to an injury-related bleeding disorder, which is remarkable for the lack of correlation between bleeding symptoms and FXI coagulant activity (FXI:C). The number of mutations previously reported in our interactive web database (http://www.FactorXI.org) is now significantly increased to 183 through our new patient studies and from literature surveys. Eight novel missense mutations give a total of 120 throughout the FXI gene (F11). The most abundant defects in FXI are revealed to be those from low-protein plasma levels (Type I: CRM-) that originate from protein misfolding, rather than from functional defects (Type II: CRM+). A total of 70 Ap missense mutations were analysed using a consensus Ap domain structure generated from the FXI dimer crystal structure. This showed that all parts of the Ap domain were affected. The 47 SP missense mutations were also distributed throughout the SP domain structure. The periphery of the Ap beta-sheet structure is sensitive to structural perturbation caused by residue changes throughout the Ap domain, yet this beta-sheet is crucial for FXI dimer formation. Residues located at the Ap4:Ap4 interface in the dimer are much less directly involved. We conclude that the abundance of Type I defects in FXI results from the sensitivity of the Ap domain folding to residue changes within this, and discuss how structural knowledge of the mutations improves our understanding of FXI deficiencies.

  2. [Electronic cigarettes - effects on health. Previous reports].

    Science.gov (United States)

    Napierała, Marta; Kulza, Maksymilian; Wachowiak, Anna; Jabłecka, Katarzyna; Florek, Ewa

    2014-01-01

    Currently very popular in the market of tobacco products have gained electronic cigarettes (ang. E-cigarettes). These products are considered to be potentially less harmful in compared to traditional tobacco products. However, current reports indicate that the statements of the producers regarding to the composition of the e- liquids not always are sufficient, and consumers often do not have reliable information on the quality of the product used by them. This paper contain a review of previous reports on the composition of e-cigarettes and their impact on health. Most of the observed health effects was related to symptoms of the respiratory tract, mouth, throat, neurological complications and sensory organs. Particularly hazardous effects of the e-cigarettes were: pneumonia, congestive heart failure, confusion, convulsions, hypotension, aspiration pneumonia, face second-degree burns, blindness, chest pain and rapid heartbeat. In the literature there is no information relating to passive exposure by the aerosols released during e-cigarette smoking. Furthermore, the information regarding to the use of these products in the long term are not also available.

  3. Report of a patient with a constitutional missense mutation in SMARCB1, Coffin-Siris phenotype, and schwannomatosis.

    Science.gov (United States)

    Gossai, Nathan; Biegel, Jaclyn A; Messiaen, Ludwine; Berry, Susan A; Moertel, Christopher L

    2015-12-01

    We report a patient with a constitutional missense mutation in SMARCB1, Coffin-Siris Syndrome (CSS), and schwannomatosis. CSS is a rare congenital syndrome with characteristic clinical findings. This thirty-three-year-old man was diagnosed early in life with the constellation of moderate intellectual disability, hypotonia, mild microcephaly, coarse facies, wide mouth with full lips, hypoplasia of the digits, and general hirsutism. At age 26, he was found to have schwannomatosis after presenting with acute spinal cord compression. Blood and tissue analysis of multiple subsequent schwannoma resections revealed a germline missense mutation of SMARCB1, acquired loss of 22q including SMARCB1 and NF2 and mutation of the remaining NF2 wild-type allele-thus completing the four-hit, three-event mechanism associated with schwannomatosis. Variations in five genes have been associated with the Coffin-Siris phenotype: ARID1A, ARID1B, SMARCA4, SMARCB1, and SMARCE1. Of these genes, SMARCB1 has a well-established association with schwannomatosis and malignancy. This is the first report of a patient with a constitutional missense mutation of SMARCB1 resulting in CSS and subsequent development of schwannomatosis. This finding demonstrates that a SMARCB1 mutation may be the initial "hit" (constitutional) for a genetic disorder with subsequent risk of developing schwannomas and other malignancies, and raises the possibility that other patients with switch/sucrose non-fermenting (SWI/SNF) mutations may be at increased risk for tumors. © 2015 Wiley Periodicals, Inc.

  4. Brugada syndrome with a novel missense mutation in SCN5A gene: A case report from Bangladesh

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    Md. Zahidus Sayeed

    2014-01-01

    Full Text Available Brugada syndrome is an inherited cardiac arrhythmia that follows autosomal dominant transmission and can cause sudden death. We report a case of Brugada syndrome in a 55-year-old male patient presented with recurrent palpitation, atypical chest pain and presyncope. ECG changes were consistent with type 1 Brugada. Gene analysis revealed a novel missense mutation in SCN5A gene with a genetic variation of D785N and a nucleotide change at 2353G-A. One of his children also had the same mutation. To our knowledge this is the first genetically proved case of Brugada syndrome in Bangladesh.

  5. Urethrotomy has a much lower success rate than previously reported.

    Science.gov (United States)

    Santucci, Richard; Eisenberg, Lauren

    2010-05-01

    We evaluated the success rate of direct vision internal urethrotomy as a treatment for simple male urethral strictures. A retrospective chart review was performed on 136 patients who underwent urethrotomy from January 1994 through March 2009. The Kaplan-Meier method was used to analyze stricture-free probability after the first, second, third, fourth and fifth urethrotomy. Patients with complex strictures (36) were excluded from the study for reasons including previous urethroplasty, neophallus or previous radiation, and 24 patients were lost to followup. Data were available for 76 patients. The stricture-free rate after the first urethrotomy was 8% with a median time to recurrence of 7 months. For the second urethrotomy stricture-free rate was 6% with a median time to recurrence of 9 months. For the third urethrotomy stricture-free rate was 9% with a median time to recurrence of 3 months. For procedures 4 and 5 stricture-free rate was 0% with a median time to recurrence of 20 and 8 months, respectively. Urethrotomy is a popular treatment for male urethral strictures. However, the performance characteristics are poor. Success rates were no higher than 9% in this series for first or subsequent urethrotomy during the observation period. Most of the patients in this series will be expected to experience failure with longer followup and the expected long-term success rate from any (1 through 5) urethrotomy approach is 0%. Urethrotomy should be considered a temporizing measure until definitive curative reconstruction can be planned. 2010 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  6. Compound heterozygosity for two GHR missense mutations in a patient affected by Laron Syndrome: a case report.

    Science.gov (United States)

    Moia, Stefania; Tessaris, Daniele; Einaudi, Silvia; de Sanctis, Luisa; Bona, Gianni; Bellone, Simonetta; Prodam, Flavia

    2017-10-12

    Mutations localized in the Growth Hormone Receptor (GHR) gene are often associated with the pathogenesis of Laron Syndrome, an autosomal recessive hereditary disorder characterized by severe growth retardation. Biochemically, patients present normal to high circulating GH levels, in presence of very low or undetectable IGF-I levels, which do not rise after rhGH treatment. We describe the case of a 3.8 years old girl with symmetrical short stature (-3.76 SDS), low IGF-1 and IGFBP-3, in presence of normal GH levels. Parents were not relatives and there was no family history of short stature. During the second day of birth, she developed severe hypoglycaemia that required glucose infusion. She presented frontal bossing and depressed nasal bridge. IGF-1 generation test showed no response, suggesting a GH resistance evidence. In the hypothesis of Laron Syndrome, we decided to perform a molecular analysis of Growth Hormone Receptor (GHR) gene. This analysis demonstrated that the patient was compound heterozygote for two missense mutations. GHR gene mutations are a well demonstrated cause of GH insensitivity. In heterozygous patients, probably the normal stature may be achieved by a compensatory mechanism of GH secretion or signalling. On the contrary, in homozygous or compound heterozygous patients these compensatory mechanisms are inadequate, and short stature may be the consequence.

  7. A novel missense HGD gene mutation, K57N, in a patient with alkaptonuria.

    Science.gov (United States)

    Grasko, Jonathan M; Hooper, Amanda J; Brown, Jeffrey W; McKnight, C James; Burnett, John R

    2009-05-01

    Alkaptonuria is a rare recessive disorder of phenylalanine/tyrosine metabolism due to a defect in the enzyme homogentisate 1,2-dioxygenase (HGD) caused by mutations in the HGD gene. We report the case of a 38 year-old male with known alkaptonuria who was referred to an adult metabolic clinic after initially presenting to an emergency department with renal colic and subsequently passing black ureteric calculi. He complained of severe debilitating lower back pain, worsening over the last few years. A CT scan revealed marked degenerative changes and severe narrowing of the disc spaces along the entire lumbar spine. Sequencing of the HGD gene revealed that he was a compound heterozygote for a previously described missense mutation in exon 13 (G360R) and a novel missense mutation in exon 3 (K57N). Lys(57) is conserved among species and mutation of this residue is predicted to affect HGD protein function by interfering with substrate traffic at the active site. In summary, we describe an alkaptonuric patient and report a novel missense HGD mutation, K57N.

  8. A Novel Missense Mutation of the NSD1 Gene Associated with Overgrowth in Three Generations of an Italian Family: Case Report, Differential Diagnosis, and Review of Mutations of NSD1 Gene in Familial Sotos Syndrome

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    Gianluigi Laccetta

    2017-11-01

    Full Text Available Sotos syndrome (SoS is characterized by overgrowth of prenatal onset, learning disability, and characteristic facial appearance; it is usually due to haploinsufficiency of NSD1 gene at chromosome 5q35. An Italian child was born at 37 weeks of gestation (weight 2,910 g, 25th–50th centiles; length 50 cm, 75th centile; head circumference 36 cm, 97th centile showing cryptorchidism on the right side, hypertelorism, dolichocephaly, broad and prominent forehead, and narrow jaw; the pregnancy was worsened by maternal preeclampsia and gestational diabetes, and his mother had a previous history of four early miscarriages. The patient showed neonatal jaundice, hypotonia, feeding difficulties, frequent vomiting, and gastroesophageal reflux. After the age of 6 months, his weight, length, and head circumference were above the 97th centile; psychomotor development was delayed. At the age of 9 years, the patient showed also joint laxity and scoliosis. DNA sequence analysis of NSD1 gene detected a novel heterozygous mutation (c.521T>A, p.Val174Asp in exon 2. The same mutant allele was also found in the mother and in the maternal grandfather of the proband; both the mother and the maternal grandfather of the proband showed isolated overgrowth with height above the 97th centile in absence of other features of SoS. At present 23 familial cases of SoS have been described (two cases with mutation in exon 2 of NSD1 gene; no familial cases of SoS with mutation of NSD1 gene and isolated overgrowth have been reported. Probably, point mutations of NSD1 gene, and particularly mutations between exon 20 and exon 23, are not likely to affect reproductive fitness. Epigenetic mechanisms and intrauterine environment may influence phenotypes, therefore genetic tests are not useful to predict the phenotype but they are indispensable for the diagnosis of SoS. This is the first Italian familial case of SoS with genetic confirmation and the third report in which a

  9. Logic of Accounting: The Case of Reporting Previous Options in Norwegian Activation Encounters

    Science.gov (United States)

    Solberg, Janne

    2017-01-01

    The article deals with the enactment of client resistance in Norwegian vocational rehabilitation encounters. More specific, a practice here called "reporting previous options" is analyzed by using the resources of ethnomethodological conversation analysis (CA) in five instances as doing some sort of accounting. In response to the…

  10. Erysipelothrix endocarditis with previous cutaneous lesion: report of a case and review of the literature

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    Marion P. Rocha

    1989-08-01

    Full Text Available This report describes the first documented case of Erysipelothrix rhusiopathiae endocarditis in Latin America. The patient was a 51-years-old male, moderate alcoholic, with a previous history of aortic failure. He was used to fishing and cooking as a hobby and had his left hand wounded by a fish-bone. The disease began with erysipeloid form and developed to septicemia and endocarditis. He was treated with antibiotics and surgery for aortic valve replacement. There are only 46 cases of E. rhusiopathiae endocarditis reported to date. The authors wonder if several other cases might go unreported for lack of microbiological laboratorial diagnosis.

  11. The first missense mutation of NHS gene in a Tunisian family with clinical features of NHS syndrome including cardiac anomaly.

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    Chograni, Manèl; Rejeb, Imen; Jemaa, Lamia Ben; Châabouni, Myriam; Bouhamed, Habiba Chaabouni

    2011-08-01

    Nance-Horan Syndrome (NHS) or X-linked cataract-dental syndrome is a disease of unknown gene action mechanism, characterized by congenital cataract, dental anomalies, dysmorphic features and, in some cases, mental retardation. We performed linkage analysis in a Tunisian family with NHS in which affected males and obligate carrier female share a common haplotype in the Xp22.32-p11.21 region that contains the NHS gene. Direct sequencing of NHS coding exons and flanking intronic sequences allowed us to identify the first missense mutation (P551S) and a reported SNP-polymorphism (L1319F) in exon 6, a reported UTR-SNP (c.7422 C>T) and a novel one (c.8239 T>A) in exon 8. Both variations P551S and c.8239 T>A segregate with NHS phenotype in this family. Although truncations, frame-shift and copy number variants have been reported in this gene, no missense mutations have been found to segregate previously. This is the first report of a missense NHS mutation causing NHS phenotype (including cardiac defects). We hypothesize also that the non-reported UTR-SNP of the exon 8 (3'-UTR) is specific to the Tunisian population.

  12. Granulomatous lobular mastitis: report of a case with previously undescribed histopathological abnormalities.

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    Axelsen, R A; Reasbeck, P

    1988-10-01

    A 41-yr-old multiparous woman presented with a discrete breast lump which proved histologically to be an example of granulomatous lobular mastitis. The clinical and histological features were similar to those noted in previous reports. Additional histological features in the present case were an intense mononuclear cell infiltration of lobular and ductal epithelium, associated with nuclear fragments morphologically suggestive of apoptosis. These appearances, which have not previously been described, are illustrated, together with the more classical features of the condition well demonstrated by the present case. The novel histological features noted here suggest that the development of granulomatous lobular mastitis may be at least in part immunologically mediated, and that the cellular infiltrates seen may be a manifestation of cell-mediated destruction of mammary epithelium.

  13. Eikenella corrodens endocarditis and liver abscess in a previously healthy male, a case report

    DEFF Research Database (Denmark)

    Nordholm, Anne Christine; Vøgg, Ruth Ottilia Birgitta; Permin, Henrik

    2018-01-01

    BACKGROUND: Eikenella corrodens is one of the HACEK bacteria constituting part of the normal flora of the oropharynx, however, still an uncommon pathogen. We report a case of a large Eikenella corrodens liver abscess with simultaneously endocarditis in a previously healthy male. CASE PRESENTATION...... on pneumonia treatment, a PET-CT scan was performed, which showed a large multiloculated abscess in the liver. The abscess was drained using ultrasound guidance. Culture demonstrated Eikenella corrodens. Transesophageal echocardiography revealed aortic endocarditis. The patient was treated with antibiotics...... corrodens concurrent liver abscess and endocarditis. The case report highlights that Eikenella corrodens should be considered as a cause of liver abscess. Empirical treatment of pyogenic liver abscess will most often cover Eikenella corrodens, but the recommended treatment is a third generation...

  14. A previously unreported variant of the synostotic sagittal suture: Case report and review of salient literature

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    Madison Budinich

    2016-12-01

    Full Text Available Introduction: Sagittal synostosis is a rare congenital disease caused by the premature fusion of the sagittal suture. Craniosynostosis occurs for a variety of reasons, different for every case, and often the etiology is unclear but the anomaly can frequently be seen as part of Crouzon's or Apert's syndromes. Herein, we discuss a rare case of craniosynostosis where the patient presented with a, to our knowledge, a previously undescribed variant of sagittal synostosis. Case report: A 3-month-old female infant presented to a craniofacial clinic for a consultation regarding an abnormal head shape. Images of the skull were performed, demonstrating that the patient had craniosynostosis. The patient displayed no other significant symptoms besides abnormalities in head shape. The sagittal suture was found to extend into the occipital bone where it was synostotic. Conclusion: To our knowledge, a synostotic sagittal suture has not been reported that extended posteriorly it involve the occipital bone. Those who interpret imaging or operate on this part of the skull should consider such a variation. Keywords: Anatomy, Craniosynostosis, Skull, Malformation, Pediatrics

  15. Adenylosuccinate lyase (ADSL) and infantile autism: Absence of previously reported point mutation

    Energy Technology Data Exchange (ETDEWEB)

    Fon, E.A.; Sarrazin, J.; Rouleau, G.A. [Montreal General Hospital (Canada)] [and others

    1995-12-18

    Autism is a heterogeneous neuropsychiatric syndrome of unknown etiology. There is evidence that a deficiency in the enzyme adenylosuccinate lyase (ADSL), essential for de novo purine biosynthesis, could be involved in the pathogenesis of certain cases. A point mutation in the ADSL gene, resulting in a predicted serine-to-proline substitution and conferring structural instability to the mutant enzyme, has been reported previously in 3 affected siblings. In order to determine the prevalence of the mutation, we PCR-amplified the exon spanning the site of this mutation from the genomic DNA of patients fulfilling DSM-III-R criteria for autistic disorder. None of the 119 patients tested were found to have this mutation. Furthermore, on preliminary screening using single-strand conformation polymorphism (SSCP), no novel mutations were detected in the coding sequence of four ADSL exons, spanning approximately 50% of the cDNA. In light of these findings, it appears that mutations in the ADSL gene represent a distinctly uncommon cause of autism. 12 refs., 2 figs.

  16. Missense mutation in GRN gene affecting RNA splicing and plasma progranulin level in a family affected by frontotemporal lobar degeneration.

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    Luzzi, Simona; Colleoni, Lara; Corbetta, Paola; Baldinelli, Sara; Fiori, Chiara; Girelli, Francesca; Silvestrini, Mauro; Caroppo, Paola; Giaccone, Giorgio; Tagliavini, Fabrizio; Rossi, Giacomina

    2017-06-01

    Gene coding for progranulin, GRN, is a major gene linked to frontotemporal lobar degeneration. While most of pathogenic GRN mutations are null mutations leading to haploinsufficiency, GRN missense mutations do not have an obvious pathogenicity, and only a few have been revealed to act through different pathogenetic mechanisms, such as cytoplasmic missorting, protein degradation, and abnormal cleavage by elastase. The aim of this study was to disclose the pathogenetic mechanisms of the GRN A199V missense mutation, which was previously reported not to alter physiological progranulin features but was associated with a reduced plasma progranulin level. After investigating the family pedigree, we performed genetic and biochemical analysis on its members and performed RNA expression studies. We found that the mutation segregates with the disease and discovered that its pathogenic feature is the alteration of GRN mRNA splicing, actually leading to haploinsufficiency. Thus, when facing with a missense GRN mutation, its pathogenetic effects should be investigated, especially if associated with low plasma progranulin levels, to determine its nature of either benign polymorphism or pathogenic mutation. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Self-reported previous knee injury and low knee function increase knee injury risk in adolescent female football.

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    Clausen, M B; Tang, L; Zebis, M K; Krustrup, P; Hölmich, P; Wedderkopp, N; Andersen, L L; Christensen, K B; Møller, M; Thorborg, K

    2016-08-01

    Knee injuries are common in adolescent female football. Self-reported previous knee injury and low Knee injury and Osteoarthritis Outcome Score (KOOS) are proposed to predict future knee injuries, but evidence regarding this in adolescent female football is scarce. The aim of this study was to investigate self-reported previous knee injury and low KOOS subscale score as risk factors for future knee injuries in adolescent female football. A sample of 326 adolescent female football players, aged 15-18, without knee injury at baseline, were included. Data on self-reported previous knee injury and KOOS questionnaires were collected at baseline. Time-loss knee injuries and football exposures were reported weekly by answers to standardized text-message questions, followed by injury telephone interviews. A priori, self-reported previous knee injury and low KOOS subscale scores (female football. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  18. FATP4 missense and nonsense mutations cause similar features in Ichthyosis Prematurity Syndrome

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    Dahl Niklas

    2011-03-01

    Full Text Available Abstract Background Ichthyosis Prematurity Syndrome (IPS is an autosomal recessive disorder characterized by premature birth, non-scaly ichthyosis and atopic manifestations. The disease was recently shown to be caused by mutations in the gene encoding the fatty acid transport protein 4 (FATP4 and a specific reduction in the incorporation of very long chain fatty acids (VLCFA into cellular lipids. Findings We screened probands from five families segregating IPS for mutations in the FATP4 gene. Four probands were compound heterozygous for four different mutations of which three are novel. Four patients were heterozygous and one patient homozygous for the previously reported non-sense mutation p.C168X (c.504c > a. All patients had clinical characteristics of IPS and a similar clinical course. Conclusions Missense mutations and non-sense mutations in FATP4 are associated with similar clinical features suggesting that missense mutations have a severe impact on FATP4 function. The results broaden the mutational spectrum in FATP4 associated with IPS for molecular diagnosis of and further functional analysis of FATP4.

  19. A case report: mixed thrombus formation in a previously sutured right atrium.

    Science.gov (United States)

    Yunfei, Ling; Dongxu, Li; Shuhua, Luo; Yabo, Wang; San, Deep; Changping, Gan; Ke, Lin; Qi, An

    2014-08-01

    We describe the case of a 19-year-old Chinese woman who nine months prior underwent repair of an atrial septal defect and came to our hospital with a right atrial mass attached to the anterior wall of the right atrium on transthoracic echocardiography. Pathologic examination revealed the mass was a mixed-type thrombosis with some unusual organization, which previously was not described in literature.

  20. Health effects of low-level radiation in shipyard workers: report of previous work

    International Nuclear Information System (INIS)

    Matanoski, G.M.

    1984-01-01

    Progress over the course of the Nuclear Shipyard Workers Study is reported. The derivation of the study population, the gathering of health histories, the US Navy radiation protection program, and the determination of radiation exposures is described

  1. Absence of psilocybin in species of fungi previously reported to contain psilocybin and related tryptamine derivatives

    OpenAIRE

    Stijve, T.; Kuyper, Th.W.

    1988-01-01

    Seven taxa of agarics reported in literature to contain psilocybin (viz. Psathyrella candolleana, Gymnopilus spectabilis, G. fulgens, Hygrocybe psittacina var. psittacina and var. californica, Rickenella fibula, R. swartzii) have been analysed for psilocybin and related tryptamines with negative results.

  2. Absence of psilocybin in species of fungi previously reported to contain psilocybin and related tryptamine derivatives

    NARCIS (Netherlands)

    Stijve, T.; Kuyper, Th.W.

    1988-01-01

    Seven taxa of agarics reported in literature to contain psilocybin (viz. Psathyrella candolleana, Gymnopilus spectabilis, G. fulgens, Hygrocybe psittacina var. psittacina and var. californica, Rickenella fibula, R. swartzii) have been analysed for psilocybin and related tryptamines with negative

  3. Identification of a novel missense mutation of MAF in a Japanese family with congenital cataract by whole exome sequencing: a clinical report and review of literature.

    Science.gov (United States)

    Narumi, Yoko; Nishina, Sachiko; Tokimitsu, Motoharu; Aoki, Yoko; Kosaki, Rika; Wakui, Keiko; Azuma, Noriyuki; Murata, Toshinori; Takada, Fumio; Fukushima, Yoshimitsu; Kosho, Tomoki

    2014-05-01

    Congenital cataracts are the most important cause of severe visual impairment in infants. Genetic factors contribute to the disease development and 29 genes are known to cause congenital cataracts. Identifying the genetic cause of congenital cataracts can be difficult because of genetic heterogeneity. V-maf avian musculoaponeurotic fibrosarcoma oncogene homolog (MAF) encodes a basic region/leucine zipper transcription factor that plays a key role as a regulator of embryonic lens fiber cell development. MAF mutations have been reported to cause juvenile-onset pulverulent cataract, microcornea, iris coloboma, and other anterior segment dysgenesis. We report on six patients in a family who have congenital cataracts were identified MAF mutation by whole exome sequencing (WES). The heterozygous MAF mutation Q303L detected in the present family occurs in a well conserved glutamine residue at the basic region of the DNA-binding domain. All affected members showed congenital cataracts. Three of the six members showed microcornea and one showed iris coloboma. Congenital cataracts with MAF mutation exhibited phenotypically variable cataracts within the family. Review of the patients with MAF mutations supports the notion that congenital cataracts caused by MAF mutations could be accompanied by microcornea and/or iris coloboma. WES is a useful tool for detecting disease-causing mutations in patients with genetically heterogeneous conditions. © 2014 Wiley Periodicals, Inc.

  4. Groin Problems in Male Soccer Players Are More Common Than Previously Reported

    DEFF Research Database (Denmark)

    Harøy, Joar; Clarsen, Ben; Thorborg, Kristian

    2017-01-01

    surveillance method developed to capture acute and overuse problems. STUDY DESIGN: Descriptive epidemiology study. METHODS: We registered groin problems during a 6-week period of match congestion using the Oslo Sports Trauma Research Center Overuse Injury Questionnaire. A total of 240 players from 15 teams......BACKGROUND: The majority of surveillance studies in soccer have used a time-loss injury definition, and many groin problems result from overuse, leading to gradually increasing pain and/or reduced performance without necessarily causing an absence from soccer training or match play. Thus......, the magnitude of groin problems in soccer has probably been underestimated in previous studies based on traditional injury surveillance methods. PURPOSE: To investigate the prevalence of groin problems among soccer players of both sexes and among male soccer players at different levels of play through a new...

  5. Alveolar nerve repositioning with rescue implants for management of previous treatment. A clinical report.

    Science.gov (United States)

    Amet, Edward M; Uehlein, Chris

    2013-12-01

    The goal of modern implant dentistry is to return patients to oral health in a rapid and predictable fashion, following a diagnostically driven treatment plan. If only a limited number of implants can be placed, or some fail and the prosthetic phase of implant dentistry is chosen to complete the patient's treatment, the final outcome may result in partial patient satisfaction and is commonly referred to as a "compromise." Previous All-on-4 implant treatment for the patient presented here resulted in a compromise, with an inadequate support system for the mandibular prosthesis and a maxillary complete denture with poor esthetics. The patient was unable to function adequately and also was disappointed with the resulting appearance. Correction of the compromised treatment consisted of bilateral inferior alveolar nerve elevation and repositioning without bone removal for lateral transposition, to gain room for rescue implants for a totally implant-supported and stabilized prosthesis. Treatment time to return the patient to satisfactory comfort, function, facial esthetics, and speech was approximately 2 weeks. The definitive mandibular prosthesis was designed for total implant support and stability with patient retrievability. Adequate space between the mandibular bar system and the soft tissue created a high water bridge effect for self-cleansing. Following a short interim mandibular healing period, the maxillary sinuses were bilaterally grafted to compensate for bone inadequacies and deficiencies for future maxillary implant reconstruction. © 2013 by the American College of Prosthodontists.

  6. [Lessons from abroad. Current and previous crisis in other countries. SESPAS report 2014].

    Science.gov (United States)

    Rivadeneyra-Sicilia, Ana; Minué Lorenzo, Sergio; Artundo Purroy, Carlos; Márquez Calderón, Soledad

    2014-06-01

    The evidence available on the impact of previous crises on health reveals different patterns attributable to study designs, the characteristics of each crisis, and other factors related to the socioeconomic and political context. There is greater consensus on the mediating role of government policy responses to financial crises. These responses may magnify or mitigate the adverse effects of crises on population health. Some studies have shown a significant deterioration in some health indicators in the context of the current crisis, mainly in relation to mental health and communicable diseases. Alcohol and tobacco use have also declined in some European countries. In addition, this crisis is being used by some governments to push reforms aimed at privatizing health services, thereby restricting the right to health and healthcare. Specifically, action is being taken on the three axes that determine health system financing: the population covered, the scope of services, and the share of the costs covered. These measures are often arbitrarily implemented based on ideological decisions rather than on the available evidence and therefore adverse consequences are to be expected in terms of financial protection, efficiency, and equity. Copyright © 2013 SESPAS. Published by Elsevier Espana. All rights reserved.

  7. Increased Symptom Reporting in Young Athletes Based on History of Previous Concussions.

    Science.gov (United States)

    Moser, Rosemarie Scolaro; Schatz, Philip

    2017-01-01

    Research documents increased symptoms in adolescents with a history of two or more concussions. This study examined baseline evaluations of 2,526 younger athletes, ages 10 to 14. Between-groups analyses examined Post Concussion Symptom Scale symptoms by concussion history group (None, One, Two+) and clusters of Physical, Cognitive, Emotional, and Sleep symptoms. Healthy younger athletes with a concussion history reported greater physical, emotional, and sleep-related symptoms than those with no history of concussion, with a greater endorsement in physical/sleep symptom clusters. Findings suggest younger athletes with a history of multiple concussions may experience residual symptoms.

  8. Leiomyosarcoma of the Prostate: Case Report and Review of 54 Previously Published Cases

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    Gerasimos P. Vandoros

    2008-01-01

    Full Text Available Prostate leiomyosarcoma is an extremely rare and highly aggressive neoplasm that accounts for less than 0.1% of primary prostate malignancies. We present a patient with primary leiomyosarcoma of the prostate and review 54 cases reported in the literature to discuss the clinical, diagnostic and therapeutic aspects of this uncommon tumor. Median survival was estimated at 17 months (95% C.I. 20.7–43.7 months and the 1-, 3-, and 5-year actuarial survival rates were 68%, 34%, and 26%, respectively. The only factors predictive of long-term survival were negative surgical margins and absence of metastatic disease at presentation. A multidisciplinary approach is necessary for appropriate management of this dire entity.

  9. Absence of a primary role for TTN missense variants in arrhythmogenic cardiomyopathy: From a clinical and pathological perspective.

    Science.gov (United States)

    Chen, Kai; Song, Jiangping; Wang, Zhen; Rao, Man; Chen, Liang; Hu, Shengshou

    2018-05-01

    Arrhythmogenic cardiomyopathy (ACM) is an inheritable heart disease characterized by fibro-fatty replacement of the myocardium. TTN missense variants were previously reported as a pathogenic factor for ACM. TTN missense variants are commonly identified in ACM, but have limited effect on the phenotype of ACM. We sequenced 15 ACM-related genes in 35 patients who had a heart transplantation and quantified myocardium, and fibrous and adipose tissue in blocks of the explanted heart. Clinical and pathological characteristics were compared between patients with TTN variants and others. Pedigree analysis was performed in 3 families with TTN variants. TTN variants were detected in 11 patients (all missense, 9 heterozygous and 2 oligogenic form). The TTN truncating variant was absent in the cohort. Patients with TTN variants had late onset age of the disease (31 ±13 years vs 17 ±3 years, P = 0.049) and age of heart transplantation (41 ±14 years vs 24 ±9 years, P = 0.027), larger left ventricle end-diastolic diameter (62 ±10 mm vs 45 ±10 mm, P = 0.019), smaller right ventricular outflow tract (34 ±14 mm vs 50 ±15 mm, P = 0.046), more myocardium (40.8% ±29.4% vs 13.8% ±11.0%, P = 0.017), and less adipose tissue (43.0% ±30.9% vs 66.9% ±18.5%, P = 0.036) in right ventricle than those with desmosomal variants. There was few difference between patients with TTN variants and those without variants. Pedigrees showed none of the family members with TTN missense variants had a disease phenotype, indicating a very low penetrance. TTN missense variants was commonly identified in ACM patients in this cohort, but hardly played a primary role in ACM as causative variants. © 2018 Wiley Periodicals, Inc.

  10. Ruptured Rudimentary Horn Pregnancy at 25 Weeks with Previous Vaginal Delivery: A Case Report

    Directory of Open Access Journals (Sweden)

    Deepa V. Kanagal

    2012-01-01

    Full Text Available Unicornuate uterus with rudimentary horn occurs due to failure of complete development of one of the Mullerian ducts and incomplete fusion with the contralateral side. Pregnancy in a noncommunicating rudimentary horn is extremely rare and usually terminates in rupture during first or second trimester of pregnancy. Diagnosis of rudimentary horn pregnancy and its rupture in a woman with prior vaginal delivery is difficult. It can be missed in routine ultrasound scan and in majority of cases it is detected after rupture. It requires a high index of suspicion. We report a case of G2PlL1 with rupture rudimentary horn pregnancy at 25 weeks of gestation which was misdiagnosed as intrauterine pregnancy with fetal demise by ultrasound, and termination was attempted and the case was later referred to our hospital after the patient developed hemoperitoneum and shock with a diagnosis of rupture uterus. Laparotomy revealed rupture of right rudimentary horn pregnancy with massive hemoperitoneum. Timely laparotomy, excision of the horn, and blood transfusion saved the patient.

  11. Stevens-Johnson Syndrome Induced by Carbamazepine Treatment in a Patient Who Previously Had Carbamazepine Induced Pruritus - A Case Report -

    OpenAIRE

    Bae, Hyun Min; Park, Yoo Jung; Kim, Young Hoon; Moon, Dong Eon

    2013-01-01

    Stevens-Johnson syndrome (SJS) is a rare but life-threatening skin reaction disease and carbamazepine is one of its most common causes. We report a case of SJS secondary to carbamazepine in a patient with previous pruritus due to carbamazepine which was given for treatment of trigeminal neuralgia. We would like to caution all providers that carbamazepine readministration should be avoided in the patient with a previous history of SJS or adverse skin reaction. In addition, we strongly recommen...

  12. Germline Missense Changes in the APC Gene and Their Relationship to Disease.

    Science.gov (United States)

    Scott, Rodney J; Crooks, Renee; Rose, Lindy; Attia, John; Thakkinstian, Ammarin; Thomas, Lesley; Spigelman, Allan D; Meldrum, Cliff J

    2004-05-15

    Familial adenomatous polyposis (FAP) is characterized by the presence of hundreds to thousands of adenomas that carpet the entire colon and rectum. Nonsense and frameshift mutations in the adenomatous polyposis coli (APC) gene account for the majority of mutations identified to date and predispose primarily to the typical disease phenotype. Some APC mutations are associated with a milder form of the disease known as attenuated FAP. Virtually all mutations that have been described in the APC gene result in the formation of a premature stop codon and very little is known about missense mutations apart from a common Ashkenazi Jewish mutation (1307 K) and a British E1317Q missense change. The incidence of missense mutations in the APC gene has been underreported since the APC gene lends itself to analysis using an artificial transcription and translation assay known as the Protein Truncation Test (PTT) or the In Vitro Synthetic Protein assay (IVSP).In this report we have used denaturing high performance liquid chromatography to analyse the entire coding sequence of the APC gene to determine if a cohort of patients adhering to the diagnostic criteria of FAP to assess the frequency of missense mutations in the APC gene. Altogether 112 patients were studied and 22 missense mutations were identified. From the total of 22 missense changes, 13 were silent changes and the remaining 9 resulted in amino acid substitutions. One or more of these changes were identified multiple times in 62.5% of the population under study.The results reveal that missense mutations in the APC gene appear not to radically alter protein function but may be associated with more subtle processing of RNA transcripts which in turn could result in the expression of differentially spliced forms of the APC gene which may interfere with the functional activity of the APC protein.

  13. Germline Missense Changes in the APC Gene and Their Relationship to Disease

    Directory of Open Access Journals (Sweden)

    Scott Rodney J

    2004-05-01

    Full Text Available Abstract Familial adenomatous polyposis (FAP is characterized by the presence of hundreds to thousands of adenomas that carpet the entire colon and rectum. Nonsense and frameshift mutations in the adenomatous polyposis coli (APC gene account for the majority of mutations identified to date and predispose primarily to the typical disease phenotype. Some APC mutations are associated with a milder form of the disease known as attenuated FAP. Virtually all mutations that have been described in the APC gene result in the formation of a premature stop codon and very little is known about missense mutations apart from a common Ashkenazi Jewish mutation (1307 K and a British E1317Q missense change. The incidence of missense mutations in the APC gene has been underreported since the APC gene lends itself to analysis using an artificial transcription and translation assay known as the Protein Truncation Test (PTT or the In Vitro Synthetic Protein assay (IVSP. In this report we have used denaturing high performance liquid chromatography to analyse the entire coding sequence of the APC gene to determine if a cohort of patients adhering to the diagnostic criteria of FAP to assess the frequency of missense mutations in the APC gene. Altogether 112 patients were studied and 22 missense mutations were identified. From the total of 22 missense changes, 13 were silent changes and the remaining 9 resulted in amino acid substitutions. One or more of these changes were identified multiple times in 62.5% of the population under study. The results reveal that missense mutations in the APC gene appear not to radically alter protein function but may be associated with more subtle processing of RNA transcripts which in turn could result in the expression of differentially spliced forms of the APC gene which may interfere with the functional activity of the APC protein.

  14. Two missense mutations in KCNQ1 cause pituitary hormone deficiency and maternally inherited gingival fibromatosis

    DEFF Research Database (Denmark)

    Tommiska, Johanna; Känsäkoski, Johanna; Skibsbye, Lasse

    2017-01-01

    unrelated families harbor either of two missense mutations, c.347G>T p.(Arg116Leu) or c.1106C>T p.(Pro369Leu), in KCNQ1, a gene previously implicated in the long QT interval syndrome. Kcnq1 is expressed in hypothalamic GHRH neurons and pituitary somatotropes. Co-expressing KCNQ1 with the KCNE2 β...

  15. Self-reported previous knee injury and low knee function increase knee injury risk in adolescent female football

    DEFF Research Database (Denmark)

    Clausen, Mikkel Bek; Tang, L; Zebis, M K

    2016-01-01

    with low KOOS subscale scores (Sport/Recreational (RR: 2.2) and Quality of Life (RR: 3.0) (P time-loss knee...... questionnaires were collected at baseline. Time-loss knee injuries and football exposures were reported weekly by answers to standardized text-message questions, followed by injury telephone interviews. A priori, self-reported previous knee injury and low KOOS subscale scores (... as independent variables in the risk factor analyses. The study showed that self-reported previous knee injury significantly increased the risk of time-loss knee injury [relative risk (RR): 3.65, 95% confidence (CI) 1.73-7.68; P time-loss knee injury was also significantly increased in players...

  16. Selected missense mutations impair frataxin processing in Friedreich ataxia.

    Science.gov (United States)

    Clark, Elisia; Butler, Jill S; Isaacs, Charles J; Napierala, Marek; Lynch, David R

    2017-08-01

    Frataxin (FXN) is a highly conserved mitochondrial protein. Reduced FXN levels cause Friedreich ataxia, a recessive neurodegenerative disease. Typical patients carry GAA repeat expansions on both alleles, while a subgroup of patients carry a missense mutation on one allele and a GAA repeat expansion on the other. Here, we report that selected disease-related FXN missense mutations impair FXN localization, interaction with mitochondria processing peptidase, and processing. Immunocytochemical studies and subcellular fractionation were performed to study FXN import into the mitochondria and examine the mechanism by which mutations impair FXN processing. Coimmunoprecipitation was performed to study the interaction between FXN and mitochondrial processing peptidase. A proteasome inhibitor was used to model traditional therapeutic strategies. In addition, clinical profiles of subjects with and without point mutations were compared in a large natural history study. FXN I 154F and FXN G 130V missense mutations decrease FXN 81-210 levels compared with FXN WT , FXN R 165C , and FXN W 155R , but do not block its association with mitochondria. FXN I 154F and FXN G 130V also impair FXN maturation and enhance the binding between FXN 42-210 and mitochondria processing peptidase. Furthermore, blocking proteosomal degradation does not increase FXN 81-210 levels. Additionally, impaired FXN processing also occurs in fibroblasts from patients with FXN G 130V . Finally, clinical data from patients with FXN G 130V and FXN I 154F mutations demonstrates a lower severity compared with other individuals with Friedreich ataxia. These data suggest that the effects on processing associated with FXN G 130V and FXN I 154F mutations lead to higher levels of partially processed FXN, which may contribute to the milder clinical phenotypes in these patients.

  17. Lack of Cetuximab induced skin toxicity in a previously irradiated field: case report and review of the literature

    Science.gov (United States)

    2010-01-01

    Introduction Mutation, amplification or dysregulation of the EGFR family leads to uncontrolled division and predisposes to cancer. Inhibiting the EGFR represents a form of targeted cancer therapy. Case report We report the case of 79 year old gentlemen with a history of skin cancer involving the left ear who had radiation and surgical excision. He had presented with recurrent lymph node in the left upper neck. We treated him with radiation therapy concurrently with Cetuximab. He developed a skin rash over the face and neck area two weeks after starting Cetuximab, which however spared the previously irradiated area. Conclusion The etiology underlying the sparing of the previously irradiated skin maybe due to either decrease in the population of EGFR expressing cells or decrease in the EGFR expression. We raised the question that "Is it justifiable to use EGFR inhibitors for patients having recurrence in the previously irradiated field?" We may need further research to answer this question which may guide the physicians in choosing appropriate drug in this scenario. PMID:20478052

  18. Vibratory Urticaria Associated with a Missense Variant in ADGRE2.

    Science.gov (United States)

    Boyden, Steven E; Desai, Avanti; Cruse, Glenn; Young, Michael L; Bolan, Hyejeong C; Scott, Linda M; Eisch, A Robin; Long, R Daniel; Lee, Chyi-Chia R; Satorius, Colleen L; Pakstis, Andrew J; Olivera, Ana; Mullikin, James C; Chouery, Eliane; Mégarbané, André; Medlej-Hashim, Myrna; Kidd, Kenneth K; Kastner, Daniel L; Metcalfe, Dean D; Komarow, Hirsh D

    2016-02-18

    Patients with autosomal dominant vibratory urticaria have localized hives and systemic manifestations in response to dermal vibration, with coincident degranulation of mast cells and increased histamine levels in serum. We identified a previously unknown missense substitution in ADGRE2 (also known as EMR2), which was predicted to result in the replacement of cysteine with tyrosine at amino acid position 492 (p.C492Y), as the only nonsynonymous variant cosegregating with vibratory urticaria in two large kindreds. The ADGRE2 receptor undergoes autocatalytic cleavage, producing an extracellular subunit that noncovalently binds a transmembrane subunit. We showed that the variant probably destabilizes an autoinhibitory subunit interaction, sensitizing mast cells to IgE-independent vibration-induced degranulation. (Funded by the National Institutes of Health.).

  19. Shunt malfunction causing acute neurological deterioration in 2 patients with previously asymptomatic Chiari malformation Type I. Report of two cases.

    Science.gov (United States)

    Elliott, Robert; Kalhorn, Stephen; Pacione, Donato; Weiner, Howard; Wisoff, Jeffrey; Harter, David

    2009-08-01

    Patients with symptomatic Chiari malformation Type I (CM-I) typically exhibit a chronic, slowly progressive disease course with evolution of symptoms. However, some authors have reported acute neurological deterioration in the setting of CM-I and acquired Chiari malformations. Although brainstem dysfunction has been documented in patients with CM-II and hydrocephalus or shunt malfunction, to the authors' knowledge only 1 report describing ventriculoperitoneal (VP) shunt malfunction causing neurological deterioration in a patient with CM-I exists. The authors report on their experience with the treatment of previously asymptomatic CM-I in 2 children who experienced quite different manifestations of acute neurological deterioration secondary to VP shunt malfunction. Presumably, VP shunt malfunction created a positive rostral pressure gradient across a stenotic foramen magnum, resulting in tetraparesis from foramen magnum syndrome in 1 patient and acute ataxia and cranial nerve deficits from syringobulbia in the other. Although urgent shunt revisions yielded partial recovery of neurological function in both patients, marked improvement occurred only after posterior fossa decompression.

  20. Placenta Percreta Invading Broad Ligament and Parametrium in a Woman with Two Previous Cesarean Sections: A Case Report

    Directory of Open Access Journals (Sweden)

    Mansoureh Vahdat

    2012-01-01

    Full Text Available Introduction. The incidence of placenta accreta has dramatically increased due to increasing caesarean section rate all over the world. Placenta percreta is the most severe form of placenta accretes. It frequently results in maternal morbidity and mortality mainly caused by massive obstetric hemorrhage or emergency hysterectomy. Percreta invading into the broad ligament has rarely been previously reported. Case presenting. We presented a case of placenta percreta invading left broad ligament and parametrium in a woman with two previous cesarean sections, which led to massive intraoperative hemorrhage during hysterectomy and transient ischemic encephalopathy. Conclusion. In cases of parametrial involvement, it would be more difficult to decide whether to remove placenta or leave it in site. In surgical removal neither local excision of placental bed and uterine repair nor traditional hysterectomy is adequate if parametrium invaded by placenta. We suggest delayed elective hysterectomy in such cases. So, pregnancy-induced pelvic congestion would be decreased, we can gather an expert team of gynecologists, urologists, and vascular surgeons, we could get plenty of blood products, and we may have the chance to administer methotrexate.

  1. [Double mutant alleles in the EXT1 gene not previously reported in a teenager with hereditary multiple exostoses].

    Science.gov (United States)

    Cammarata-Scalisi, Francisco; Cozar, Mónica; Grinberg, Daniel; Balcells, Susana; Asteggiano, Carla G; Martínez-Domenech, Gustavo; Bracho, Ana; Sánchez, Yanira; Stock, Frances; Delgado-Luengo, Wilmer; Zara-Chirinos, Carmen; Chacín, José Antonio

    2015-04-01

    Hereditary forms of multiple exostoses, now called EXT1/EXT2-CDG within Congenital Disorders of Glycosylation, are the most common benign bone tumors in humans and clinical description consists of the formation of several cartilage-capped bone tumors, usually benign and localized in the juxta-epiphyseal region of long bones, although wide body dissemination in severe cases is not uncommon. Onset of the disease is variable ranging from 2-3 years up to 13-15 years with an estimated incidence ranging from 1/18,000 to 1/50,000 cases in European countries. We present a double mutant alleles in the EXT1 gene not previously reported in a teenager and her family with hereditary multiple exostoses.

  2. A novel MKRN3 missense mutation causing familial precocious puberty.

    Science.gov (United States)

    de Vries, L; Gat-Yablonski, G; Dror, N; Singer, A; Phillip, M

    2014-12-01

    Central precocious puberty may be familial in about a quarter of the idiopathic cases. However, little is known about the genetic causes responsible for the disorder. In this report we describe a family with central precocious puberty associated with a mutation in the makorin RING-finger protein 3 (MKRN3) gene. A novel missense mutation (p.H420Q) in the imprinted MKRN3 gene was identified in the four affected siblings, in their unaffected father and in his affected mother. An in silico mutant MKRN3 model predicts that the mutation p.H420Q leads to reduced zinc binding and, subsequently, impaired RNA binding. These findings support the fundamental role of the MKRN3 protein in determining pubertal timing. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  3. Missense variants in plakophilin-2 in arrhythmogenic right ventricular cardiomyopathy patients--disease-causing or innocent bystanders?

    Science.gov (United States)

    Christensen, Alex Hørby; Benn, Marianne; Tybjaerg-Hansen, Anne; Haunso, Stig; Svendsen, Jesper Hastrup

    2010-01-01

    Mutations in genes encoding desmosomal proteins have been linked to arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). We hypothesized that a Scandinavian ARVC/D population would have a different spectrum of plakophilin-2 (PKP2) mutations and that some of the reported missense mutations may not be pathogenic. We screened 53 unrelated patients fulfilling Task Force criteria for ARVC/D for mutations in PKP2 by direct sequencing. Seven different mutations were identified: two insertion/deletions (E329fsX352, P401fsX406), 1 splice site (2146-2A>T), 1 non-sense (R79X) and 4 missense mutations (Q62K in 2 patients, G489R, G673V) of undeterminable pathogeneity. None of these mutations was present in 650 controls. Five of the mutations were novel. Seven patients carried reported missense mutations (D26N, S140F, V587I); however, these mutations were identified in our healthy controls, although at a lower frequency. Evaluation of all reported missense mutations in PKP2 showed unclear pathogeneity of several reported mutations. Fifteen percent of Danish ARVC/D patients carried PKP2 mutations. Our finding of reported disease-causing mutations at a low frequency among healthy controls suggests that these variants are disease modifying but not directly disease causing. We recommend conservative interpretation of missense variants in PKP2, functional characterization and large-scale sequencing to clarify normal variation in the gene.

  4. Missense Mutations in CRYAB Are Liable for Recessive Congenital Cataracts.

    Directory of Open Access Journals (Sweden)

    Xiaodong Jiao

    Full Text Available This study was initiated to identify causal mutations responsible for autosomal recessive congenital cataracts in consanguineous familial cases.Affected individuals underwent a detailed ophthalmological and clinical examination, and slit-lamp photographs were ascertained for affected individuals who have not yet been operated for the removal of the cataractous lens. Blood samples were obtained, and genomic DNA was extracted from white blood cells. A genome-wide scan was completed with short tandem repeat (STR markers, and the logarithm of odds (LOD scores were calculated. Protein coding exons of CRYAB were sequenced, bi-directionally. Evolutionary conservation was investigated by aligning CRYAB orthologues, and the expression of Cryab in embryonic and postnatal mice lens was investigated with TaqMan probe.The clinical and ophthalmological examinations suggested that all affected individuals had nuclear cataracts. Genome-wide linkage analysis suggested a potential region on chromosome 11q23 harboring CRYAB. DNA sequencing identified a missense variation: c.34C>T (p.R12C in CRYAB that segregated with the disease phenotype in the family. Subsequent interrogation of our entire cohort of familial cases identified a second familial case localized to chromosome 11q23 harboring a c.31C>T (p.R11C mutation. In silico analyses suggested that the mutations identified in familial cases, p.R11C and p.R12C will not be tolerated by the three-dimensional structure of CRYAB. Real-time PCR analysis identified the expression of Cryab in mouse lens as early as embryonic day 15 (E15 that increased significantly until postnatal day 6 (P6 with steady level of expression thereafter.Here, we report two novel missense mutations, p.R11C and p.R12C, in CRYAB associated with autosomal recessive congenital nuclear cataracts.

  5. Pushing the boundaries in liver graft utilisation in transplantation: Case report of a donor with previous bile duct injury repair.

    Science.gov (United States)

    Sultana, Asma; Powell, James J; Oniscu, Gabriel C

    2017-01-01

    Liver transplantation is a recognised treatment for extensive bile duct injuries with secondary biliary cirrhosis or recurring sepsis. However, there have been no reports of successful liver transplantation from a donor who sustained a previous bile duct injury. Here we discuss the case of a liver transplant from a 51-year-old brain dead donor who had suffered a Strasberg E1 bile duct injury and had undergone a Roux-en-Y hepaticojejunostomy 24 years prior to donation. The liver was successfully recovered and transplanted into a 56-year-old male recipient with end stage liver disease consequent to alpha 1 antitrypsin deficiency. The graft continues to function well 36 months post-transplant, with normal liver function tests and imaging revealing a patent hepaticojejunostomy. The potential associated vascular injuries should be identified during bench preparation whilst the management of biliary reconstruction at the time of transplant should follow the principles of biliary reconstruction in cases with biliary injuries, extending the hilar opening into the left duct. This case highlights the successful utilisation of a post bile duct injury repair liver, employing an experienced procurement team and careful bench assessment and reconstruction. Copyright © 2017. Published by Elsevier Ltd.

  6. Novel Missense Mitochondrial ND4L Gene Mutations in Friedreich's Ataxia

    Directory of Open Access Journals (Sweden)

    Mohammad Mehdi Heidari

    2011-05-01

    Full Text Available AbstractObjective(sThe mitochondrial defects in Friedreich's ataxia have been reported in many researches. Mitochondrial DNA is one of the candidates for defects in mitochondrion, and complex I is the first and one of the largest catalytic complexes of oxidative phosphorylation (OXPHOS system. Materials and MethodsWe searched the mitochondrial ND4L gene for mutations by TTGE and sequencing on 30 FRDA patients and 35 healthy controls.ResultsWe found 3 missense mutations [m.10506A>G (T13A, m.10530G>A (V21M, and m.10653G>A (A62T] in four patients whose m.10530G>A and m.10653G>A were not reported previously. In two patients, heteroplasmic m.10530G>A mutation was detected. They showed a very early ataxia syndrome. Our results showed that the number of mutations in FRDA patients was higher than that in the control cases (P= 0.0287.ConclusionAlthough this disease is due to nuclear gene mutation, the presence of these mutations might be responsible for further mitochondrial defects and the increase of the gravity of the disease. Thus, it should be considered in patients with this disorder.

  7. External cephalic version among women with a previous cesarean delivery: report on 36 cases and review of the literature.

    Science.gov (United States)

    Abenhaim, Haim A; Varin, Jocelyne; Boucher, Marc

    2009-01-01

    Whether or not women with a previous cesarean section should be considered for an external cephalic version remains unclear. In our study, we sought to examine the relationship between a history of previous cesarean section and outcomes of external cephalic version for pregnancies at 36 completed weeks of gestation or more. Data on obstetrical history and on external cephalic version outcomes was obtained from the C.H.U. Sainte-Justine External Cephalic Version Database. Baseline clinical characteristics were compared among women with and without a history of previous cesarean section. We used logistic regression analysis to evaluate the effect of previous cesarean section on success of external cephalic version while adjusting for parity, maternal body mass index, gestational age, estimated fetal weight, and amniotic fluid index. Over a 15-year period, 1425 external cephalic versions were attempted of which 36 (2.5%) were performed on women with a previous cesarean section. Although women with a history of previous cesarean section were more likely to be older and para >2 (38.93% vs. 15.0%), there were no difference in gestational age, estimated fetal weight, and amniotic fluid index. Women with a prior cesarean section had a success rate similar to women without [50.0% vs. 51.6%, adjusted OR: 1.31 (0.48-3.59)]. Women with a previous cesarean section who undergo an external cephalic version have similar success rates than do women without. Concern about procedural success in women with a previous cesarean section is unwarranted and should not deter attempting an external cephalic version.

  8. Analyses of MMP20 Missense Mutations in Two Families with Hypomaturation Amelogenesis Imperfecta.

    Science.gov (United States)

    Kim, Youn Jung; Kang, Jenny; Seymen, Figen; Koruyucu, Mine; Gencay, Koray; Shin, Teo Jeon; Hyun, Hong-Keun; Lee, Zang Hee; Hu, Jan C-C; Simmer, James P; Kim, Jung-Wook

    2017-01-01

    Amelogenesis imperfecta is a group of rare inherited disorders that affect tooth enamel formation, quantitatively and/or qualitatively. The aim of this study was to identify the genetic etiologies of two families presenting with hypomaturation amelogenesis imperfecta. DNA was isolated from peripheral blood samples obtained from participating family members. Whole exome sequencing was performed using DNA samples from the two probands. Sequencing data was aligned to the NCBI human reference genome (NCBI build 37.2, hg19) and sequence variations were annotated with the dbSNP build 138. Mutations in MMP20 were identified in both probands. A homozygous missense mutation (c.678T>A; p.His226Gln) was identified in the consanguineous Family 1. Compound heterozygous MMP20 mutations (c.540T>A, p.Tyr180 * and c.389C>T, p.Thr130Ile) were identified in the non-consanguineous Family 2. Affected persons in Family 1 showed hypomaturation AI with dark brown discoloration, which is similar to the clinical phenotype in a previous report with the same mutation. However, the dentition of the Family 2 proband exhibited slight yellowish discoloration with reduced transparency. Functional analysis showed that the p.Thr130Ile mutant protein had reduced activity of MMP20, while there was no functional MMP20 in the Family 1 proband. These results expand the mutational spectrum of the MMP20 and broaden our understanding of genotype-phenotype correlations in amelogenesis imperfecta.

  9. Analyses of MMP20 Missense Mutations in Two Families with Hypomaturation Amelogenesis Imperfecta

    Directory of Open Access Journals (Sweden)

    Jung-Wook Kim

    2017-04-01

    Full Text Available Amelogenesis imperfecta is a group of rare inherited disorders that affect tooth enamel formation, quantitatively and/or qualitatively. The aim of this study was to identify the genetic etiologies of two families presenting with hypomaturation amelogenesis imperfecta. DNA was isolated from peripheral blood samples obtained from participating family members. Whole exome sequencing was performed using DNA samples from the two probands. Sequencing data was aligned to the NCBI human reference genome (NCBI build 37.2, hg19 and sequence variations were annotated with the dbSNP build 138. Mutations in MMP20 were identified in both probands. A homozygous missense mutation (c.678T>A; p.His226Gln was identified in the consanguineous Family 1. Compound heterozygous MMP20 mutations (c.540T>A, p.Tyr180* and c.389C>T, p.Thr130Ile were identified in the non-consanguineous Family 2. Affected persons in Family 1 showed hypomaturation AI with dark brown discoloration, which is similar to the clinical phenotype in a previous report with the same mutation. However, the dentition of the Family 2 proband exhibited slight yellowish discoloration with reduced transparency. Functional analysis showed that the p.Thr130Ile mutant protein had reduced activity of MMP20, while there was no functional MMP20 in the Family 1 proband. These results expand the mutational spectrum of the MMP20 and broaden our understanding of genotype-phenotype correlations in amelogenesis imperfecta.

  10. Dyskeratosis congenita--two siblings with a new missense mutation in the DKC1 gene.

    Science.gov (United States)

    Coelho, Joana Dias; Lestre, Sara; Kay, Teresa; Lopes, Maria João Paiva; Fiadeiro, Teresa; Apetato, Margarida

    2011-01-01

    Dyskeratosis congenital is reported in two siblings. They presented with the classic triad of mucocutaneous features: leukoplakia of the tongue, dystrophic nails, and a widespread reticulate pigmentation on the neck and upper chest. A genetic analysis was performed and a new missense mutation S356P, hemizygous, was identified in the DKC1 gene in both patients. Acitretin was started at a low-dose in both patients, resulting in clinical improvement and important, positive psychosocial effects. © 2011 Wiley Periodicals, Inc.

  11. Protein structure and phenotypic analysis of pathogenic and population missense variants in STXBP1

    OpenAIRE

    Suri, Mohnish; Evers, Jochem M. G.; Laskowski, Roman A.; O'Brien, Sinead; Baker, Kate; Clayton‐Smith, Jill; Dabir, Tabib; Josifova, Dragana; Joss, Shelagh; Kerr, Bronwyn; Kraus, Alison; McEntagart, Meriel; Morton, Jenny; Smith, Audrey; Splitt, Miranda

    2017-01-01

    Abstract Background Syntaxin‐binding protein 1, encoded by STXBP1, is highly expressed in the brain and involved in fusing synaptic vesicles with the plasma membrane. Studies have shown that pathogenic loss‐of‐function variants in this gene result in various types of epilepsies, mostly beginning early in life. We were interested to model pathogenic missense variants on the protein structure to investigate the mechanism of pathogenicity and genotype–phenotype correlations. Methods We report 11...

  12. The Natural History of Juvenile or Subacute GM2 Gangliosidosis: 21 New Cases and Literature Review of 134 Previously Reported

    Science.gov (United States)

    Maegawa, Gustavo H. B.; Stockley, Tracy; Tropak, Michael; Banwell, Brenda; Blaser, Susan; Kok, Fernando; Giugliani, Roberto; Mahuran, Don; Clarke, Joe T. R.

    2010-01-01

    OBJECTIVE Juvenile GM2 gangliosidosis is a group of inherited neurodegenerative diseases caused by deficiency of lysosomal β-hexosaminidase resulting in GM2 ganglioside accumulation in brain. The purpose of this study was to delineate the natural history of the condition and identify genotype-phenotype correlations that might be helpful in predicting the course of the disease in individual patients. METHODS A cohort of 21 patients with juvenile GM2 gangliosidosis, 15 with the Tay-Sachs variant and 6 with the Sandhoff variant, was studied prospectively in 2 centers. Our experience was compared with previously published reports on 134 patients. Information about clinical features, β-hexosaminidase enzyme activity, and mutation analysis was collected. RESULTS In our cohort of patients, the mean (±SD) age of onset of symptoms was 5.3 ± 4.1 years, with a mean follow-up time of 8.4 years. The most common symptoms at onset were gait disturbances (66.7%), incoordination (52.4%), speech problems (28.6%), and developmental delay (28.6%). The age of onset of gait disturbances was 7.1 ± 5.6 years. The mean time for progression to becoming wheelchair-bound was 6.2 ± 5.5 years. The mean age of onset of speech problems was 7.0 ± 5.6 years, with a mean time of progression to anarthria of 5.6 ± 5.3 years. Muscle wasting (10.6 ± 7.4 years), proximal weakness (11.1 ± 7.7 years), and incontinence of sphincters (14.6 ± 9.7 years) appeared later in the course of the disease. Psychiatric disturbances and neuropathy were more prevalent in patients with the Sandhoff variant than in those with the Tay-Sachs variant. However, dysphagia, sphincter incontinence, and sleep problems occurred earlier in those with the Tay-Sachs variant. Cerebellar atrophy was the most common finding on brain MRI (52.9%). The median survival time among the studied and reviewed patients was 14.5 years. The genotype-phenotype correlation revealed that in patients with the Tay-Sachs variant, the presence

  13. Analysis of over 10,000 Cases finds no association between previously reported candidate polymorphisms and ovarian cancer outcome

    DEFF Research Database (Denmark)

    White, Kristin L; Vierkant, Robert A; Fogarty, Zachary C

    2013-01-01

    Ovarian cancer is a leading cause of cancer-related death among women. In an effort to understand contributors to disease outcome, we evaluated single-nucleotide polymorphisms (SNP) previously associated with ovarian cancer recurrence or survival, specifically in angiogenesis, inflammation, mitosis...

  14. Familial tumoral calcinosis and hyperostosis-hyperphosphataemia syndrome are different manifestations of the same disease: novel missense mutations in GALNT3

    International Nuclear Information System (INIS)

    Joseph, Leo; Joseph, Selvanayagam; Hing, Sandra N.; Idowu, Bernadine D.; Delaney, David; Presneau, Nadege; O'Donnell, Paul; Diss, Tim; Flanagan, Adrienne Margaret

    2010-01-01

    To report on the biochemistry and clinical and genetic findings of two siblings, the younger sister presenting with recurrent bone pain of the radius and ulna, and medullary sclerosis, and the older brother with soft tissue calcific deposits (tumoral calcinosis) but who later developed bone pain. Both were found to be hyperphosphaturic. The index family comprised four individuals (father, mother, brother, sister). The affected siblings were the offspring of a non-consanguineous Indian family of Tamil origin. Bidirectional sequencing was performed on the DNA from the index family and on 160 alleles from a population of 80 unrelated unaffected control individuals of Tamil extraction and 72 alleles from individuals of non-Tamil origin. Two symptomatic siblings were found to harbour previously unreported compound heterozygous missense UDP-N-acetyl-D-galactosamine: polypeptide N-acetylgalactosaminyltransferase 3 (GalNAc-transferase; GALNT3) mutations in exon 4 c.842A>G and exon 5 c.1097T>G. This sequence variation was not detected in the control DNA. This is the first report of siblings exhibiting stigmata of familial tumoral calcinosis and hyperostosis-hyperphosphataemia syndrome with documented evidence of autosomal recessive missense GALNT3 mutations. The findings from this family add further evidence to the literature that familial tumoral calcinosis and hyperostosis-hyperphosphataemia syndrome are manifestations of the same disease and highlight the importance of appropriate metabolic and genetic investigations. (orig.)

  15. Familial tumoral calcinosis and hyperostosis-hyperphosphataemia syndrome are different manifestations of the same disease: novel missense mutations in GALNT3

    Energy Technology Data Exchange (ETDEWEB)

    Joseph, Leo; Joseph, Selvanayagam [Vinodhagan Memorial Hospital and Dr. Joseph' s Ortho Clinic, Department of Orthopaedic Surgery, Thanjavur (India); Hing, Sandra N.; Idowu, Bernadine D.; Delaney, David [Royal National Orthopaedic Hospital NHS Trust, Department of Histopathology, Stanmore, Middlesex (United Kingdom); Presneau, Nadege [University College London (UCL), Cancer Institute, London (United Kingdom); O' Donnell, Paul [Royal National Orthopaedic Hospital NHS Trust, Department of Radiology, Stanmore, Middlesex (United Kingdom); University College London (UCL), Institute of Orthopaedics and Musculoskeletal Science, Stanmore (United Kingdom); University College London (UCL), The Institute of Orthopaedics and Musculoskeletal Science, London (United Kingdom); Diss, Tim [University College London Hospital (UCLH) NHS Trust, Rockefeller Building, Department of Histopathology, London (United Kingdom); Flanagan, Adrienne Margaret [Royal National Orthopaedic Hospital NHS Trust, Department of Histopathology, Stanmore, Middlesex (United Kingdom); University College London (UCL), Cancer Institute, London (United Kingdom); University College London Hospital (UCLH) NHS Trust, Rockefeller Building, Department of Histopathology, London (United Kingdom); University College London (UCL), Institute of Orthopaedics and Musculoskeletal Science, Stanmore (United Kingdom); Institute of Orthopaedics and Musculoskeletal Science, Stanmore, Middlesex (United Kingdom)

    2010-01-15

    To report on the biochemistry and clinical and genetic findings of two siblings, the younger sister presenting with recurrent bone pain of the radius and ulna, and medullary sclerosis, and the older brother with soft tissue calcific deposits (tumoral calcinosis) but who later developed bone pain. Both were found to be hyperphosphaturic. The index family comprised four individuals (father, mother, brother, sister). The affected siblings were the offspring of a non-consanguineous Indian family of Tamil origin. Bidirectional sequencing was performed on the DNA from the index family and on 160 alleles from a population of 80 unrelated unaffected control individuals of Tamil extraction and 72 alleles from individuals of non-Tamil origin. Two symptomatic siblings were found to harbour previously unreported compound heterozygous missense UDP-N-acetyl-D-galactosamine: polypeptide N-acetylgalactosaminyltransferase 3 (GalNAc-transferase; GALNT3) mutations in exon 4 c.842A>G and exon 5 c.1097T>G. This sequence variation was not detected in the control DNA. This is the first report of siblings exhibiting stigmata of familial tumoral calcinosis and hyperostosis-hyperphosphataemia syndrome with documented evidence of autosomal recessive missense GALNT3 mutations. The findings from this family add further evidence to the literature that familial tumoral calcinosis and hyperostosis-hyperphosphataemia syndrome are manifestations of the same disease and highlight the importance of appropriate metabolic and genetic investigations. (orig.)

  16. Nonsense and missense mutation of mitochondrial ND6 gene promotes cell migration and invasion in human lung adenocarcinoma

    International Nuclear Information System (INIS)

    Yuan, Yang; Wang, Weixing; Li, Huizhong; Yu, Yongwei; Tao, Jin; Huang, Shengdong; Zeng, Zhiyong

    2015-01-01

    Previous study showed that mitochondrial ND6 (mitND6) gene missense mutation resulted in NADH dehydrogenase deficiency and was associated with tumor metastasis in several mouse tumor cell lines. In the present study, we investigated the possible role of mitND6 gene nonsense and missense mutations in the metastasis of human lung adenocarcinoma. The presence of mitND6 gene mutations was screened by DNA sequencing of tumor tissues from 87 primary lung adenocarcinoma patients and the correlation of the mutations with the clinical features was analyzed. In addition, we constructed cytoplasmic hybrid cells with denucleared primary lung adenocarcinoma cell as the mitochondria donor and mitochondria depleted lung adenocarcinoma A549 cell as the nuclear donor. Using these cells, we studied the effects of mitND6 gene nonsense and missense mutations on cell migration and invasion through wounding healing and matrigel-coated transwell assay. The effects of mitND6 gene mutations on NADH dehydrogenase activity and ROS production were analyzed by spectrophotometry and flow cytometry. mitND6 gene nonsense and missense mutations were detected in 11 of 87 lung adenocarcinoma specimens and was correlated with the clinical features including age, pathological grade, tumor stage, lymph node metastasis and survival rate. Moreover, A549 cell containing mitND6 gene nonsense and missense mutation exhibited significantly lower activity of NADH dehydrogenase, higher level of ROS, higher capacity of cell migration and invasion, and higher pAKT and pERK1/ERK2 expression level than cells with the wild type mitND6 gene. In addition, NADH dehydrogenase inhibitor rotenone was found to significantly promote the migration and invasion of A549 cells. Our data suggest that mitND6 gene nonsense and missense mutation might promote cell migration and invasion in lung adenocarcinoma, probably by NADH dehydrogenase deficiency induced over-production of ROS

  17. Rib cage deformity during two-stage tissue expander breast reconstruction in patient with previous radiotherapy: a case report

    Directory of Open Access Journals (Sweden)

    Aleš Porčnik

    2016-02-01

    Full Text Available Patients undergoing two-stage breast reconstruction with tissue expander and a history of previous irradiation are predisposed to a various chest-wall deformations more than non-irradiated patients. If chest-wall depression with/without rib fracture is found intra-operatively, bigger implant should be used, with a subsequent radiologic evaluation. In the future, the development of a new, modified expander with a harder base could minimise such complications.

  18. A Case Report of Salmonella muenchen Enteritis Causing Rhabdomyolysis and Myocarditis in a Previously Healthy 26-Year-Old Man.

    Science.gov (United States)

    Chapple, Will; Martell, Jon; Wilson, Joy S; Matsuura, Don T

    2017-04-01

    This case report examines an unusual presentation of a non-typhoidal Salmonella serovar with limited prevalence in the literature. This is the first case report to associate specifically the Salmonella muenchen serovar with rhabdomyolysis and myocarditis. This case report reviews the diagnostic criteria for myocarditis and explores the diagnostic dilemma of troponin elevation in the setting of rhabdomyolysis. It demonstrates that Salmonella muenchen has the ability to present in a broad range of individuals with complications extending beyond classical gastrointestinal symptoms. This report also concludes that diagnosis of the many possible complications from non-typhoidal Salmonella infections can be difficult due to patient comorbidities, variability in the severity of the illnesses, laboratory test limitations, and imaging limitations. When a patient presents with elevated troponins in the setting of rhabdomyolysis a careful workup should be done to evaluate for ischemic causes, myocarditis, or false elevation secondary to rhabdomyolysis.

  19. Continuation of the summarizing interim report on previous results of the Gorleben site survey as of May 1983

    International Nuclear Information System (INIS)

    1990-04-01

    In addition to results from the 1983 interim report, this report contains, in order to supplement the surface explorations, seismic reflection measurements, hydrogeologic and seismologic investigations, sorption experiments, and studies of glacial development in the site region and of long-term safety of final waste repositories in salt domes. The site's high grade of suitability for becoming a final radioactive waste repository, the legal basis as well as quality assurance are evaluated. (orig.) [de

  20. RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes.

    Science.gov (United States)

    Reijnders, Margot R F; Ansor, Nurhuda M; Kousi, Maria; Yue, Wyatt W; Tan, Perciliz L; Clarkson, Katie; Clayton-Smith, Jill; Corning, Ken; Jones, Julie R; Lam, Wayne W K; Mancini, Grazia M S; Marcelis, Carlo; Mohammed, Shehla; Pfundt, Rolph; Roifman, Maian; Cohn, Ronald; Chitayat, David; Millard, Tom H; Katsanis, Nicholas; Brunner, Han G; Banka, Siddharth

    2017-09-07

    RAC1 is a widely studied Rho GTPase, a class of molecules that modulate numerous cellular functions essential for normal development. RAC1 is highly conserved across species and is under strict mutational constraint. We report seven individuals with distinct de novo missense RAC1 mutations and varying degrees of developmental delay, brain malformations, and additional phenotypes. Four individuals, each harboring one of c.53G>A (p.Cys18Tyr), c.116A>G (p.Asn39Ser), c.218C>T (p.Pro73Leu), and c.470G>A (p.Cys157Tyr) variants, were microcephalic, with head circumferences between -2.5 to -5 SD. In contrast, two individuals with c.151G>A (p.Val51Met) and c.151G>C (p.Val51Leu) alleles were macrocephalic with head circumferences of +4.16 and +4.5 SD. One individual harboring a c.190T>G (p.Tyr64Asp) allele had head circumference in the normal range. Collectively, we observed an extraordinary spread of ∼10 SD of head circumferences orchestrated by distinct mutations in the same gene. In silico modeling, mouse fibroblasts spreading assays, and in vivo overexpression assays using zebrafish as a surrogate model demonstrated that the p.Cys18Tyr and p.Asn39Ser RAC1 variants function as dominant-negative alleles and result in microcephaly, reduced neuronal proliferation, and cerebellar abnormalities in vivo. Conversely, the p.Tyr64Asp substitution is constitutively active. The remaining mutations are probably weakly dominant negative or their effects are context dependent. These findings highlight the importance of RAC1 in neuronal development. Along with TRIO and HACE1, a sub-category of rare developmental disorders is emerging with RAC1 as the central player. We show that ultra-rare disorders caused by private, non-recurrent missense mutations that result in varying phenotypes are challenging to dissect, but can be delineated through focused international collaboration. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  1. In Silico Analysis of FMR1 Gene Missense SNPs.

    Science.gov (United States)

    Tekcan, Akin

    2016-06-01

    The FMR1 gene, a member of the fragile X-related gene family, is responsible for fragile X syndrome (FXS). Missense single-nucleotide polymorphisms (SNPs) are responsible for many complex diseases. The effect of FMR1 gene missense SNPs is unknown. The aim of this study, using in silico techniques, was to analyze all known missense mutations that can affect the functionality of the FMR1 gene, leading to mental retardation (MR) and FXS. Data on the human FMR1 gene were collected from the Ensembl database (release 81), National Centre for Biological Information dbSNP Short Genetic Variations database, 1000 Genomes Browser, and NHLBI Exome Sequencing Project Exome Variant Server. In silico analysis was then performed. One hundred-twenty different missense SNPs of the FMR1 gene were determined. Of these, 11.66 % of the FMR1 gene missense SNPs were in highly conserved domains, and 83.33 % were in domains with high variety. The results of the in silico prediction analysis showed that 31.66 % of the FMR1 gene SNPs were disease related and that 50 % of SNPs had a pathogenic effect. The results of the structural and functional analysis revealed that although the R138Q mutation did not seem to have a damaging effect on the protein, the G266E and I304N SNPs appeared to disturb the interaction between the domains and affect the function of the protein. This is the first study to analyze all missense SNPs of the FMR1 gene. The results indicate the applicability of a bioinformatics approach to FXS and other FMR1-related diseases. I think that the analysis of FMR1 gene missense SNPs using bioinformatics methods would help diagnosis of FXS and other FMR1-related diseases.

  2. 24 CFR 1710.558 - Previously accepted state filings-notice of revocation rights on property report cover page.

    Science.gov (United States)

    2010-04-01

    ... will give the purchaser written notification of purchaser's default or breach of contract and the... purchaser loses rights and interest in the lot because of the purchaser's default or breach of contract... Report prior to signing a contract or agreement, you may cancel your contract or agreement by giving...

  3. Leptotrichia endocarditis: report of two cases from the International Collaboration on Endocarditis (ICE) database and review of previous cases

    NARCIS (Netherlands)

    Caram, L. B.; Linefsky, J. P.; Read, K. M.; Murdoch, D. R.; Lalani, T.; Woods, C. W.; Reller, L. B.; Kanj, S. S.; Premru, M. M.; Ryan, S.; Al-Hegelan, M.; Donnio, P. Y.; Orezzi, C.; Paiva, M. G.; Tribouilloy, C.; Watkin, R.; Harris, O.; Eisen, D. P.; Corey, G. R.; Cabell, C. H.; Petti, C. A.; Gordon, David; Devi, Uma; Spelman, Denis; van der Meer, Jan T. M.; Kauffman, Carol; Bradley, Suzanne; Armstrong, William; Giannitsioti, Efthymia; Giamarellou, Helen; Lerakis, Stamatios; del Rio, Ana; Moreno, Asuncion; Mestres, Carlos A.; Paré, Carlos; de la Maria, Cristina Garcia; de Lazzario, Elisa; Marco, Francesc; Gatell, Jose M.; Miró, José M.; Almela, Manel; Azqueta, Manuel; Jiménez-Expósito, Maria Jesús; de Benito, Natividad; Perez, Noel; Almirante, Benito; Fernandez-Hidalgo, Nuria; de Vera, Pablo Rodriguez; Tornos, Pilar; Falcó, Vicente

    2008-01-01

    Leptotrichia species typically colonize the oral cavity and genitourinary tract. We report the first two cases of endocarditis secondary to L. goodfellowii sp. nov. Both cases were identified using 16S rRNA gene sequencing. Review of the English literature revealed only two other cases of

  4. Case report of electronic cigarettes possibly associated with eosinophilic pneumonitis in a previously healthy active-duty sailor.

    Science.gov (United States)

    Thota, Darshan; Latham, Emi

    2014-07-01

    Electronic cigarettes (e-cigarettes) are a technology that has been touted as a safe and effective alternative to traditional cigarettes. There is, however, a paucity of literature showing the adverse outcomes of e-cigarettes and a correlation with acute eosinophilic pneumonia (AEP). To present a possible association between e-cigarettes and AEP. A 20-year-old previously healthy man was found to develop AEP after smoking an e-cigarette. He was treated with antibiotics and steroids and his symptoms improved. Though an alternative to traditional cigarettes, e-cigarettes can have unpredictable and potentially serious adverse effects. More research needs to be conducted to determine their safety. If seeing a patient in the ED with pulmonary symptoms after use of e-cigarettes, AEP should be considered in the differential. Published by Elsevier Inc.

  5. NDST1 missense mutations in autosomal recessive intellectual disability.

    Science.gov (United States)

    Reuter, Miriam S; Musante, Luciana; Hu, Hao; Diederich, Stefan; Sticht, Heinrich; Ekici, Arif B; Uebe, Steffen; Wienker, Thomas F; Bartsch, Oliver; Zechner, Ulrich; Oppitz, Cornelia; Keleman, Krystyna; Jamra, Rami Abou; Najmabadi, Hossein; Schweiger, Susann; Reis, André; Kahrizi, Kimia

    2014-11-01

    NDST1 was recently proposed as a candidate gene for autosomal recessive intellectual disability in two families. It encodes a bifunctional GlcNAc N-deacetylase/N-sulfotransferase with important functions in heparan sulfate biosynthesis. In mice, Ndst1 is crucial for embryonic development and homozygous null mutations are perinatally lethal. We now report on two additional unrelated families with homozygous missense NDST1 mutations. All mutations described to date predict the substitution of conserved amino acids in the sulfotransferase domain, and mutation modeling predicts drastic alterations in the local protein conformation. Comparing the four families, we noticed significant overlap in the clinical features, including both demonstrated and apparent intellectual disability, muscular hypotonia, epilepsy, and postnatal growth deficiency. Furthermore, in Drosophila, knockdown of sulfateless, the NDST ortholog, impairs long-term memory, highlighting its function in cognition. Our data confirm NDST1 mutations as a cause of autosomal recessive intellectual disability with a distinctive phenotype, and support an important function of NDST1 in human development. © 2014 Wiley Periodicals, Inc.

  6. Central posterior capsule pigmentation in a patient with pigment dispersion and previous ocular trauma: a case report.

    Science.gov (United States)

    Al-Mezaine, Hani S

    2010-01-01

    We report a 55-year-old man with unusually dense, unilateral central posterior capsule pigmentation associated with the characteristic clinical features of pigment dispersion syndrome, including a Krukenberg's spindle and dense trabecular pigmentation in both eyes. A history of an old blunt ocular trauma probably caused separation of the anterior hyaloid from the back of the lens, thereby creating an avenue by which pigment could reach the potential space of Berger's from the posterior chamber.

  7. Central posterior capsule pigmentation in a patient with pigment dispersion and previous ocular trauma: A case report

    Directory of Open Access Journals (Sweden)

    Al-Mezaine Hani

    2010-01-01

    Full Text Available We report a 55-year-old man with unusually dense, unilateral central posterior capsule pigmentation associated with the characteristic clinical features of pigment dispersion syndrome, including a Krukenberg′s spindle and dense trabecular pigmentation in both eyes. A history of an old blunt ocular trauma probably caused separation of the anterior hyaloid from the back of the lens, thereby creating an avenue by which pigment could reach the potential space of Berger′s from the posterior chamber.

  8. A novel missense mutation in the NDP gene in a child with Norrie disease and severe neurological involvement including infantile spasms.

    Science.gov (United States)

    Lev, Dorit; Weigl, Yuval; Hasan, Mariana; Gak, Eva; Davidovich, Michael; Vinkler, Chana; Leshinsky-Silver, Esther; Lerman-Sagie, Tally; Watemberg, Nathan

    2007-05-01

    Norrie disease (ND) is a rare X-linked recessive disorder characterized by congenital blindness and in some cases, mental retardation and deafness. Other neurological complications, particularly epilepsy, are rare. We report on a novel mutation identified in a patient with ND and profound mental retardation. The patient was diagnosed at the age of 6 months due to congenital blindness. At the age of 8 months he developed infantile spasms, which were diagnosed at 11 months as his EEG demonstrated hypsarrhythmia. Mutation analysis of the ND gene (NDP) of the affected child and his mother revealed a novel missense mutation at position c.134T > A resulting in amino acid change at codon V45E. To the best of our knowledge, such severe neurological involvement has not been previously reported in ND patients. The severity of the phenotype may suggest the functional importance of this site of the NDP gene.

  9. Missense Mutation in the USH2A Gene: Association with Recessive Retinitis Pigmentosa without Hearing Loss

    OpenAIRE

    Rivolta, Carlo; Sweklo, Elizabeth A.; Berson, Eliot L.; Dryja, Thaddeus P.

    2000-01-01

    Microdeletions Glu767(1-bp del), Thr967(1-bp del), and Leu1446(2-bp del) in the human USH2A gene have been reported to cause Usher syndrome type II, a disorder characterized by retinitis pigmentosa (RP) and mild-to-severe hearing loss. Each of these three frameshift mutations is predicted to lead to an unstable mRNA transcript that, if translated, would result in a truncated protein lacking the carboxy terminus. Here, we report Cys759Phe, a novel missense mutation in this gene that changes an...

  10. Two novel missense mutations in bovine ATGL gene and their ...

    African Journals Online (AJOL)

    Adipose triglyceride lipase (ATGL) as a triglyceride-specific lipase, plays a key role in the triglyceride liposis mobilization of fat tissue. In this study, based on the pyrosequencing technology, two novel missense mutations were identified, which were 3289 G>C in exon 6 bringing E277Q and 3514 A>T in exon 7 bringing ...

  11. Dominant missense mutations in ABCC9 cause Cantu syndrome

    NARCIS (Netherlands)

    Harakalova, M.; van Harssel, J.J.; Terhal, P.A.; van Lieshout, S.; Duran, K.; Renkens, I.; Amor, D.J.; Wilson, L.C.; Kirk, E.P.; Turner, C.L.; Shears, D.; Garcia-Minaur, S.; Lees, M.M.; Ross, A.; Venselaar, H.; Vriend, G.; Takanari, H.; Rook, M.B.; van der Heyden, M.A.; Asselbergs, F.W.; Breur, H.M.; Swinkels, M.E.; Scurr, I.J.; Smithson, S.F.; Knoers, N.V.; van der Smagt, J.J.; Nijman, I.J.; Kloosterman, W.P.; van Haelst, M.M.; van Haaften, G.; Cuppen, E.

    2012-01-01

    Cantu syndrome is characterized by congenital hypertrichosis, distinctive facial features, osteochondrodysplasia and cardiac defects. By using family-based exome sequencing, we identified a de novo mutation in ABCC9. Subsequently, we discovered novel dominant missense mutations in ABCC9 in 14 of the

  12. Dominant missense mutations in ABCC9 cause Cantu syndrome.

    NARCIS (Netherlands)

    Harakalova, M.; Harssel, J.J. van; Terhal, P.A.; Lieshout, S. van; Duran, K.; Renkens, I.; Amor, D.J.; Wilson, L.C.; Kirk, E.P.; Turner, C.L.; Shears, D.; Garcia-Minaur, S.; Lees, M.M.; Ross, A.; Venselaar, H.; Vriend, G.; Takanari, H.; Rook, M.B.; Heyden, M.A. van der; Asselbergs, F.W.; Breur, H.M.; Swinkels, M.E.; Scurr, I.J.; Smithson, S.F.; Knoers, N.V.A.M.; Smagt, J.J. van der; Nijman, IJ; Kloosterman, W.P.; Haelst, M.M. van; Haaften, G. van; Cuppen, E.

    2012-01-01

    Cantu syndrome is characterized by congenital hypertrichosis, distinctive facial features, osteochondrodysplasia and cardiac defects. By using family-based exome sequencing, we identified a de novo mutation in ABCC9. Subsequently, we discovered novel dominant missense mutations in ABCC9 in 14 of the

  13. Unexpected finding of T-cell lymphoma in a previously healthy 16-year-old patient after a thorax trauma: a case report

    DEFF Research Database (Denmark)

    Bach Okholm-Hansen, Anna; Brorson, Stig

    2014-01-01

    INTRODUCTION: We describe the clinical course and emphasize the difficulties in diagnosing T-cell lymphoblastic lymphoma. The differential diagnostic difficulties have previously been described in regard to pneumonia, but to the best of the authors' knowledge this is the first case report to desc...... relevant to pediatricians, surgeons, anesthesiologists, and general practitioners....

  14. Structural and functional analysis of rare missense mutations in human chorionic gonadotrophin β-subunit

    DEFF Research Database (Denmark)

    Nagirnaja, Liina; Venclovas, Česlovas; Rull, Kristiina

    2012-01-01

    Heterodimeric hCG is one of the key hormones determining early pregnancy success. We have previously identified rare missense mutations in hCGβ genes with potential pathophysiological importance. The present study assessed the impact of these mutations on the structure and function of hCG by appl...... of intact hCG as also supported by an in silico analysis. In summary, the accumulated data indicate that only mutations with neutral or mild functional consequences might be tolerated in the major hCGβ genes CGB5 and CGB8.......Heterodimeric hCG is one of the key hormones determining early pregnancy success. We have previously identified rare missense mutations in hCGβ genes with potential pathophysiological importance. The present study assessed the impact of these mutations on the structure and function of h......CG by applying a combination of in silico (sequence and structure analysis, molecular dynamics) and in vitro (co-immunoprecipitation, immuno- and bioassays) approaches. The carrier status of each mutation was determined for 1086 North-Europeans [655 patients with recurrent miscarriage (RM)/431 healthy controls...

  15. Missense variants in plakophilin-2 in arrhythmogenic right ventricular cardiomyopathy patients - disease - causing or innocent bystanders?

    DEFF Research Database (Denmark)

    Christensen, A.H.; Benn, M.; Tybjaerg-Hansen, A.

    2009-01-01

    Objectives: Mutations in genes encoding desmosomal proteins have been linked to arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). We hypothesized that a Scandinavian ARVC/D population would have a different spectrum of plakophilin-2 (PKP2) mutations and that some of the reported...... missense mutations may not be pathogenic. Methods: We screened 53 unrelated patients fulfilling Task Force criteria for ARVC/D for mutations in PKP2 by direct sequencing. Results: Seven different mutations were identified: two insertion/deletions (E329fsX352, P401fsX406), 1 splice site (2146-2A>T), 1 non...

  16. Making Sense of Missense in the Lynch Syndrome: The Clinical Perspective

    Science.gov (United States)

    Lynch, Henry T.; Jascur, Thomas; Lanspa, Stephen; Boland, C. Richard

    2010-01-01

    The DNA mismatch repair system provides critical genetic housekeeping, and its failure is associated with tumorigenesis. Through distinct domains on the DNA mismatch repair proteins, the system recognizes and repairs errors occurring during DNA synthesis, but signals apoptosis when the DNA damage cannot be repaired. Certain missense mutations in the mismatch repair genes can selectively alter just one of these functions. This impacts the clinical features of tumors associated with defective DNA mismatch repair activity. New work reported by Xie et al. in this issue of the journal (beginning on page XXX) adds to the understanding of DNA mismatch repair. PMID:20978117

  17. Effects of missense mutations in sortase A gene on enzyme activity in Streptococcus mutans.

    Science.gov (United States)

    Zhuang, P L; Yu, L X; Tao, Y; Zhou, Y; Zhi, Q H; Lin, H C

    2016-04-11

    Streptococcus mutans (S. mutans) is the major aetiological agent of dental caries, and the transpeptidase Sortase A (SrtA) plays a major role in cariogenicity. The T168G and G470A missense mutations in the srtA gene may be linked to caries susceptibility, as demonstrated in our previous studies. This study aimed to investigate the effects of these missense mutations of the srtA gene on SrtA enzyme activity in S. mutans. The point mutated recombinant S.mutans T168G and G470A sortases were expressed in expression plasmid pET32a. S. mutans UA159 sortase coding gene srtA was used as the template for point mutation. Enzymatic activity was assessed by quantifying increases in the fluorescence intensity generated when a substrate Dabcyl-QALPNTGEE-Edans was cleaved by SrtA. The kinetic constants were calculated based on the curve fit for the Michaelis-Menten equation. SrtA△N40(UA159) and the mutant enzymes, SrtA△N40(D56E) and SrtA△N40(R157H), were expressed and purified. A kinetic analysis showed that the affinity of SrtA△N40(D56E) and SrtA△N40(R157H) remained approximately equal to the affinity of SrtA△N40(UA159), as determined by the Michaelis constant (K m ). However, the catalytic rate constant (k cat ) and catalytic efficiency (k cat /K m ) of SrtA△N40(D56E) were reduced compared with those of SrtA△N40(R157H) and SrtA△N40(UA159), whereas the k cat and k cat /K m values of SrtA△N40(R157H) were slightly lower than those of SrtA△N40(UA159). The findings of this study indicate that the T168G missense mutation of the srtA gene results in a significant reduction in enzymatic activity compared with S. mutans UA159, suggesting that the T168G missense mutation of the srtA gene may be related to low cariogenicity.

  18. Missense mutations in the WD40 domain of AHI1 cause non-syndromic retinitis pigmentosa.

    Science.gov (United States)

    Nguyen, Thanh-Minh T; Hull, Sarah; Roepman, Ronald; van den Born, L Ingeborgh; Oud, Machteld M; de Vrieze, Erik; Hetterschijt, Lisette; Letteboer, Stef J F; van Beersum, Sylvia E C; Blokland, Ellen A; Yntema, Helger G; Cremers, Frans P M; van der Zwaag, Paul A; Arno, Gavin; van Wijk, Erwin; Webster, Andrew R; Haer-Wigman, Lonneke

    2017-09-01

    Recent findings suggesting that Abelson helper integration site 1 ( AHI1 ) is involved in non-syndromic retinal disease have been debated, as the functional significance of identified missense variants was uncertain. We assessed whether AHI1 variants cause non-syndromic retinitis pigmentosa (RP). Exome sequencing was performed in three probands with RP. The effects of the identified missense variants in AHI1 were predicted by three-dimensional structure homology modelling. Ciliary parameters were evaluated in patient's fibroblasts, and recombinant mutant proteins were expressed in ciliated retinal pigmented epithelium cells. In the three patients with RP, three sets of compound heterozygous variants were detected in AHI1 (c.2174G>A; p.Trp725* and c.2258A>T; p.Asp753Val, c.660delC; p.Ser221Glnfs*10 and c.2090C>T; p.Pro697Leu, c.2087A>G; p.His696Arg and c.2429C>T; p.Pro810Leu). All four missense variants were present in the conserved WD40 domain of Jouberin, the ciliary protein encoded by AHI1 , with variable predicted implications for the domain structure. No significant changes in the percentage of ciliated cells, nor in cilium length or intraflagellar transport were detected. However, expression of mutant recombinant Jouberin in ciliated cells showed a significantly decreased enrichment at the ciliary base. This report confirms that mutations in AHI1 can underlie autosomal recessive RP. Moreover, it structurally and functionally validates the effect of the RP-associated AHI1 variants on protein function, thus proposing a new genotype-phenotype correlation for AHI1 mutation associated retinal ciliopathies. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  19. E-cadherin destabilization accounts for the pathogenicity of missense mutations in hereditary diffuse gastric cancer.

    Directory of Open Access Journals (Sweden)

    Joana Simões-Correia

    Full Text Available E-cadherin is critical for the maintenance of tissue architecture due to its role in cell-cell adhesion. E-cadherin mutations are the genetic cause of Hereditary Diffuse Gastric Cancer (HDGC and missense mutations represent a clinical burden, due to the uncertainty of their pathogenic role. In vitro and in vivo, most mutations lead to loss-of-function, although the causal factor is unknown for the majority. We hypothesized that destabilization could account for the pathogenicity of E-cadherin missense mutations in HDGC, and tested our hypothesis using in silico and in vitro tools. FoldX algorithm was used to calculate the impact of each mutation in E-cadherin native-state stability, and the analysis was complemented with evolutionary conservation, by SIFT. Interestingly, HDGC patients harbouring germline E-cadherin destabilizing mutants present a younger age at diagnosis or death, suggesting that the loss of native-state stability of E-cadherin accounts for the disease phenotype. To elucidate the biological relevance of E-cadherin destabilization in HDGC, we investigated a group of newly identified HDGC-associated mutations (E185V, S232C and L583R, of which L583R is predicted to be destabilizing. We show that this mutation is not functional in vitro, exhibits shorter half-life and is unable to mature, due to premature proteasome-dependent degradation, a phenotype reverted by stabilization with the artificial mutation L583I (structurally tolerated. Herein we report E-cadherin structural models suitable to predict the impact of the majority of cancer-associated missense mutations and we show that E-cadherin destabilization leads to loss-of-function in vitro and increased pathogenicity in vivo.

  20. A Novel Homozygous Missense Mutation in HOXC13 Leads to Autosomal Recessive Pure Hair and Nail Ectodermal Dysplasia.

    Science.gov (United States)

    Li, Xiaoxiao; Orseth, Meredith Lee; Smith, J Michael; Brehm, Mary Abigail; Agim, Nnenna Gebechi; Glass, Donald Alexander

    2017-03-01

    Pure hair and nail ectodermal dysplasia (PHNED) is a rare disorder that presents with hypotrichosis and nail dystrophy while sparing other ectodermal structures such as teeth and sweat glands. We describe a homozygous novel missense mutation in the HOXC13 gene that resulted in autosomal recessive PHNED in a Hispanic child. The mutation c.812A>G (p.Gln271Arg) is located within the DNA-binding domain of the HOXC13 gene, cosegregates within the family, and is predicted to be maximally damaging. This is the first reported case of a missense HOXC13 mutation resulting in PHNED and the first reported case of PHNED identified in a North American family. Our findings illustrate the critical role of HOXC13 in human hair and nail development. © 2017 Wiley Periodicals, Inc.

  1. Novel Homozygous Missense Mutation in RYR1 Leads to Severe Congenital Ptosis, Ophthalmoplegia, and Scoliosis in the Absence of Myopathy.

    Science.gov (United States)

    Dilaver, Nafi; Mazaheri, Neda; Maroofian, Reza; Zeighami, Jawaher; Seifi, Tahere; Zamani, Mina; Sedaghat, Alireza; Shariati, Gholam Reza; Galehdari, Hamid

    2017-12-01

    Ryanodine receptor 1 ( RYR1 ) is an intracellular calcium receptor primarily expressed in skeletal muscle with a role in excitation contraction. Both dominant and recessive mutations in the RYR1 gene cause a range of RYR1 -related myopathies and/or susceptibility to malignant hyperthermia (MH). Recently, an atypical manifestation of ptosis, variably presenting with ophthalmoplegia, facial paralysis, and scoliosis but without significant muscle weakness, has been reported in 9 cases from 4 families with bialleic variants in RYR1 . Two affected children from a consanguineous family with severe congenital ptosis, ophthalmoplegia, scoliosis, and distinctive long faces but without skeletal myopathy were studied. To identify the cause of the hereditary condition, DNA from the proband was subjected to whole exome sequencing (WES). WES revealed a novel homozygous missense variant in RYR1 (c.14066T>A; p.IIe4689Asn), which segregated within the family. Although the phenotype of the affected siblings in this study was similar to previously described cases, the clinical features were more severely expressed. Our findings contribute to the expansion of phenotypes related to RYR1 dysfunction. Additionally, it supports a new RYR1 -related clinical presentation without musculoskeletal involvement. It is important that individuals with RYR1 mutations are considered susceptible to MH, as 70% of the MH cases are caused by mutations in the RYR1 gene.

  2. The streptomycin-treated mouse intestine selects Escherichia coli envZ missense mutants that interact with dense and diverse intestinal microbiota.

    Science.gov (United States)

    Leatham-Jensen, Mary P; Frimodt-Møller, Jakob; Adediran, Jimmy; Mokszycki, Matthew E; Banner, Megan E; Caughron, Joyce E; Krogfelt, Karen A; Conway, Tyrrell; Cohen, Paul S

    2012-05-01

    Previously, we reported that the streptomycin-treated mouse intestine selected nonmotile Escherichia coli MG1655 flhDC deletion mutants of E. coli MG1655 with improved colonizing ability that grow 15% faster in vitro in mouse cecal mucus and 15 to 30% faster on sugars present in mucus (M. P. Leatham et al., Infect. Immun. 73:8039-8049, 2005). Here, we report that the 10 to 20% remaining motile E. coli MG1655 are envZ missense mutants that are also better colonizers of the mouse intestine than E. coli MG1655. One of the flhDC mutants, E. coli MG1655 ΔflhD, and one of the envZ missense mutants, E. coli MG1655 mot-1, were studied further. E. coli MG1655 mot-1 is more resistant to bile salts and colicin V than E. coli MG1655 ΔflhD and grows ca. 15% slower in vitro in mouse cecal mucus and on several sugars present in mucus compared to E. coli MG1655 ΔflhD but grows 30% faster on galactose. Moreover, E. coli MG1655 mot-1 and E. coli MG1655 ΔflhD appear to colonize equally well in one intestinal niche, but E. coli MG1655 mot-1 appears to use galactose to colonize a second, smaller intestinal niche either not colonized or colonized poorly by E. coli MG1655 ΔflhD. Evidence is also presented that E. coli MG1655 is a minority member of mixed bacterial biofilms in the mucus layer of the streptomycin-treated mouse intestine. We offer a hypothesis, which we call the "Restaurant" hypothesis, that explains how nutrient acquisition in different biofilms comprised of different anaerobes can account for our results.

  3. A novel missense mutation of the DDHD1 gene associated with juvenile amyotrophic lateral sclerosis

    Directory of Open Access Journals (Sweden)

    Chujun Wu

    2016-12-01

    Full Text Available Background: Juvenile amyotrophic lateral sclerosis (jALS is a rare form of ALS with an onset age of less than 25 years and is frequently thought to be genetic in origin. DDHD1 gene mutations have been reported to be associated with the SPG28 subtype of autosomal recessive HSP but have never been reported in jALS patients.Methods: Gene screens for the causative genes of ALS, HSP and CMT using next-generation sequencing (NGS technologies were performed on a jALS patient. Sanger sequencing was used to validate identified variants and perform segregation analysis.Results: We identified a novel c.1483A>G (p.Met495Val homozygous missense mutation of the DDHD1 gene in the jALS patient. All of his parents and young bother were heterozygous for this mutation. The mutation was not found in 800 Chinese control subjects or the data of dbSNP, ExAC and 1000G.Conclusion: The novel c.1483A>G (p.Met495Val missense mutation of the DDHD1 gene could be a causative mutation of autosomal recessive jALS.

  4. [Metatropic dysplasia in a girl with c.1811_1812delinsAT mutation in exon 11 of the TRPV4 gene not previously reported].

    Science.gov (United States)

    Cammarata-Scalisi, Francisco; Matysiak-Scholze, Uta; Heinze, Jessica; Barrera, Albaro; Lacruz-Rengel, María Angelina; Bracho, Ana; Guerrero, Yudith

    2015-01-01

    Metatropic dysplasia is a skeletal disorder with clinical heterogeneity, characterized by craniofacial dysmorphy including frontal bossing and midface hypoplasia, short trunk,progressive kyphoscoliosis and shortened limbs. The TRPV4 gene is located on 12q24.11, coding a cation channel with nonselective permeability to calcium; it is expressed and involved in many physiological processes through responses to different stimuli. Over 50 mutations in TRPV4 have been described. We present a seven months old girl with heterozygous mutation c.1811_1812delinsAT; p.I604N in intron 11 not previously reported in the TRPV4 gene and with clinical findings compatible with metatropic dysplasia.

  5. New Record of Sillago sinica (Pisces: Sillaginidae in Korean Waters, and Re-identification of Sillago parvisquamis Previously Reported from Korea as S. sinica

    Directory of Open Access Journals (Sweden)

    Seung Eun Bae

    2013-10-01

    Full Text Available A single specimen of the genus Sillago, collected from Gwangyang, Korea, in May 2009, is characterized by XI first dorsal fin spines, 3 or 4 rows of melanophore pattern along the second dorsal fin membrane, and a darkish posterior margin of the caudal fin. Our specimen was identified as Sillago sinica reported as a new species; this identification is confirmed by mitochondrial DNA cytochrome oxidase subunit I sequences, which show that our specimen corresponds to S. sinica (d=0.000 and differs from the congeneric species Sillago parvisquamis (d=0.170. Comparisons of Korean specimens previously reported as S. parvisquamis with specimens of S. sinica show that the S. parvisquamis specimens are actually S. sinica. We propose the new Korean name “buk-bang-jeom-bo-ri-myeol” for S. sinica.

  6. A novel missense mutation in the CLCN7 gene linked to benign autosomal dominant osteopetrosis: a case series

    Directory of Open Access Journals (Sweden)

    Rashid Ban Mousa

    2013-01-01

    Full Text Available Abstract Introduction Osteopetrosis is a rare inherited genetic disease characterized by sclerosis of the skeleton. The absence or malfunction of osteoclasts is found to be strongly associated with the disease evolution. Currently, four clinically distinct forms of the disease have been recognized: the infantile autosomal recessive osteopetrosis, the malignant and the intermediate forms, and autosomal dominant osteopetrosis, type I and type II forms. The autosomal recessive types are the most severe forms with symptoms in very early childhood, whereas the autosomal dominant classes exhibit a heterogeneous trait with milder symptoms, often at later childhood or adulthood. Case presentation Case 1 is the 12-year-old daughter (index patient of an Iraqi-Kurdish family who, at the age of eight years, was diagnosed clinically to have mild autosomal dominant osteopetrosis. Presently, at 12-years old, she has severe complications due to the disease progression. In addition, the same family previously experienced the death of a female child in her late childhood. The deceased child had been misdiagnosed, at that time, with thalassemia major. In this report, we extended our investigation to identify the type of the inheritance patterns of osteopetrosis using molecular techniques, because consanguineous marriages exist within the family history. We have detected one heterozygous mutation in exon 15 of the Chloride Channel 7 gene in the index patient (Case 1, whereas other mutations were not detected in the associated genes TCIRG1, OSTM1, RANK, and RANKL. The missense mutation (CGG>TGG located in exon 15 (c.1225C>T of the Chloride Channel 7 gene changed the amino acid position 409 from arginine to tryptophan (p.R409W, c.1225C>T. Case 2 is the 16-year-old son (brother of the index patient of the same family who was diagnosed clinically with mild autosomal dominant osteopetrosis. We have identified the same heterozygous mutation in exon 15 of the Chloride

  7. A novel missense mutation in the CLCN7 gene linked to benign autosomal dominant osteopetrosis: a case series.

    Science.gov (United States)

    Rashid, Ban Mousa; Rashid, Nawshirwan Gafoor; Schulz, Ansgar; Lahr, Georgia; Nore, Beston Faiek

    2013-01-09

    Osteopetrosis is a rare inherited genetic disease characterized by sclerosis of the skeleton. The absence or malfunction of osteoclasts is found to be strongly associated with the disease evolution. Currently, four clinically distinct forms of the disease have been recognized: the infantile autosomal recessive osteopetrosis, the malignant and the intermediate forms, and autosomal dominant osteopetrosis, type I and type II forms. The autosomal recessive types are the most severe forms with symptoms in very early childhood, whereas the autosomal dominant classes exhibit a heterogeneous trait with milder symptoms, often at later childhood or adulthood. Case 1 is the 12-year-old daughter (index patient) of an Iraqi-Kurdish family who, at the age of eight years, was diagnosed clinically to have mild autosomal dominant osteopetrosis. Presently, at 12-years old, she has severe complications due to the disease progression. In addition, the same family previously experienced the death of a female child in her late childhood. The deceased child had been misdiagnosed, at that time, with thalassemia major. In this report, we extended our investigation to identify the type of the inheritance patterns of osteopetrosis using molecular techniques, because consanguineous marriages exist within the family history. We have detected one heterozygous mutation in exon 15 of the Chloride Channel 7 gene in the index patient (Case 1), whereas other mutations were not detected in the associated genes TCIRG1, OSTM1, RANK, and RANKL. The missense mutation (CGG>TGG) located in exon 15 (c.1225C>T) of the Chloride Channel 7 gene changed the amino acid position 409 from arginine to tryptophan (p.R409W, c.1225C>T).Case 2 is the 16-year-old son (brother of the index patient) of the same family who was diagnosed clinically with mild autosomal dominant osteopetrosis. We have identified the same heterozygous mutation in exon 15 of the Chloride channel 7 gene in this patient (Case 2). The missense

  8. Prospective evaluation of patient-reported quality-of-life outcomes following SBRT ± cetuximab for locally-recurrent, previously-irradiated head and neck cancer

    International Nuclear Information System (INIS)

    Vargo, John A.; Heron, Dwight E.; Ferris, Robert L.; Rwigema, Jean-Claude M.; Wegner, Rodney E.; Kalash, Ronny; Ohr, James; Kubicek, Greg J.; Burton, Steven

    2012-01-01

    Purpose: Stereotactic body radiotherapy (SBRT) has emerged as a promising salvage strategy for unresectable, previously-irradiated recurrent squamous cell carcinomas of the head and neck (rSCCHN). Here-in, we report the first prospective evaluation of patient-reported quality-of-life (PR-QoL) following re-irradiation with SBRT ± cetuximab for rSCCHN. Materials and methods: From November 2004 to May 2011, 150 patients with unresectable, rSCCHN in a previously-irradiated field receiving >40 Gy were treated with SBRT to 40–50 Gy in 5 fractions ± concurrent cetuximab. PR-QoL was prospectively acquired using University of Washington Quality-of-Life Revised (UW-QoL-R). Results: Overall PR-QoL, health-related PR-QoL, and select domains commonly affected by re-irradiation progressively increase following an initial 1-month decline with statistically significant improvements noted in swallowing (p = 0.025), speech (p = 0.017), saliva (p = 0.041), activity (p = 0.032) and recreation (p = 0.039). Conclusions: Especially for patients surviving >1-year, improved tumor control associated with SBRT re-irradiation may ameliorate decreased PR-QoL resulting from rSCCHN. These improvements in PR-QoL transcend all measured domains in a validated PR-QoL assessment tool independent of age, use of cetuximab, tumor volume, and interval since prior irradiation.

  9. Identification and functional analysis of SOX10 missense mutations in different subtypes of Waardenburg syndrome.

    Science.gov (United States)

    Chaoui, Asma; Watanabe, Yuli; Touraine, Renaud; Baral, Viviane; Goossens, Michel; Pingault, Veronique; Bondurand, Nadege

    2011-12-01

    Waardenburg syndrome (WS) is a rare disorder characterized by pigmentation defects and sensorineural deafness, classified into four clinical subtypes, WS1-S4. Whereas the absence of additional features characterizes WS2, association with Hirschsprung disease defines WS4. WS is genetically heterogeneous, with six genes already identified, including SOX10. About 50 heterozygous SOX10 mutations have been described in patients presenting with WS2 or WS4, with or without myelination defects of the peripheral and central nervous system (PCWH, Peripheral demyelinating neuropathy-Central dysmyelinating leukodystrophy-Waardenburg syndrome-Hirschsprung disease, or PCW, PCWH without HD). The majority are truncating mutations that most often remove the main functional domains of the protein. Only three missense mutations have been thus far reported. In the present study, novel SOX10 missense mutations were found in 11 patients and were examined for effects on SOX10 characteristics and functions. The mutations were associated with various phenotypes, ranging from WS2 to PCWH. All tested mutations were found to be deleterious. Some mutants presented with partial cytoplasmic redistribution, some lost their DNA-binding and/or transactivation capabilities on various tissue-specific target genes. Intriguingly, several mutants were redistributed in nuclear foci. Whether this phenomenon is a cause or a consequence of mutation-associated pathogenicity remains to be determined, but this observation could help to identify new SOX10 modes of action. © 2011 Wiley-Liss, Inc.

  10. Prospective monitoring and self-report of previous falls among older women at high risk of falls and fractures: a study of comparison and agreement.

    Science.gov (United States)

    Garcia, Patrícia A; Dias, João M D; Silva, Silvia L A; Dias, Rosângela C

    2015-01-01

    The identification of the occurrence of falls is an important step for screening and for rehabilitation processes for the elderly. The methods of monitoring these events are susceptible to recording biases, and the choice of the most accurate method remains challenging. (i) To investigate the agreement between retrospective self-reporting and prospective monitoring of methods of recording falls, and (ii) to compare the retrospective self-reporting of falls and the prospective monitoring of falls and recurrent falls over a 12-month period among older women at high risk of falls and fractures. A total of 118 community-dwelling older women with low bone density were recruited. The incidence of falls was monitored prospectively in 116 older women (2 losses) via monthly phone calls over the course of a year. At the end of this monitoring period, the older women were asked about their recall of falls in the same 12-month period. The agreement between the two methods was analyzed, and the sensitivity and specificity of self-reported previous falls in relation to the prospective monitoring were calculated. There was moderate agreement between the prospective monitoring and the retrospective self-reporting of falls in classifying fallers (Kappa = 0.595) and recurrent fallers (Kappa = 0.589). The limits of agreement were 0.35 ± 1.66 falls. The self-reporting of prior falls had a 67.2% sensitivity and a 94.2% specificity in classifying fallers among older women and a 50% sensitivity and a 98.9% specificity in classifying recurrent fallers. Self-reporting of falls over a 12-month period underestimated 32.8% of falls and 50% of recurrent falls. The findings recommend caution if one is considering replacing monthly monitoring with annual retrospective questioning.

  11. Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844–848

    NARCIS (Netherlands)

    Koczkowska, M. (Magdalena); Chen, Y. (Yunjia); Callens, T. (Tom); Gomes, A. (Alicia); Sharp, A. (Angela); Johnson, S. (Sherrell); Hsiao, M.-C. (Meng-Chang); Chen, Z. (Zhenbin); Balasubramanian, M. (Meena); Barnett, C.P. (Christopher P.); Becker, T.A. (Troy A.); Ben-Shachar, S. (Shay); D.R. Bertola (Débora Romeo); J.O. Blakeley (Jaishri O.); Burkitt-Wright, E.M.M. (Emma M.M.); Callaway, A. (Alison); Crenshaw, M. (Melissa); Cunha, K.S. (Karin S.); Cunningham, M. (Mitch); M.D. D'Agostino (Maria Daniela); K. Dahan (Karin); De Luca, A. (Alessandro); A. Destrée (Anne); Dhamija, R. (Radhika); Eoli, M. (Marica); Evans, D.G.R. (D. Gareth R.); Galvin-Parton, P. (Patricia); George-Abraham, J.K. (Jaya K.); K.W. Gripp (Karen); Guevara-Campos, J. (Jose); Hanchard, N.A. (Neil A.); Hernández-Chico, C. (Concepcion); Immken, L. (LaDonna); S. Janssens (Sandra); K.J. Jones (Kristi); Keena, B.A. (Beth A.); Kochhar, A. (Aaina); Liebelt, J. (Jan); Martir-Negron, A. (Arelis); Mahoney, M.J. (Maurice J.); I. Maystadt (Isabelle); McDougall, C. (Carey); M. McEntagart (Meriel); N.J. Mendelsohn; Miller, D.T. (David T.); G. Mortier (Geert); J. Morton (Jenny); Pappas, J. (John); S.R. Plotkin (Scott R.); Pond, D. (Dinel); Rosenbaum, K. (Kenneth); Rubin, K. (Karol); Russell, L. (Laura); Rutledge, L.S. (Lane S.); Saletti, V. (Veronica); Schonberg, R. (Rhonda); Schreiber, A. (Allison); Seidel, M. (Meredith); Siqveland, E. (Elizabeth); D.W. Stockton (David); Trevisson, E. (Eva); N.J. Ullrich (Nicole J.); M. Upadhyaya (Meena); A.S. Thornton (Andrew); H. Verhelst (H.); M.R. Wallace (Margaret); Yap, Y.-S. (Yoon-Sim); Zackai, E. (Elaine); Zonana, J. (Jonathan); Zurcher, V. (Vickie); K. Claes (Kathleen); Martin, Y. (Yolanda); B. Korf (Bruce); E. Legius (Eric); L.M. Messiaen (Ludwine)

    2018-01-01

    textabstractNeurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1:2,000–3,000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations

  12. Splicing analysis of 14 BRCA1 missense variants classifies nine variants as pathogenic

    DEFF Research Database (Denmark)

    Ahlborn, Lise B; Dandanell, Mette; Steffensen, Ane Y

    2015-01-01

    by functional analysis at the protein level. Results from a validated mini-gene splicing assay indicated that nine BRCA1 variants resulted in splicing aberrations leading to truncated transcripts and thus can be considered pathogenic (c.4987A>T/p.Met1663Leu, c.4988T>A/p.Met1663Lys, c.5072C>T/p.Thr1691Ile, c......Pathogenic germline mutations in the BRCA1 gene predispose carriers to early onset breast and ovarian cancer. Clinical genetic screening of BRCA1 often reveals variants with uncertain clinical significance, complicating patient and family management. Therefore, functional examinations are urgently...... needed to classify whether these uncertain variants are pathogenic or benign. In this study, we investigated 14 BRCA1 variants by in silico splicing analysis and mini-gene splicing assay. All 14 alterations were missense variants located within the BRCT domain of BRCA1 and had previously been examined...

  13. Characterization of cancer-associated missense mutations in MDM2

    OpenAIRE

    Chauhan, Krishna M.; Ramakrishnan, Gopalakrishnan; Kollareddy, Madhusudhan; Martinez, Luis A.

    2015-01-01

    MDM2 is an E3 ubiquitin ligase that binds the N-terminus of p53 and promotes its ubiquitin-dependent degradation. Elevated levels of MDM2 due to overexpression or gene amplification can contribute to tumor development by suppressing p53 activity. Since MDM2 is an oncogene, we explored the possibility that other genetic lesions, namely missense mutations, might alter its activities. We selected mutations in MDM2 that reside in one of the 4 key regions of the protein: p53 binding domain, acidic...

  14. Hepatocellular Carcinoma Metastasis to the Orbit in a Coinfected HIV+ HBV+ Patient Previously Treated with Orthotopic Liver Transplantation: A Case Report

    Directory of Open Access Journals (Sweden)

    S. Guerriero

    2011-01-01

    Full Text Available Hepatocellular carcinoma rarely metastasizes to the orbit. We report a 45-year-old male, HBV+, HIV+, with a past history of a liver transplant for ELSD (end-stage liver disease with hepatocellular carcinoma and recurrent HCC, who presented with proptosis and diplopia of the left eye. CT scans of the head revealed a large, irregular mass in the left orbit causing superior and lateral destruction of the orbital bone. Biopsy specimens of the orbital tumor showed features of metastatic foci of hepatocellular carcinoma. Only 16 other cases of HCC metastasis to the orbit have been described in literature, and this is the first case in a previously transplanted HIV+, HBV+ patient.

  15. Late-onset Stargardt disease is associated with missense mutations that map outside known functional regions of ABCR (ABCA4).

    Science.gov (United States)

    Yatsenko, A N; Shroyer, N F; Lewis, R A; Lupski, J R

    2001-04-01

    Based on recent studies of the photoreceptor-specific ABC transporter gene ABCR (ABCA4) in Stargardt disease (STGD1) and other retinal dystrophies, we and others have developed a model in which the severity of retinal disease correlates inversely with residual ABCR activity. This model predicts that patients with late-onset STGDI may retain partial ABCR activity attributable to mild missense alleles. To test this hypothesis, we used late-onset STGDI patients (onset: > or =35 years) to provide an in vivo functional analysis of various combinations of mutant alleles. We sequenced directly the entire coding region of ABCR and detected mutations in 33/50 (66%) disease chromosomes, but surprisingly, 11/33 (33%) were truncating alleles. Importantly, all 22 missense mutations were located outside the known functional domains of ABCR (ATP-binding or transmembrane), whereas in our general cohort of STGDI subjects, alterations occurred with equal frequency across the entire protein. We suggest that these missense mutations in regions of unknown function are milder alleles and more susceptible to modifier effects. Thus, we have corroborated a prediction from the model of ABCR pathogenicity that (1) one mutant ABCR allele is always missense in late-onset STGD1 patients, and (2) the age-of-onset is correlated with the amount of ABCR activity of this allele. In addition, we report three new pseudodominant families that now comprise eight of 178 outbred STGD1 families and suggest a carrier frequency of STGD1-associated ABCR mutations of about 4.5% (approximately 1/22).

  16. Most of rare missense alleles in humans are deleterious:implications for evolution of complex disease and associationstudies

    Energy Technology Data Exchange (ETDEWEB)

    Kryukov, Gregory V.; Pennacchio, Len A.; Sunyaev, Shamil R.

    2006-10-24

    The accumulation of mildly deleterious missense mutations inindividual human genomes has been proposed to be a genetic basis forcomplex diseases. The plausibility of this hypothesis depends onquantitative estimates of the prevalence of mildly deleterious de novomutations and polymorphic variants in humans and on the intensity ofselective pressure against them. We combined analysis of mutationscausing human Mendelian diseases, human-chimpanzee divergence andsystematic data on human SNPs and found that about 20 percent of newmissense mutations in humans result in a loss of function, while about 27percent are effectively neutral. Thus, more than half of new missensemutations have mildly deleterious effects. These mutations give rise tomany low frequency deleterious allelic variants in the human populationas evident from a new dataset of 37 genes sequenced in over 1,500individual human chromosomes. Surprisingly, up to 70 percent of lowfrequency missense alleles are mildly deleterious and associated with aheterozygous fitness loss in the range 0.001-0.003. Thus, the low allelefrequency of an amino acid variant can by itself serve as a predictor ofits functional significance. Several recent studies have reported asignificant excess of rare missense variants in disease populationscompared to controls in candidate genes or pathways. These studies wouldbe unlikely to work if most rare variants were neutral or if rarevariants were not a significant contributor to the genetic component ofphenotypic inheritance. Our results provide a justification for thesetypes of candidate gene (pathway) association studies and imply thatmutation-selection balance may be a feasible mechanism for evolution ofsome common diseases.

  17. A novel homozygous missense variant in NECTIN4 (PVRL4) causing ectodermal dysplasia cutaneous syndactyly syndrome.

    Science.gov (United States)

    Ahmad, Farooq; Nasir, Abdul; Thiele, Holger; Umair, Muhammad; Borck, Guntram; Ahmad, Wasim

    2018-02-12

    Ectodermal dysplasia syndactyly syndrome 1 (EDSS1) is a rare form of ectodermal dysplasia including anomalies of hair, nails, and teeth along with bilateral cutaneous syndactyly of hands and feet. In the present report, we performed a clinical and genetic characterization of a consanguineous Pakistani family with four individuals affected by EDSS1. We performed exome sequencing using DNA of one affected individual. Exome data analysis identified a novel homozygous missense variant (c.242T>C; p.(Leu81Pro)) in NECTIN4 (PVRL4). Sanger sequencing validated this variant and confirmed its cosegregation with the disease phenotype in the family members. Thus, our report adds a novel variant to the NECTIN4 mutation spectrum and contributes to the NECTIN4-related clinical characterization. © 2018 John Wiley & Sons Ltd/University College London.

  18. Missense mutation in the USH2A gene: association with recessive retinitis pigmentosa without hearing loss.

    Science.gov (United States)

    Rivolta, C; Sweklo, E A; Berson, E L; Dryja, T P

    2000-06-01

    Microdeletions Glu767(1-bp del), Thr967(1-bp del), and Leu1446(2-bp del) in the human USH2A gene have been reported to cause Usher syndrome type II, a disorder characterized by retinitis pigmentosa (RP) and mild-to-severe hearing loss. Each of these three frameshift mutations is predicted to lead to an unstable mRNA transcript that, if translated, would result in a truncated protein lacking the carboxy terminus. Here, we report Cys759Phe, a novel missense mutation in this gene that changes an amino-acid residue within the fifth laminin-epidermal growth factor-like domain of the USH2A gene and that is associated with recessive RP without hearing loss. This single mutation was found in 4.5% of 224 patients with recessive RP, suggesting that USH2A could cause more cases of nonsyndromic recessive RP than does any other gene identified to date.

  19. Reverse Shoulder Arthroplasty for the Treatment of Rotator Cuff Deficiency: A Concise Follow-up, at a Minimum of 10 Years, of Previous Reports.

    Science.gov (United States)

    Cuff, Derek J; Pupello, Derek R; Santoni, Brandon G; Clark, Rachel E; Frankle, Mark A

    2017-11-15

    We previously evaluated 94 patients (96 shoulders) who underwent reverse shoulder arthroplasty using a central compressive screw with 5.0-mm peripheral locking screws for baseplate fixation and a center of rotation lateral to the glenoid as treatment for end-stage rotator cuff deficiency. The purpose of this study was to report updated results at a minimum follow-up of 10 years. Forty patients (42 shoulders) were available for clinical follow-up. In the patients available for study, implant survivorship, with the end point being revision for any reason, was 90.7%. Since our 5-year report, 2 patients underwent revision surgery; 1 patient sustained a periprosthetic fracture 7 years postoperatively and 1 patient had a dislocation because of chronic shoulder instability at 8 years postoperatively. At a minimum follow-up of 10 years, the patients continued to maintain their improved outcome scores and range of motion, which were comparable with earlier follow-up evaluations. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

  20. BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer

    NARCIS (Netherlands)

    Shimelis, Hermela; Mesman, Romy L. S.; Von Nicolai, Catharina; Ehlen, Asa; Guidugli, Lucia; Martin, Charlotte; Calléja, Fabienne M. G. R.; Meeks, Huong; Hallberg, Emily; Hinton, Jamie; Lilyquist, Jenna; Hu, Chunling; Aalfs, Cora M.; Aittomäki, Kristiina; Andrulis, Irene; Anton-Culver, Hoda; Arndt, Volker; Beckmann, Matthias W.; Benitez, Javier; Bogdanova, Natalia V.; Bojesen, Stig E.; Bolla, Manjeet K.; Borresen-Dale, Anne-Lise; Brauch, Hiltrud; Brennan, Paul; Brenner, Hermann; Broeks, Annegien; Brouwers, Barbara; Brüning, Thomas; Burwinkel, Barbara; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Cheng, Ching-Yu; Choi, Ji-Yeob; Collée, J. Margriet; Cox, Angela; Cross, Simon S.; Czene, Kamila; Darabi, Hatef; Dennis, Joe; Dörk, Thilo; Dos-Santos-Silva, Isabel; Dunning, Alison M.; Fasching, Peter A.; Figueroa, Jonine; Flyger, Henrik; García-Closas, Montserrat; Giles, Graham G.; Glendon, Gord; Guénel, Pascal; Haiman, Christopher A.; Hall, Per; Hamann, Ute; Hartman, Mikael; Hogervorst, Frans B.; Hollestelle, Antoinette; Hopper, John L.; Ito, Hidemi; Jakubowska, Anna; Kang, Daehee; Kosma, Veli-Matti; Kristensen, Vessela; Lai, Kah-Nyin; Lambrechts, Diether; Marchand, Loic Le; Li, Jingmei; Lindblom, Annika; Lophatananon, Artitaya; Lubinski, Jan; Machackova, Eva; Mannermaa, Arto; Margolin, Sara; Marme, Frederik; Matsuo, Keitaro; Miao, Hui; Michailidou, Kyriaki; Milne, Roger L.; Muir, Kenneth; Neuhausen, Susan L.; Nevanlinna, Heli; Olson, Janet E.; Olswold, Curtis; Oosterwijk, Jan J. C.; Osorio, Ana; Peterlongo, Paolo; Peto, Julian; Pharoah, Paul D. P.; Pylkäs, Katri; Radice, Paolo; Rashid, Muhammad Usman; Rhenius, Valerie; Rudolph, Anja; Sangrajrang, Suleeporn; Sawyer, Elinor J.; Schmidt, Marjanka K.; Schoemaker, Minouk J.; Seynaeve, Caroline; Shah, Mitul; Shen, Chen-Yang; Shrubsole, Martha; Shu, Xiao-Ou; Slager, Susan; Southey, Melissa C.; Stram, Daniel O.; Swerdlow, Anthony; teo, Soo H.; Tomlinson, Ian; Torres, Diana; Truong, Thérèse; van Asperen, Christi J.; van der Kolk, Lizet E.; Wang, Qin; Winqvist, Robert; Wu, Anna H.; Yu, Jyh-Cherng; Zheng, Wei; Zheng, Ying; Leary, Jennifer; Walker, Logan; Foretova, Lenka; Fostira, Florentia; Claes, Kathleen B. M.; Varesco, Liliana; Moghadasi, Setareh; Easton, Douglas F.; Spurdle, Amanda; Devilee, Peter; Vrieling, Harry; Monteiro, Alvaro N. A.; Goldgar, David E.; Carreira, Aura; Vreeswijk, Maaike P. G.; Couch, Fergus J.

    2017-01-01

    Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk

  1. Case report of right hamate hook fracture in a patient with previous fracture history of left hamate hook: is it hamate bipartite?

    Directory of Open Access Journals (Sweden)

    Norton Sandra

    2006-10-01

    Full Text Available Abstract Background Hamate hook fracture is a common fracture in golfers and others who play sports that involve rackets or sticks such as tennis or hockey. This patient had a previous hamate fracture in the opposing wrist along with potential features of hamate bipartite. Case presentation A 19 year old male presented with a complaint of right wrist pain on the ulnar side of the wrist with no apparent mechanism of injury. The pain came on gradually one week before being seen in the office and he reported no prior care for the complaint. His history includes traumatic left hamate hook fracture with surgical excision. Conclusion The patient was found to have marked tenderness over the hamate and with a prior fracture to the other wrist, computed tomography of the wrist was ordered revealing a fracture to the hamate hook in the right wrist. He was referred for surgical evaluation and the hook of the hamate was excised. Post-surgically, the patient was able to return to normal activity within eight weeks. This case is indicative of fracture rather than hamate bipartite. This fracture should be considered in a case of ulnar sided wrist pain where marked tenderness is noted over the hamate, especially after participation in club or racket sports.

  2. Characterization of Cladosporols from the Marine Algal-Derived Endophytic Fungus Cladosporium cladosporioides EN-399 and Configurational Revision of the Previously Reported Cladosporol Derivatives.

    Science.gov (United States)

    Li, Hong-Lei; Li, Xiao-Ming; Mándi, Attila; Antus, Sándor; Li, Xin; Zhang, Peng; Liu, Yang; Kurtán, Tibor; Wang, Bin-Gui

    2017-10-06

    Four new cladosporol derivatives, cladosporols F-I (1-4), the known cladosporol C (5), and its new epimer, cladosporol J (6), were isolated and identified from the marine algal-derived endophytic fungus Cladosporium cladosporioides EN-399. Their structures were determined by detailed interpretation of NMR and MS data, and the absolute configurations were established on the basis of TDDFT-ECD and OR calculations. The configurational assignment of cladosporols F (1) and G (2) showed that the previously reported absolute configuration of cladosporol A and all the related cladosporols need to be revised from (4'R) to (4'S). Compounds 1-6 showed antibacterial activity against Escherichia coli, Micrococcus luteus, and Vibrio harveyi with MIC values ranging from 4 to 128 μg/mL. Compound 3 showed significant cytotoxicity against A549, Huh7, and LM3 cell lines with IC 50 values of 5.0, 1.0, and 4.1 μM, respectively, and compound 5 showed activity against H446 cell line with IC 50 value of 4.0 μM.

  3. Arrhythmias and sudden death among older children and young adults following tetralogy of Fallot repair in the current era: are previously reported risk factors still applicable?

    Science.gov (United States)

    Arya, Swati; Kovach, Julie; Singh, Harinder; Karpawich, Peter P

    2014-01-01

    Young adult patients (pts) with repaired tetralogy of Fallot (TOF) remain at risk for arrhythmias (Ar) and sudden cardiac death (SCD). Based on past studies with earlier pt subsets, Ar/SCD events were associated with right ventricular (RV) systolic pressures >60 mm Hg, outflow tract gradients >20 mm Hg, and QRS duration >180 ms. However, there are limited recent studies to evaluate these risk factors in the current patient generation. Patients with TOF followed over the past 50 years were grouped by presence of any arrhythmias (group 1), absence of arrhythmias (group 2), and presence of SCD or significant ventricular arrhythmias (group 3) and correlated with current pt age, gender, age at repair, repair types, echocardiogram, cardiac magnetic resonance imaging, electrocardiogram/Holter, hemodynamics, and electrophysiology findings. Of 109 pts, 52 were male aged 17-58 years. Of these, 59 (54%) had Ar, two of whom had SCD. These 59 pts were chronologically older at the time of analysis, with repair at an older age and wider QRS duration (78-240, mean 158 ms) when compared with those without Ar. However, there was no correlation with surgical era, surgical repair, gender, RV pressure >60 mm Hg, right ventricular outflow tract gradient >20 mm Hg, or RV end-diastolic volume on CMRI. Ar/SCD risk continues to correlate with repair age and advancing pt age. QRS duration is longer in these patients but at a shorter interval (mean 158 ms) and less RV pressure (mean 43 mm Hg) than previously reported. In the current TOF patient generation, neither surgical era, type of repair, RV outflow gradient nor RV volume correlate with Ar/SCD. Electrophysiologic testing to verify and identify arrhythmias remains clinically effective. © 2013 Wiley Periodicals, Inc.

  4. Two microcephaly-associated novel missense mutations in CASK specifically disrupt the CASK-neurexin interaction.

    Science.gov (United States)

    LaConte, Leslie E W; Chavan, Vrushali; Elias, Abdallah F; Hudson, Cynthia; Schwanke, Corbin; Styren, Katie; Shoof, Jonathan; Kok, Fernando; Srivastava, Sarika; Mukherjee, Konark

    2018-03-01

    Deletion and truncation mutations in the X-linked gene CASK are associated with severe intellectual disability (ID), microcephaly and pontine and cerebellar hypoplasia in girls (MICPCH). The molecular origin of CASK-linked MICPCH is presumed to be due to disruption of the CASK-Tbr-1 interaction. This hypothesis, however, has not been directly tested. Missense variants in CASK are typically asymptomatic in girls. We report three severely affected girls with heterozygous CASK missense mutations (M519T (2), G659D (1)) who exhibit ID, microcephaly, and hindbrain hypoplasia. The mutation M519T results in the replacement of an evolutionarily invariant methionine located in the PDZ signaling domain known to be critical for the CASK-neurexin interaction. CASK M519T is incapable of binding to neurexin, suggesting a critically important role for the CASK-neurexin interaction. The mutation G659D is in the SH3 (Src homology 3) domain of CASK, replacing a semi-conserved glycine with aspartate. We demonstrate that the CASK G659D mutation affects the CASK protein in two independent ways: (1) it increases the protein's propensity to aggregate; and (2) it disrupts the interface between CASK's PDZ (PSD95, Dlg, ZO-1) and SH3 domains, inhibiting the CASK-neurexin interaction despite residing outside of the domain deemed critical for neurexin interaction. Since heterozygosity of other aggregation-inducing mutations (e.g., CASK W919R ) does not produce MICPCH, we suggest that the G659D mutation produces microcephaly by disrupting the CASK-neurexin interaction. Our results suggest that disruption of the CASK-neurexin interaction, not the CASK-Tbr-1 interaction, produces microcephaly and cerebellar hypoplasia. These findings underscore the importance of functional validation for variant classification.

  5. A case of recurrent encephalopathy with SCN2A missense mutation.

    Science.gov (United States)

    Fukasawa, Tatsuya; Kubota, Tetsuo; Negoro, Tamiko; Saitoh, Makiko; Mizuguchi, Masashi; Ihara, Yukiko; Ishii, Atsushi; Hirose, Shinichi

    2015-06-01

    Voltage-gated sodium channels regulate neuronal excitability, as well as survival and the patterning of neuronal connectivity during development. Mutations in SCN2A, which encodes the Na(+) channel Nav1.2, cause epilepsy syndromes and predispose children to acute encephalopathy. Here, we report the case of a young male with recurrent acute encephalopathy who carried a novel missense mutation in the SCN2A gene. He was born by normal delivery and developed repetitive apneic episodes at 2days of age. Diffusion-weighted imaging revealed high-intensity areas in diffuse subcortical white matter, bilateral thalami, and basal nuclei. His symptoms improved gradually without any specific treatment, but he exhibited a motor milestone delay after the episode. At the age of 10months, he developed acute cerebellopathy associated with a respiratory syncytial viral infection. He received high-dose intravenous gammaglobulin and methylprednisolone pulse therapy and seemed to have no obvious sequelae after the episode. He then developed severe diffuse encephalopathy associated with gastroenteritis at the age of 14months. He received high-dose intravenous gammaglobulin and methylprednisolone pulse therapy but was left with severe neurological sequelae. PCR-based analysis revealed a novel de novo missense mutation, c.4979T>G (p.Leu1660Trp), in the SCN2A gene. This case suggests that SCN2A mutations might predispose children to repetitive encephalopathy with variable clinical and imaging findings. Copyright © 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  6. Novel homozygous missense mutation in ALDH7A1 causes neonatal pyridoxine dependent epilepsy.

    Science.gov (United States)

    Coci, Emanuele G; Codutti, Luca; Fink, Christian; Bartsch, Sophie; Grüning, Gunnar; Lücke, Thomas; Kurth, Ingo; Riedel, Joachim

    2017-04-01

    Pyridoxine dependent epilepsy (PDE) (OMIM#266100) is a neonatal form of epilepsy, caused by dysfunction of the enzyme α-aminoadipic semialdehyde dehydrogenase (ALDH7A1 or Antiquitin). This enzyme converts α-aminoadipic semialdehyde (α-AASA) into α-aminoadipate (AAA), a critical step in the lysine metabolism of the brain. ALDH7A1 dysfunction causes an accumulation of α-AASA and δ 1 -piperideine-6-carboxylic acid (P6C), which are in equilibrium with each other. P6C binds and inactivates pyridoxal 5'-phosphate (PLP), the active form of pyridoxine. Individuals affected by ALDH7A1 deficiency show pre-natal and post-natal seizures, which respond to oral pyridoxine but not to other pediatric anti-epileptic drugs. We discovered a novel missense mutation (c.566G > A, p.Gly189Glu) in homozygous state residing in the NAD+ binding domain coding region of exon 6 and affecting an highly conserved amino acid residue. The seizures stopped under post-natal pyridoxine therapy, nevertheless a longer follow-up is needed to evaluate the intellectual development of the child, who is additionally treated with oral l-arginine since the 13th month of life. Developmental delay with or without structural cortex abnormalities were reported in several patients. A brain MRI scan revealed hyperintense white matter in the right cerebellum compatible with cerebellar gliosis. Taken together, our studies enlarge the group of missense pathogenic mutations of ALDH7A1 gene and reveal a novel cerebellar finding within the PDE patients cohort. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. Missense variants in plakophilin-2 in arrhythmogenic right ventricular cardiomyopathy patients--disease-causing or innocent bystanders?

    DEFF Research Database (Denmark)

    Christensen, Alex Hørby; Benn, Marianne; Tybjaerg-Hansen, Anne

    2010-01-01

    Objectives: Mutations in genes encoding desmosomal proteins have been linked to arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). We hypothesized that a Scandinavian ARVC/D population would have a different spectrum of plakophilin-2 (PKP2) mutations and that some of the reported...... missense mutations may not be pathogenic. Methods: We screened 53 unrelated patients fulfilling Task Force criteria for ARVC/D for mutations in PKP2 by direct sequencing. Results: Seven different mutations were identified: two insertion/deletions (E329fsX352, P401fsX406), 1 splice site (2146-2A>T), 1 non...

  8. A missense mutation in melanocortin 1 receptor is associated with the red coat colour in donkeys.

    Science.gov (United States)

    Abitbol, M; Legrand, R; Tiret, L

    2014-12-01

    The seven donkey breeds recognised by the French studbook are characterised by few coat colours: black, bay and grey. Normand bay donkeys seldom give birth to red foals, a colour more commonly seen and recognised in American miniature donkeys. Red resembles the equine chestnut colour, previously attributed to a mutation in the melanocortin 1 receptor gene (MC1R). We used a panel of 124 donkeys to identify a recessive missense c.629T>C variant in MC1R that showed a perfect association with the red coat colour. This variant leads to a methionine to threonine substitution at position 210 in the protein. We showed that methionine 210 is highly conserved among vertebrate melanocortin receptors. Previous in silico and in vitro analyses predicted this residue to lie within a functional site. Our in vivo results emphasised the pivotal role played by this residue, the alteration of which yielded a phenotype fully compatible with a loss of function of MC1R. We thus propose to name the c.629T>C allele in donkeys the e allele, which further enlarges the panel of recessive MC1R loss-of-function alleles described in animals and humans. © 2014 Stichting International Foundation for Animal Genetics.

  9. A diagnostic dilemma: Left-sided appendicitis in a 10 year old boy with previously undiagnosed intestinal malrotation. A case report

    Directory of Open Access Journals (Sweden)

    Ashvini Shekhar

    2015-01-01

    Conclusion: Left sided acute appendicitis is a diagnostic dilemma, thus often leading to management delays. It is pertinent to remember that malrotation of the gut is more common than previously thought, and not just a disease of infancy. It is advisable to consider imaging studies while balancing the risk-benefit-ratio of radiation exposure, especially in paediatric cases to cinch the diagnosis.

  10. Laparoscopy After Previous Laparotomy

    Directory of Open Access Journals (Sweden)

    Zulfo Godinjak

    2006-11-01

    Full Text Available Following the abdominal surgery, extensive adhesions often occur and they can cause difficulties during laparoscopic operations. However, previous laparotomy is not considered to be a contraindication for laparoscopy. The aim of this study is to present that an insertion of Veres needle in the region of umbilicus is a safe method for creating a pneumoperitoneum for laparoscopic operations after previous laparotomy. In the last three years, we have performed 144 laparoscopic operations in patients that previously underwent one or two laparotomies. Pathology of digestive system, genital organs, Cesarean Section or abdominal war injuries were the most common causes of previouslaparotomy. During those operations or during entering into abdominal cavity we have not experienced any complications, while in 7 patients we performed conversion to laparotomy following the diagnostic laparoscopy. In all patients an insertion of Veres needle and trocar insertion in the umbilical region was performed, namely a technique of closed laparoscopy. Not even in one patient adhesions in the region of umbilicus were found, and no abdominal organs were injured.

  11. Genotype-Phenotype Correlations Emerging from the Identification of Missense Mutations in MBTPS2

    NARCIS (Netherlands)

    Bornholdt, D.; Atkinson, T.P.; Bouadjar, B.; Catteau, B.; Cox, H.; Silva, D. De; Fischer, J.; Gunasekera, C.N.; Hadj-Rabia, S.; Happle, R.; Holder-Espinasse, M.; Kaminski, E.; Konig, A.; Megarbane, A.; Megarbane, H.; Neidel, U.; Oeffner, F.; Oji, V.; Theos, A.; Traupe, H.; Vahlquist, A.; Bon, B.W. van; Virtanen, M.; Grzeschik, K.H.

    2013-01-01

    Missense mutations affecting membrane-bound transcription factor protease site 2 (MBTPS2) have been associated with Ichthyosis Follicularis with Atrichia and Photophobia (IFAP) syndrome with or without BRESHECK syndrome, with keratosis follicularis spinulosa decalvans, and Olmsted syndrome. This

  12. Hotspots of missense mutation identify novel neurodevelopmental disorder genes and functional domains

    Science.gov (United States)

    Geisheker, Madeleine R.; Heymann, Gabriel; Wang, Tianyun; Coe, Bradley P.; Turner, Tychele N.; Stessman, Holly A.F.; Hoekzema, Kendra; Kvarnung, Malin; Shaw, Marie; Friend, Kathryn; Liebelt, Jan; Barnett, Christopher; Thompson, Elizabeth M.; Haan, Eric; Guo, Hui; Anderlid, Britt-Marie; Nordgren, Ann; Lindstrand, Anna; Vandeweyer, Geert; Alberti, Antonino; Avola, Emanuela; Vinci, Mirella; Giusto, Stefania; Pramparo, Tiziano; Pierce, Karen; Nalabolu, Srinivasa; Michaelson, Jacob J.; Sedlacek, Zdenek; Santen, Gijs W.E.; Peeters, Hilde; Hakonarson, Hakon; Courchesne, Eric; Romano, Corrado; Kooy, R. Frank; Bernier, Raphael A.; Nordenskjöld, Magnus; Gecz, Jozef; Xia, Kun; Zweifel, Larry S.; Eichler, Evan E.

    2017-01-01

    Although de novo missense mutations have been predicted to account for more cases of autism than gene-truncating mutations, most research has focused on the latter. We identified the properties of de novo missense mutations in patients with neurodevelopmental disorders (NDDs) and highlight 35 genes with excess missense mutations. Additionally, 40 amino acid sites were recurrently mutated in 36 genes, and targeted sequencing of 20 sites in 17,689 NDD patients identified 21 new patients with identical missense mutations. One recurrent site (p.Ala636Thr) occurs in a glutamate receptor subunit, GRIA1. This same amino acid substitution in the homologous but distinct mouse glutamate receptor subunit Grid2 is associated with Lurcher ataxia. Phenotypic follow-up in five individuals with GRIA1 mutations shows evidence of specific learning disabilities and autism. Overall, we find significant clustering of de novo mutations in 200 genes, highlighting specific functional domains and synaptic candidate genes important in NDD pathology. PMID:28628100

  13. Factor VII deficiency: a novel missense variant and genotype-phenotype correlation in patients from Southern Italy.

    Science.gov (United States)

    Tiscia, Giovanni; Favuzzi, Giovanni; Chinni, Elena; Colaizzo, Donatella; Fischetti, Lucia; Intrieri, Mariano; Margaglione, Maurizio; Grandone, Elvira

    2017-01-01

    This study aimed at attempting to correlate genotype and phenotype in factor VII deficiency. Here, we present molecular and clinical findings of 10 patients with factor VII deficiency. From 2013 to 2016, 10 subjects were referred to our center because of a prolonged prothrombin time identified during routine or presurgery examinations or after a laboratory assessment of a bleeding episode. Mutation characterization was performed using the bioinformatics applications PROMO, SIFT, and Polyphen-2. Structural changes in the factor VII protein were analyzed using the SPDB viewer tool. Of the 10 variants we identified, 1 was responsible for a novel missense change (c.1199G>C, p.Cys400Ser); in 2 cases we identified the c.-54G>A and c.509G>A (p.Arg170His) polymorphic variants in the 5'-upstream region of the factor VII gene and exon 6, respectively. To our knowledge, neither of these polymorphic variants has been described previously in factor VII-deficient patients. In silico predictions showed differences in binding sites for transcription factors caused by the c.-54G>A variant and a probable damaging effect of the p.Cys400Ser missense change on factor VII active conformation, leading to breaking of the Cys400-Cys428 disulfide bridge. Our findings further suggest that, independently of factor VII levels and of variants potentially affecting factor VII levels, environmental factors, e.g., trauma, could heavily influence the clinical phenotype of factor VII-deficient patients.

  14. De novo adamantinomatous craniopharyngioma presenting anew in an elderly patient with previous normal CT and MRI studies: A case report and implications on pathogenesis

    Directory of Open Access Journals (Sweden)

    Amy Walker, B.S.

    2015-09-01

    Full Text Available Adamantinomatous craniopharyngiomas are histologically benign epithelial tumors which arise from embryonic remnants of the craniopharyngeal duct and Rathke’s pouch. They are thought to have a congenital origin and are histologically unique from papillary craniopharyngioma. We describe the case of an elderly male who presented with symptoms related to a large craniopharyngioma with previously normal brain magnetic resonance and computed tomography imaging studies. These findings dispute the embryogenic theory that craniopharyngiomas observed in adults develop from the persistent slow growth of embryonic remnants.

  15. Calibration of Multiple In Silico Tools for Predicting Pathogenicity of Mismatch Repair Gene Missense Substitutions

    Science.gov (United States)

    Thompson, Bryony A.; Greenblatt, Marc S.; Vallee, Maxime P.; Herkert, Johanna C.; Tessereau, Chloe; Young, Erin L.; Adzhubey, Ivan A.; Li, Biao; Bell, Russell; Feng, Bingjian; Mooney, Sean D.; Radivojac, Predrag; Sunyaev, Shamil R.; Frebourg, Thierry; Hofstra, Robert M.W.; Sijmons, Rolf H.; Boucher, Ken; Thomas, Alun; Goldgar, David E.; Spurdle, Amanda B.; Tavtigian, Sean V.

    2015-01-01

    Classification of rare missense substitutions observed during genetic testing for patient management is a considerable problem in clinical genetics. The Bayesian integrated evaluation of unclassified variants is a solution originally developed for BRCA1/2. Here, we take a step toward an analogous system for the mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) that confer colon cancer susceptibility in Lynch syndrome by calibrating in silico tools to estimate prior probabilities of pathogenicity for MMR gene missense substitutions. A qualitative five-class classification system was developed and applied to 143 MMR missense variants. This identified 74 missense substitutions suitable for calibration. These substitutions were scored using six different in silico tools (Align-Grantham Variation Grantham Deviation, multivariate analysis of protein polymorphisms [MAPP], Mut-Pred, PolyPhen-2.1, Sorting Intolerant From Tolerant, and Xvar), using curated MMR multiple sequence alignments where possible. The output from each tool was calibrated by regression against the classifications of the 74 missense substitutions; these calibrated outputs are interpretable as prior probabilities of pathogenicity. MAPP was the most accurate tool and MAPP + PolyPhen-2.1 provided the best-combined model (R2 = 0.62 and area under receiver operating characteristic = 0.93). The MAPP + PolyPhen-2.1 output is sufficiently predictive to feed as a continuous variable into the quantitative Bayesian integrated evaluation for clinical classification of MMR gene missense substitutions. PMID:22949387

  16. Application of the electromagnetic borehole flowmeter and evaluation of previous pumping tests at Paducah Gaseous Diffusion Plant. Final report, June 15, 1992--August 31, 1992

    Energy Technology Data Exchange (ETDEWEB)

    Young, S.C.; Julian, S.C.; Neton, M.J.

    1993-01-01

    Multi-well pumping tests have been concluded at wells MW79, MW108, and PW1 at the Paducah Gaseous Diffusion Plant (PGDP) to determine the hydraulic properties of the Regional Gravel Aquifer (RGA). Soil cores suggest that the RGA consists of a thin sandy facies (2 to 6 feet) at the top of a thicker (> 10 feet) gravelly facies. Previous analyses have not considered any permeability contrast between the two facies. To assess the accuracy of this assumption, TVA personnel conducted borehole flowmeter tests at wells MW108 and PW1. Well MW79 could not be tested. The high K sand unit is probably 10 times more permeable than comparable zone in the gravelly portion of the RGA. Previous analyses of the three multi-well aquifer tests do not use the same conceptual aquifer model. Data analysis for one pumping test assumed that leakance was significant. Data analysis for another pumping test assumed that a geologic boundary was significant. By collectively analyzing all three tests with the borehole flowmeter results, the inconsistency among the three pumping tests can be explained. Disparity exists because each pumping test had a different placement of observation wells relative to the high K zone delineating by flowmeter testing.

  17. Previous ISD Program Review.

    Science.gov (United States)

    1981-03-01

    report. The detail required for such a review would be unwieldy and would comsume inordinate amounts of time. The result of the document review will...attempts have been made at writing specific behavioral objectives (SBOs). These, however, have proven to be inadequate in that they are not stated in... behavioral terms (e.g., "will understand," "will have a knowledge of," etc.). C. Development of CRO/CRTs? In nearly all cases, ISD teams are just

  18. Two case reports: Carcinoma of the cervix and carcinoma of the endometrium treated with radiotherapy after previous irradiation for benign uterine bleeding

    Energy Technology Data Exchange (ETDEWEB)

    MacLeod, C. [Royal Prince Alfred Hospital, Camperdown, NSW (Australia). Department of Radiation Oncology

    1998-08-01

    In the 1940s, 1950s and 1960s, low doses of radiotherapy were used to treat benign uterine bleeding. The cases of two women who received this form of therapy and later developed gynaecological malignancies and had high-dose pelvic radiotherapy are presented. A 76-year-old woman with an International Federation of Gynecology and Obstetrics (FIGO) stage-II B squamous cell carcinoma of the cervix received external beam radiotherapy and intra-uterine brachytherapy and a 77-year-old woman with a FIGO stage-I B endometrial adenocarcinoma received adjuvant postoperative pelvic radiotherapy. Both women had a significant past history of low-dose-rate intra-uterine irradiation for dysfunctional uterine bleeding. Therefore the theoretical question of carcinogenesis was raised, and also the practical questions of what dose had previously been given and what further dose could be safely given with regard to normal tissue tolerance. Copyright (1998) Blackwell Science Pty Ltd 20 refs.

  19. Two case reports: Carcinoma of the cervix and carcinoma of the endometrium treated with radiotherapy after previous irradiation for benign uterine bleeding

    International Nuclear Information System (INIS)

    MacLeod, C.

    1998-01-01

    In the 1940s, 1950s and 1960s, low doses of radiotherapy were used to treat benign uterine bleeding. The cases of two women who received this form of therapy and later developed gynaecological malignancies and had high-dose pelvic radiotherapy are presented. A 76-year-old woman with an International Federation of Gynecology and Obstetrics (FIGO) stage-II B squamous cell carcinoma of the cervix received external beam radiotherapy and intra-uterine brachytherapy and a 77-year-old woman with a FIGO stage-I B endometrial adenocarcinoma received adjuvant postoperative pelvic radiotherapy. Both women had a significant past history of low-dose-rate intra-uterine irradiation for dysfunctional uterine bleeding. Therefore the theoretical question of carcinogenesis was raised, and also the practical questions of what dose had previously been given and what further dose could be safely given with regard to normal tissue tolerance. Copyright (1998) Blackwell Science Pty Ltd

  20. Alpha-tubulin missense mutations correlate with antimicrotubule drug resistance in Eleusine indica.

    Science.gov (United States)

    Yamamoto, E; Zeng, L; Baird, W V

    1998-02-01

    Dinitroaniline herbicides are antimicrotubule drugs that bind to tubulins and inhibit polymerization. As a result of repeated application of dinitroaniline herbicides, highly resistant and intermediately resistant biotypes of goosegrass (Eleusine indica) developed in previously wild-type populations. Three alpha-tubulin cDNA classes (designated TUA1, TUA2, and TUA3) were isolated from each biotype. Nucleotide differences between the susceptible and the resistant (R) alpha-tubulins were identified in TUA1 and TUA2. The most significant differences were missense mutations that occurred in TUA1 of the R and intermediately resistant (I) biotypes. Such mutations convert Thr-239 to Ile in the R biotype and Met-268 to Thr in the I biotype. These amino acid substitutions alter hydrophobicity; therefore, they may alter the dinitroaniline binding property of the protein. These mutations were correlated with the dinitroaniline response phenotypes (Drp). Plants homozygous for susceptibility possessed the wild-type TUA1 allele; plants homozygous for resistance possessed the mutant tua1 allele; and plants heterozygous for susceptibility possessed both wild-type and mutant alleles. Thus, we conclude that TUA1 is at the Drp locus. Using polymerase chain reaction primer-introduced restriction analysis, we demonstrated that goosegrass genomic DNA can be diagnosed for Drp alleles. Although not direct proof, these results suggest that a mutation in an alpha-tubulin gene confers resistance to dinitroanilines in goosegrass.

  1. Limited importance of the dominant-negative effect of TP53 missense mutations

    International Nuclear Information System (INIS)

    Stoczynska-Fidelus, Ewelina; Liberski, Pawel P; Rieske, Piotr; Szybka, Malgorzata; Piaskowski, Sylwester; Bienkowski, Michal; Hulas-Bigoszewska, Krystyna; Banaszczyk, Mateusz; Zawlik, Izabela; Jesionek-Kupnicka, Dorota; Kordek, Radzislaw

    2011-01-01

    Heterozygosity of TP53 missense mutations is related to the phenomenon of the dominant-negative effect (DNE). To estimate the importance of the DNE of TP53 mutations, we analysed the percentage of cancer cases showing a single heterozygous mutation of TP53 and searched for a cell line with a single heterozygous mutation of this gene. This approach was based on the knowledge that genes with evident DNE, such as EGFR and IDH1, represent nearly 100% of single heterozygous mutations in tumour specimens and cell lines. Genetic analyses (LOH and sequencing) performed for early and late passages of several cell lines originally described as showing single heterozygous TP53 mutations (H-318, G-16, PF-382, MOLT-13, ST-486 and LS-123). Statistical analysis of IARC TP53 and SANGER databases. Genetic analyses of N-RAS, FBXW7, PTEN and STR markers to test cross-contamination and cell line identity. Cell cloning, fluorescence-activated cell sorting and SSCP performed for the PF-382 cell line. A database study revealed TP53 single heterozygous mutations in 35% of in vivo (surgical and biopsy) samples and only 10% of cultured cells (in vitro), although those numbers appeared to be overestimated. We deem that published in vivo TP53 mutation analyses are not as rigorous as studies in vitro, and we did not find any cell line showing a stable, single heterozygous mutation. G16, PF-382 and MOLT-13 cells harboured single heterozygous mutations temporarily. ST-486, H-318 and LS-123 cell lines were misclassified. Specific mutations, such as R175H, R273H, R273L or R273P, which are reported in the literature to exert a DNE, showed the lowest percentage of single heterozygous mutations in vitro (about 5%). We suggest that the currently reported percentage of TP53 single heterozygous mutations in tumour samples and cancer cell lines is overestimated. Thus, the magnitude of the DNE of TP53 mutations is questionable. This scepticism is supported by database investigations showing that retention

  2. The use of porcine small intestinal submucosa mesh (SURGISIS as a pelvic sling in a man and a woman with previous pelvic surgery: two case reports

    Directory of Open Access Journals (Sweden)

    Al-Sahaf Osama

    2009-02-01

    Full Text Available Abstract Introduction Closing the pelvic peritoneum to prevent the small bowel dropping into the pelvis after surgery for locally recurrent rectal cancer is important to prevent adhesions deep in the pelvis or complications of adjuvant radiotherapy. Achieving this could be difficult because sufficient native tissue is unavailable; we report on the use of small intestine submucosa extra-cellular matrix mesh in the obliteration of the pelvic brim. Case presentation We describe two cases in which submucosa extra-cellular matrix mesh was used to obliterate the pelvic brim following resection of a recurrent rectal tumour; the first patient, a 78-year-old Caucasian man, presented with small bowel obstruction caused by adhesions to a recurrent rectal tumour. The second patient, an 84-year-old Caucasian woman, presented with vaginal discharge caused by an entero-vaginal fistula due to a recurrent rectal tumour. Conclusion We report on the use of submucosa extra-cellular matrix mesh as a pelvic sling in cases where primary closure of the pelvic peritoneum is unfeasible. Its use had no infective complications and added minimal morbidity to the postoperative period. This is an original case report that would be of interest to general and colorectal surgeons.

  3. Functional characterization of a CRH missense mutation identified in an ADNFLE family.

    Directory of Open Access Journals (Sweden)

    Veronica Sansoni

    Full Text Available Nocturnal frontal lobe epilepsy has been historically considered a channelopathy caused by mutations in subunits of the neuronal nicotinic acetylcholine receptor or in a recently reported potassium channel. However, these mutations account for only a minority of patients, and the existence of at least a new locus for the disease has been demonstrated. In 2005, we detected two nucleotide variations in the promoter of the CRH gene coding for the corticotropin releasing hormone in 7 patients. These variations cosegregated with the disease and were demonstrated to alter the cellular levels of this hormone. Here, we report the identification in an Italian affected family of a novel missense mutation (hpreproCRH p.Pro30Arg located in the region of the CRH coding for the protein pro-sequence. The mutation was detected in heterozygosity in the two affected individuals. In vitro assays demonstrated that this mutation results in reduced levels of protein secretion in the short time thus suggesting that mutated people could present an altered capability to respond immediately to stress agents.

  4. Familial Mediterranean fever, Inflammation and Nephrotic Syndrome: Fibrillary Glomerulopathy and the M680I Missense Mutation

    Directory of Open Access Journals (Sweden)

    Semerdjian Ronald J

    2003-08-01

    Full Text Available Abstract Background Familial Mediterranean fever (FMF is an autosomal recessive disease characterized by inflammatory serositis (fever, peritonitis, synovitis and pleuritis. The gene locus responsible for FMF was identified in 1992 and localized to the short arm of chromosome 16. In 1997, a specific FMF gene locus, MEFV, was discovered to encode for a protein, pyrin that mediates inflammation. To date, more than forty missense mutations are known to exist. The diversity of mutations identified has provided insight into the variability of clinical presentation and disease progression. Case Report We report an individual heterozygous for the M680I gene mutation with a clinical diagnosis of FMF using the Tel-Hashomer criteria. Subsequently, the patient developed nephrotic syndrome with biopsy-confirmed fibrillary glomerulonephritis (FGN. Further diagnostic studies were unremarkable with clinical workup negative for amyloidosis or other secondary causes of nephrotic syndrome. Discussion Individuals with FMF are at greater risk for developing nephrotic syndrome. The most serious etiology is amyloidosis (AA variant with renal involvement, ultimately progressing to end-stage renal disease. Other known renal diseases in the FMF population include IgA nephropathy, IgM nephropathy, Henoch-Schönlein purpura as well as polyarteritis nodosa. Conclusion To our knowledge, this is the first association between FMF and the M680I mutation later complicated by nephrotic syndrome and fibrillary glomerulonephritis.

  5. Involvement of ER Stress in Dysmyelination of Pelizaeus-Merzbacher Disease with PLP1 Missense Mutations Shown by iPSC-Derived Oligodendrocytes

    Directory of Open Access Journals (Sweden)

    Yuko Numasawa-Kuroiwa

    2014-05-01

    Full Text Available Pelizaeus-Merzbacher disease (PMD is a form of X-linked leukodystrophy caused by mutations in the proteolipid protein 1 (PLP1 gene. Although PLP1 proteins with missense mutations have been shown to accumulate in the rough endoplasmic reticulum (ER in disease model animals and cell lines transfected with mutant PLP1 genes, the exact pathogenetic mechanism of PMD has not previously been clarified. In this study, we established induced pluripotent stem cells (iPSCs from two PMD patients carrying missense mutation and differentiated them into oligodendrocytes in vitro. In the PMD iPSC-derived oligodendrocytes, mislocalization of mutant PLP1 proteins to the ER and an association between increased susceptibility to ER stress and increased numbers of apoptotic oligodendrocytes were observed. Moreover, electron microscopic analysis demonstrated drastically reduced myelin formation accompanied by abnormal ER morphology. Thus, this study demonstrates the involvement of ER stress in pathogenic dysmyelination in the oligodendrocytes of PMD patients with the PLP1 missense mutation.

  6. Atypical Clinical Presentation of Xeroderma Pigmentosum in a Patient Harboring a Novel Missense Mutation in the XPC Gene: The Importance of Clinical Suspicion.

    Science.gov (United States)

    Meneses, Marina; Chavez-Bourgeois, Marion; Badenas, Celia; Villablanca, Salvador; Aguilera, Paula; Bennàssar, Antoni; Alos, Llucia; Puig, Susana; Malvehy, Josep; Carrera, Cristina

    2015-01-01

    Xeroderma pigmentosum (XP) is a genodermatosis caused by abnormal DNA repair. XP complementation group C (XPC) is the most frequent type in Mediterranean countries. We describe a case with a novel mutation in the XPC gene. A healthy Caucasian male patient was diagnosed with multiple primary melanomas. Digital follow-up and molecular studies were carried out. During digital follow-up 8 more additional melanomas were diagnosed. Molecular studies did not identify mutations in CDKN2A, CDK4 or MITF genes. Two heterozygous mutations in the XPC gene were detected: c.2287delC (p.Leu763Cysfs*4) frameshift and c.2212A>G (p.Thr738Ala) missense mutations. The p.Thr738Ala missense mutation has not been previously described. Missense mutations in the XPC gene may allow partial functionality that could explain this unusual late onset XP. Atypical clinical presentation of XPC could be misdiagnosed when genetic aberrations allow partial DNA repair capacity. © 2015 S. Karger AG, Basel.

  7. Severe Clinical Course in a Patient with Congenital Amegakaryocytic Thrombocytopenia Due to a Missense Mutation of the c-MPL Gene.

    Science.gov (United States)

    Ok Bozkaya, İkbal; Yaralı, Neşe; Işık, Pamir; Ünsal Saç, Rukiye; Tavil, Betül; Tunç, Bahattin

    2015-06-01

    Congenital amegakaryocytic thrombocytopenia (CAMT) generally begins at birth with severe thrombocytopenia and progresses to pancytopenia. It is caused by mutations in the thrombopoietin receptor gene, the myeloproliferative leukemia virus oncogene (c-MPL). The association between CAMT and c-MPL mutation type has been reported in the literature. Patients with CAMT have been categorized according to their clinical symptoms caused by different mutations. Missense mutations of c-MPL have been classified as type II and these patients have delayed onset of bone marrow failure compared to type I patients. Here we present a girl with severe clinical course of CAMT II having a missense mutation in exon 4 of the c-MPL gene who was admitted to our hospital with intracranial hemorrhage during the newborn period.

  8. Four Forensic Entomology Case Studies: Records and Behavioral Observations on Seldom Reported Cadaver Fauna With Notes on Relevant Previous Occurrences and Ecology.

    Science.gov (United States)

    Lindgren, Natalie K; Sisson, Melissa S; Archambeault, Alan D; Rahlwes, Brent C; Willett, James R; Bucheli, Sibyl R

    2015-03-01

    A yearlong survey of insect taxa associated with human decomposition was conducted at the Southeast Texas Applied Forensic Science (STAFS) facility located in the Center for Biological Field Studies of Sam Houston State University in Huntsville, TX. During this study, four insect-cadaver interactions were observed that represent previously poorly documented yet forensically significant interactions: Syrphidae maggots colonized a corpse in an aquatic situation; Psychodidae adults mated and oviposited on an algal film that was present on a corpse that had been recently removed from water; several Panorpidae were the first insects to feed upon a freshly placed corpse in the autumn; and a noctuid caterpillar was found chewing and ingesting dried human skin. Baseline knowledge of insect-cadaver interactions is the foundation of forensic entomology, and unique observations have the potential to expand our understanding of decomposition ecology. © The Author 2015. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  9. A novel missense mutation of NDP in a Chinese family with X-linked familial exudative vitreoretinopathy.

    Science.gov (United States)

    Liu, Hong Yan; Huang, Jia; Wang, Rui Li; Wang, Yue; Guo, Liang Jie; Li, Tao; Wu, Dong; Wang, Hong Dan; Guo, Qian Nan; Dong, Dao Quan

    2016-11-01

    Familial exudative vitreoretinopathy (FEVR) is a hereditary ocular disorder characterized by a failure of peripheral retinal vascularization. In this report, we describe a novel missense mutation of the Norrie disease gene (NDP) in a Chinese family with X-linked FEVR. Ophthalmologic evaluation was performed on four male patients and seven unaffected individuals after informed consent was obtained. Venous blood was collected from the 11 members of this family, and genomic DNA was extracted using standard methods. The coding exons 2 and 3 and their corresponding exon-intron junctions of NDP were amplified by polymerase chain reaction and then subjected to direct DNA sequencing. A novel missense mutation (c.310A>C) in exon 3, leading to a lysine-to-glutamine substitution at position 104 (p.Lys104Gln), was identified in all four patients with X-linked FEVR. Three unaffected female individuals (III2, IV3, and IV11) were found to be carriers of the mutation. This mutation was not detected in other unaffected individuals. The mutation c.310A>C (p.Lys104Gln) in exon 3 of NDP is associated with FEVR in the studied family. This result further enriches the mutation spectrum of FEVR. Copyright © 2016. Published by Elsevier Taiwan LLC.

  10. Missense polymorphisms in the MC1R gene of the dog, red fox, arctic fox and Chinese raccoon dog.

    Science.gov (United States)

    Nowacka-Woszuk, J; Salamon, S; Gorna, A; Switonski, M

    2013-04-01

    Coat colour variation is determined by many genes, one of which is the melanocortin receptor type 1 (MC1R) gene. In this study, we examined the whole coding sequence of this gene in four species belonging to the Canidae family (dog, red fox, arctic fox and Chinese raccoon dog). Although the comparative analysis of the obtained nucleotide sequences revealed a high conservation, which varied between 97.9 and 99.1%, we altogether identified 22 SNPs (10 in dogs, six in farmed red foxes, two in wild red foxes, three in arctic foxes and one in Chinese raccoon dog). Among them, seven appeared to be novel: one silent in the dog, three missense and one silent in the red fox, one in the 3'-flanking region in the arctic fox and one silent in the Chinese raccoon dog. In dogs and red foxes, the SNPs segregated as 10 and four haplotypes, respectively. Taking into consideration the published reports and results of this study, the highest number of missense polymorphisms was until now found in the dog (9) and red fox (7). © 2012 Blackwell Verlag GmbH.

  11. Alternating hemiplegia of childhood-related neural and behavioural phenotypes in Na+,K+-ATPase α3 missense mutant mice.

    Directory of Open Access Journals (Sweden)

    Greer S Kirshenbaum

    Full Text Available Missense mutations in ATP1A3 encoding Na(+,K(+-ATPase α3 have been identified as the primary cause of alternating hemiplegia of childhood (AHC, a motor disorder with onset typically before the age of 6 months. Affected children tend to be of short stature and can also have epilepsy, ataxia and learning disability. The Na(+,K(+-ATPase has a well-known role in maintaining electrochemical gradients across cell membranes, but our understanding of how the mutations cause AHC is limited. Myshkin mutant mice carry an amino acid change (I810N that affects the same position in Na(+,K(+-ATPase α3 as I810S found in AHC. Using molecular modelling, we show that the Myshkin and AHC mutations display similarly severe structural impacts on Na(+,K(+-ATPase α3, including upon the K(+ pore and predicted K(+ binding sites. Behavioural analysis of Myshkin mice revealed phenotypic abnormalities similar to symptoms of AHC, including motor dysfunction and cognitive impairment. 2-DG imaging of Myshkin mice identified compromised thalamocortical functioning that includes a deficit in frontal cortex functioning (hypofrontality, directly mirroring that reported in AHC, along with reduced thalamocortical functional connectivity. Our results thus provide validation for missense mutations in Na(+,K(+-ATPase α3 as a cause of AHC, and highlight Myshkin mice as a starting point for the exploration of disease mechanisms and novel treatments in AHC.

  12. A novel missense mutation of NDP in a Chinese family with X-linked familial exudative vitreoretinopathy

    Directory of Open Access Journals (Sweden)

    Hong Yan Liu

    2016-11-01

    Full Text Available Familial exudative vitreoretinopathy (FEVR is a hereditary ocular disorder characterized by a failure of peripheral retinal vascularization. In this report, we describe a novel missense mutation of the Norrie disease gene (NDP in a Chinese family with X-linked FEVR. Ophthalmologic evaluation was performed on four male patients and seven unaffected individuals after informed consent was obtained. Venous blood was collected from the 11 members of this family, and genomic DNA was extracted using standard methods. The coding exons 2 and 3 and their corresponding exon–intron junctions of NDP were amplified by polymerase chain reaction and then subjected to direct DNA sequencing. A novel missense mutation (c.310A>C in exon 3, leading to a lysine-to-glutamine substitution at position 104 (p.Lys104Gln, was identified in all four patients with X-linked FEVR. Three unaffected female individuals (III2, IV3, and IV11 were found to be carriers of the mutation. This mutation was not detected in other unaffected individuals. The mutation c.310A>C (p.Lys104Gln in exon 3 of NDP is associated with FEVR in the studied family. This result further enriches the mutation spectrum of FEVR.

  13. Alzheimer neuropathology without frontotemporal lobar degeneration hallmarks (TAR DNA-binding protein 43 inclusions) in missense progranulin mutation Cys139Arg.

    Science.gov (United States)

    Redaelli, Veronica; Rossi, Giacomina; Maderna, Emanuela; Kovacs, Gabor G; Piccoli, Elena; Caroppo, Paola; Cacciatore, Francesca; Spinello, Sonia; Grisoli, Marina; Sozzi, Giuliano; Salmaggi, Andrea; Tagliavini, Fabrizio; Giaccone, Giorgio

    2018-01-01

    Null mutations in progranulin gene (GRN) reduce the progranulin production resulting in haploinsufficiency and are tightly associated with tau-negative frontotemporal lobar degeneration with TAR DNA-binding protein 43-positive inclusions (FTLD-TDP). Missense mutations of GRN were also identified, but their effects are not completely clear, in particular unanswered is the question of what neuropathology they elicit, also considering that their occurrence has been reported in patients with typical clinical features of Alzheimer disease. They describe two fraternal twins carrying the missense GRN Cys139Arg mutation affected by late-onset dementia and we report the neuropathological study of one of them. Both patients were examined by neuroimaging, neuropsychological assessment and genetic analysis of GRN and other genes associated with dementia. The brain of one was obtained at autopsy and examined neuropathologically. One sister presented clinical and MRI features leading to the diagnosis of Alzheimer disease. The other underwent autopsy and the brain showed neuropathological hallmarks of Alzheimer disease with abundant Aβ-amyloid deposition and Braak stage V of neurofibrillary pathology, in the absence of the hallmark lesions of FTLD-TDP. Their findings may contribute to better clarify the role of progranulin in neurodegenerative diseases indicating that some GRN mutations, in particular missense ones, may act as strong risk factor for Alzheimer disease rather than induce FTLD-TDP. © 2016 International Society of Neuropathology.

  14. Homozygous loss of function BRCA1 variant causing a Fanconi-anemia-like phenotype, a clinical report and review of previous patients.

    Science.gov (United States)

    Freire, Bruna L; Homma, Thais K; Funari, Mariana F A; Lerario, Antônio M; Leal, Aline M; Velloso, Elvira D R P; Malaquias, Alexsandra C; Jorge, Alexander A L

    2018-03-01

    Fanconi Anemia (FA) is a rare and heterogeneous genetic syndrome. It is associated with short stature, bone marrow failure, high predisposition to cancer, microcephaly and congenital malformation. Many genes have been associated with FA. Previously, two adult patients with biallelic pathogenic variant in Breast Cancer 1 gene (BRCA1) had been identified in Fanconi Anemia-like condition. The proband was a 2.5 year-old girl with severe short stature, microcephaly, neurodevelopmental delay, congenital heart disease and dysmorphic features. Her parents were third degree cousins. Routine screening tests for short stature was normal. We conducted whole exome sequencing (WES) of the proband and used an analysis pipeline to identify rare nonsynonymous genetic variants that cause short stature. We identified a homozygous loss-of-function BRCA1 mutation (c.2709T > A; p. Cys903*), which promotes the loss of critical domains of the protein. Cytogenetic study with DEB showed an increased chromosomal breakage. We screened heterozygous parents of the index case for cancer and we detected, in her mother, a metastatic adenocarcinoma in an axillar lymph node with probable primary site in the breast. It is possible to consolidate the FA-like phenotype associated with biallelic loss-of-function BRCA1, characterized by microcephaly, short stature, developmental delay, dysmorphic face features and cancer predisposition. In our case, the WES allowed to establish the genetic cause of short stature in the context of a chromosome instability syndrome. An identification of BRCA1 mutations in our patient allowed precise genetic counseling and also triggered cancer screening for the patient and her family members. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  15. Feline leprosy due to Candidatus 'Mycobacterium lepraefelis': Further clinical and molecular characterisation of eight previously reported cases and an additional 30 cases.

    Science.gov (United States)

    O'Brien, Carolyn R; Malik, Richard; Globan, Maria; Reppas, George; McCowan, Christina; Fyfe, Janet A

    2017-09-01

    This paper, the last in a series of three on 'feline leprosy', provides a detailed description of disease referable to the previously unnamed species, Candidatus 'Mycobacterium lepraefelis', a close relative of the human pathogens Mycobacterium leprae and Mycobacterium lepromatosis. Cases were sourced retrospectively and prospectively for this observational study, describing clinical, geographical and molecular microbiological data for cats definitively diagnosed with Candidatus 'M lepraefelis' infection. A total of 145 cases of feline leprosy were scrutinised; 114 'new' cases were sourced from the Victorian Infectious Diseases Reference Laboratory (VIDRL) records, veterinary pathology laboratories or veterinarians, and 31 cases were derived from six published studies. Thirty-eight cats were definitively diagnosed with Candidatus 'M lepraefelis' infection. Typically, cats tended to be middle-aged or older when first infected, with a male predilection. Affected cats typically had widespread cutaneous lesions, in some cases after initially localised disease. Advanced cases were often systemically unwell. All cats had outdoor access. The histological picture was lepromatous in the majority of patients, although two cases had tuberculoid disease. In one case that underwent necropsy, lesions were evident in the liver, spleen and lungs. Treatment was varied, although most cats received a combination of oral clarithromycin and rifampicin. Prognosis for recovery was variable, but typically poor. Candidatus 'M lepraefelis' typically causes high bacterial index (lepromatous) feline leprosy that in some cases progresses to systemic mycobacteriosis. The disease has a variable clinical course and prognosis. Many cases either died or were euthanased due to the infection. Multilocus sequence analysis reveals a heterogeneous picture and further analysis of draft genome sequencing may give clues to the taxonomy and epidemiology of this organism. Prospective treatment trials and

  16. Majewski osteodysplastic primordial dwarfism type II (MOPD II) syndrome previously diagnosed as Seckel syndrome: report of a novel mutation of the PCNT gene.

    Science.gov (United States)

    Piane, Maria; Della Monica, Matteo; Piatelli, Gianluca; Lulli, Patrizia; Lonardo, Fortunato; Chessa, Luciana; Scarano, Gioacchino

    2009-11-01

    We report on a 3-year-old boy with prenatal onset of proportionate dwarfism, postnatal severe microcephaly, high forehead with receded hairline, sparse scalp hair, beaked nose, mild retrognathia and hypotonia diagnosed at birth as Seckel syndrome. At age 3 years, he became paralyzed due to a cerebrovascular malformation. Based on the clinical and radiological features showing evidence of skeletal dysplasia, the diagnosis was revised to Majewski osteodysplastic primordial dwarfism type II (MOPD II) syndrome. Western blot analysis of the patient's lymphoblastoid cell line lysate showed the absence of the protein pericentrin. Subsequent molecular analysis identified a novel homozygous single base insertion (c.1527_1528insA) in exon 10 of the PCNT gene, which leads to a frameshift (Treo510fs) and to premature protein truncation. PCNT mutations must be considered diagnostic of MOPD II syndrome. A possible role of pericentrin in the development of cerebral vessels is suggested. Copyright 2009 Wiley-Liss, Inc.

  17. Radiation port cutaneous metastases: Reports of two patients whose recurrent visceral cancers presented as skin lesions at the site of previous radiation and literature review

    Directory of Open Access Journals (Sweden)

    Brian Spencer Hoyt

    2014-01-01

    Full Text Available Radiation therapy is associated with a variety of complications, including the development of primary skin cancers in the radiated region. However, it is rare for patients with visceral cancers who are treated with radiation therapy to subsequently develop cutaneous metastasis within the radiation port. We describe two patients with internal malignancies who developed cutaneous metastases within their radiation ports following radiotherapy. In addition, we used PubMed to perform an extensive literature review and identify additional reports of cutaneous metastasis within a radiation port. We excluded patients who developed melanoma or primary skin cancers in the radiation port. We also excluded patients with non-solid organ malignancies. Herein, we summarize the characteristics of 23 additional patients who experienced radiation port cutaneous metastases and explore possible mechanisms for the occurrence of radiation port cutaneous metastases.

  18. Late type III endoleak after thoracic endovascular aneurysm repair and previous infrarenal stent graft implantation - a case report and review of the literature.

    Science.gov (United States)

    Leszczyński, Jerzy; Macioch, Waldemar; Chudziński, Witold; Gałązka, Zbigniew

    2017-09-01

    Thoracic endovascular aortic repair (TEVAR) effectively improved the results of thoracic aortic aneurysm treatment. TEVAR is a less invasive procedure that can be performed under local anesthesia with shorter hospital stay. The perioperative morbidity and mortality rates are lower for endovascular than open repair, but the rate of secondary interventions is higher for TEVAR. We report a case of an elderly man with synchronous abdominal and thoracic aortic aneurysms. A type III dangerous endoleak was recognized 3 years after TEVAR. It was successfully repaired during an endovascular procedure. There were no new endoleaks after 12 months of follow-up. TEVAR may be the only option of treatment for risky and elderly patients. However, postoperative monitoring is necessary to exclude different types of endoleaks. Most of them undergo effective endovascular repair.

  19. Classification of rare missense substitutions, using risk surfaces, with genetic- and molecular-epidemiology applications.

    Science.gov (United States)

    Tavtigian, Sean V; Byrnes, Graham B; Goldgar, David E; Thomas, Alun

    2008-11-01

    Many individually rare missense substitutions are encountered during deep resequencing of candidate susceptibility genes and clinical mutation screening of known susceptibility genes. BRCA1 and BRCA2 are among the most resequenced of all genes, and clinical mutation screening of these genes provides an extensive data set for analysis of rare missense substitutions. Align-GVGD is a mathematically simple missense substitution analysis algorithm, based on the Grantham difference, which has already contributed to classification of missense substitutions in BRCA1, BRCA2, and CHEK2. However, the distribution of genetic risk as a function of Align-GVGD's output variables Grantham variation (GV) and Grantham deviation (GD) has not been well characterized. Here, we used data from the Myriad Genetic Laboratories database of nearly 70,000 full-sequence tests plus two risk estimates, one approximating the odds ratio and the other reflecting strength of selection, to display the distribution of risk in the GV-GD plane as a series of surfaces. We abstracted contours from the surfaces and used the contours to define a sequence of missense substitution grades ordered from greatest risk to least risk. The grades were validated internally using a third, personal and family history-based, measure of risk. The Align-GVGD grades defined here are applicable to both the genetic epidemiology problem of classifying rare missense substitutions observed in known susceptibility genes and the molecular epidemiology problem of analyzing rare missense substitutions observed during case-control mutation screening studies of candidate susceptibility genes. (c) 2008 Wiley-Liss, Inc.

  20. Resolution of temporomandibular joint dysfunction (TMJD) by correcting a lateral head translation posture following previous failed traditional chiropractic therapy: a CBP® case report.

    Science.gov (United States)

    Jaeger, Jason O; Oakley, Paul A; Moore, Robert R; Ruggeroli, Edward P; Harrison, Deed E

    2018-01-01

    [Purpose] To present the case of the resolution of right temporomandibular joint dysfunction (TMJD) following the correction of a right lateral head translation posture. [Subject and Methods] A 24 year old female reported facial pain and jaw clicking in the right TMJ. Radiography revealed a 19 mm right head (shift) translation posture. TMJ vibration analysis showed characteristic abnormalities for the right TMJ. The patient was treated with CBP ® technique mirror image ® left sided exercises, and traction methods as well as spinal manipulative therapy (SMT). [Results] After 36 treatments over a 12-week time period, a complete correction of the lateral head posture was achieved corresponding with a complete resolution of jaw pain and clicking. TMJ vibration analysis demonstrated normal right side TMJ characteristics following treatment. [Conclusion] Abnormal head/neck postures, such as lateral head translation, may be an unrealized source of TMJD and may be explained through the 'regional interdependence' model or by how seemingly unrelated anatomy may be associated with a primary complaint.

  1. Phenotypic variability in 49 cases of ESCO2 mutations, including novel missense and codon deletion in the acetyltransferase domain, correlates with ESCO2 expression and establishes the clinical criteria for Roberts syndrome

    DEFF Research Database (Denmark)

    Vega, H; Trainer, A H; Gordillo, M

    2010-01-01

    Roberts syndrome (RBS) and SC phocomelia are caused by mutations in ESCO2, which codes for an acetyltransferase involved in the regulation of sister chromatid cohesion. Of 26 mutations described to date, only one missense mutation has been reported and all others are predicted to be truncating...

  2. Phenotypic variability in 49 cases of ESCO2 mutations, including novel missense and codon deletion in the acetyltransferase domain, correlates with ESCO2 expression and establishes the clinical criteria for Roberts syndrome

    NARCIS (Netherlands)

    Vega, H.; Trainer, A.H.; Gordillo, M.; Crosier, M.; Kayserili, H.; Skovby, F.; Uzielli, M.L.G.; Schnur, R.E.; Manouvrier, S.; Blair, E.; Hurst, J.A.; Forzano, F.; Meins, M.; Simola, K.O.J.; Raas-Rothschild, A; Hennekam, R.C.M.; Jabs, E.W.

    2010-01-01

    Background Roberts syndrome (RBS) and SC phocomelia are caused by mutations in ESCO2, which codes for an acetyltransferase involved in the regulation of sister chromatid cohesion. Of 26 mutations described to date, only one missense mutation has been reported and all others are predicted to be

  3. Performance of in silico prediction tools for the classification of rare BRCA1/2 missense variants in clinical diagnostics.

    Science.gov (United States)

    Ernst, Corinna; Hahnen, Eric; Engel, Christoph; Nothnagel, Michael; Weber, Jonas; Schmutzler, Rita K; Hauke, Jan

    2018-03-27

    The use of next-generation sequencing approaches in clinical diagnostics has led to a tremendous increase in data and a vast number of variants of uncertain significance that require interpretation. Therefore, prediction of the effects of missense mutations using in silico tools has become a frequently used approach. Aim of this study was to assess the reliability of in silico prediction as a basis for clinical decision making in the context of hereditary breast and/or ovarian cancer. We tested the performance of four prediction tools (Align-GVGD, SIFT, PolyPhen-2, MutationTaster2) using a set of 236 BRCA1/2 missense variants that had previously been classified by expert committees. However, a major pitfall in the creation of a reliable evaluation set for our purpose is the generally accepted classification of BRCA1/2 missense variants using the multifactorial likelihood model, which is partially based on Align-GVGD results. To overcome this drawback we identified 161 variants whose classification is independent of any previous in silico prediction. In addition to the performance as stand-alone tools we examined the sensitivity, specificity, accuracy and Matthews correlation coefficient (MCC) of combined approaches. PolyPhen-2 achieved the lowest sensitivity (0.67), specificity (0.67), accuracy (0.67) and MCC (0.39). Align-GVGD achieved the highest values of specificity (0.92), accuracy (0.92) and MCC (0.73), but was outperformed regarding its sensitivity (0.90) by SIFT (1.00) and MutationTaster2 (1.00). All tools suffered from poor specificities, resulting in an unacceptable proportion of false positive results in a clinical setting. This shortcoming could not be bypassed by combination of these tools. In the best case scenario, 138 families would be affected by the misclassification of neutral variants within the cohort of patients of the German Consortium for Hereditary Breast and Ovarian Cancer. We show that due to low specificities state-of-the-art in silico

  4. WNT10A missense mutation associated with a complete odonto-onycho-dermal dysplasia syndrome.

    Science.gov (United States)

    Nawaz, Sadia; Klar, Joakim; Wajid, Muhammad; Aslam, Muhammad; Tariq, Muhammad; Schuster, Jens; Baig, Shahid Mahmood; Dahl, Niklas

    2009-12-01

    Wnt signalling is one of a few pathways that are crucial for controlling genetic programs during embryonic development as well as in adult tissues. WNT10A is expressed in the skin and epidermis and it has shown to be critical for the development of ectodermal appendages. A nonsense mutation in WNT10A was recently identified in odonto-onycho-dermal dysplasia (OODD; MIM 257980), a rare syndrome characterised by severe hypodontia, nail dystrophy, smooth tongue, dry skin, keratoderma and hyperhydrosis of palms and soles. We identified a large consanguineous Pakistani pedigree comprising six individuals affected by a complete OODD syndrome. Autozygosity mapping using SNP array analysis showed that the affected individuals are homozygous for the WNT10A gene region. Subsequent mutation screening showed a homozygous c.392C>T transition in exon 3 of WNT10A, which predicts a p.A131V substitution in a conserved alpha-helix domain. We report here on the first inherited missense mutation in WNT10A with associated ectodermal features.

  5. A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis

    Science.gov (United States)

    Ichikawa, Shoji; Imel, Erik A.; Kreiter, Mary L.; Yu, Xijie; Mackenzie, Donald S.; Sorenson, Andrea H.; Goetz, Regina; Mohammadi, Moosa; White, Kenneth E.; Econs, Michael J.

    2007-01-01

    Familial tumoral calcinosis is characterized by ectopic calcifications and hyperphosphatemia due to inactivating mutations in FGF23 or UDP-N-acetyl-α-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3). Herein we report a homozygous missense mutation (H193R) in the KLOTHO (KL) gene of a 13-year-old girl who presented with severe tumoral calcinosis with dural and carotid artery calcifications. This patient exhibited defects in mineral ion homeostasis with marked hyperphosphatemia and hypercalcemia as well as elevated serum levels of parathyroid hormone and FGF23. Mapping of H193R mutation onto the crystal structure of myrosinase, a plant homolog of KL, revealed that this histidine residue was at the base of the deep catalytic cleft and mutation of this histidine to arginine should destabilize the putative glycosidase domain (KL1) of KL, thereby attenuating production of membrane-bound and secreted KL. Indeed, compared with wild-type KL, expression and secretion of H193R KL were markedly reduced in vitro, resulting in diminished ability of FGF23 to signal via its cognate FGF receptors. Taken together, our findings provide what we believe to be the first evidence that loss-of-function mutations in human KL impair FGF23 bioactivity, underscoring the essential role of KL in FGF23-mediated phosphate and vitamin D homeostasis in humans. PMID:17710231

  6. Functional Studies of Missense TREM2 Mutations in Human Stem Cell-Derived Microglia

    Directory of Open Access Journals (Sweden)

    Philip W. Brownjohn

    2018-04-01

    Full Text Available Summary: The derivation of microglia from human stem cells provides systems for understanding microglial biology and enables functional studies of disease-causing mutations. We describe a robust method for the derivation of human microglia from stem cells, which are phenotypically and functionally comparable with primary microglia. We used stem cell-derived microglia to study the consequences of missense mutations in the microglial-expressed protein triggering receptor expressed on myeloid cells 2 (TREM2, which are causal for frontotemporal dementia-like syndrome and Nasu-Hakola disease. We find that mutant TREM2 accumulates in its immature form, does not undergo typical proteolysis, and is not trafficked to the plasma membrane. However, in the absence of plasma membrane TREM2, microglia differentiate normally, respond to stimulation with lipopolysaccharide, and are phagocytically competent. These data indicate that dementia-associated TREM2 mutations have subtle effects on microglia biology, consistent with the adult onset of disease in individuals with these mutations. : Brownjohn and colleagues report methods to generate microglia from induced pluripotent human stem cells, which they demonstrate are highly similar to cultured primary human microglia. Microglia differentiated from patient-derived stem cells carrying neurological disease-causing mutations in the TREM2 receptor differentiate normally and respond appropriately to pathogenic stimuli, despite the absence of functional TREM2 receptor on the plasma membrane. Keywords: dementia, microglia, TREM2, Nasu-Hakola disease, frontotemporal dementia, iPSC-microglia, neuroinflammation

  7. A Novel Missense Mutation of Doublecortin: Mutation Analysis of Korean Patients with Subcortical Band Heterotopia

    Science.gov (United States)

    Kim, Myeong-Kyu; Park, Man-Seok; Kim, Byeong-Chae; Cho, Ki-Hyun; Kim, Young-Seon; Kim, Jin-Hee; Heo, Tag; Kim, Eun-Young

    2005-01-01

    The neuronal migration disorders, X-linked lissencephaly syndrome (XLIS) and subcortical band heterotopia (SBH), also called "double cortex", have been linked to missense, nonsense, aberrant splicing, deletion, and insertion mutations in doublecortin (DCX) in families and sporadic cases. Most DCX mutations identified to date are located in two evolutionarily conserved domains. We performed mutation analysis of DCX in two Korean patients with SBH. The SBH patients had mild to moderate developmental delays, drug-resistant generalized seizures, and diffuse thick SBH upon brain MRI. Sequence analysis of the DCX coding region in Patient 1 revealed a c.386 C>T change in exon 3. The sequence variation results in a serine to leucine amino acid change at position 129 (S129L), which has not been found in other family members of Patient 1 or in a large panel of 120 control X-chromosomes. We report here a novel c.386 C>T mutation of DCX that is responsible for SBH. PMID:16100463

  8. Missense variants in AIMP1 gene are implicated in autosomal recessive intellectual disability without neurodegeneration.

    Science.gov (United States)

    Iqbal, Zafar; Püttmann, Lucia; Musante, Luciana; Razzaq, Attia; Zahoor, Muhammad Yasir; Hu, Hao; Wienker, Thomas F; Garshasbi, Masoud; Fattahi, Zohreh; Gilissen, Christian; Vissers, Lisenka E L M; de Brouwer, Arjan P M; Veltman, Joris A; Pfundt, Rolph; Najmabadi, Hossein; Ropers, Hans-Hilger; Riazuddin, Sheikh; Kahrizi, Kimia; van Bokhoven, Hans

    2016-03-01

    AIMP1/p43 is a multifunctional non-catalytic component of the multisynthetase complex. The complex consists of nine catalytic and three non-catalytic proteins, which catalyze the ligation of amino acids to their cognate tRNA isoacceptors for use in protein translation. To date, two allelic variants in the AIMP1 gene have been reported as the underlying cause of autosomal recessive primary neurodegenerative disorder. Here, we present two consanguineous families from Pakistan and Iran, presenting with moderate to severe intellectual disability, global developmental delay, and speech impairment without neurodegeneration. By the combination of homozygosity mapping and next generation sequencing, we identified two homozygous missense variants, p.(Gly299Arg) and p.(Val176Gly), in the gene AIMP1 that co-segregated with the phenotype in the respective families. Molecular modeling of the variants revealed deleterious effects on the protein structure that are predicted to result in reduced AIMP1 function. Our findings indicate that the clinical spectrum for AIMP1 defects is broader than witnessed so far.

  9. Missense variants in AIMP1 gene are implicated in autosomal recessive intellectual disability without neurodegeneration

    Science.gov (United States)

    Iqbal, Zafar; Püttmann, Lucia; Musante, Luciana; Razzaq, Attia; Zahoor, Muhammad Yasir; Hu, Hao; Wienker, Thomas F; Garshasbi, Masoud; Fattahi, Zohreh; Gilissen, Christian; Vissers, Lisenka ELM; de Brouwer, Arjan PM; Veltman, Joris A; Pfundt, Rolph; Najmabadi, Hossein; Ropers, Hans-Hilger; Riazuddin, Sheikh; Kahrizi, Kimia; van Bokhoven, Hans

    2016-01-01

    AIMP1/p43 is a multifunctional non-catalytic component of the multisynthetase complex. The complex consists of nine catalytic and three non-catalytic proteins, which catalyze the ligation of amino acids to their cognate tRNA isoacceptors for use in protein translation. To date, two allelic variants in the AIMP1 gene have been reported as the underlying cause of autosomal recessive primary neurodegenerative disorder. Here, we present two consanguineous families from Pakistan and Iran, presenting with moderate to severe intellectual disability, global developmental delay, and speech impairment without neurodegeneration. By the combination of homozygosity mapping and next generation sequencing, we identified two homozygous missense variants, p.(Gly299Arg) and p.(Val176Gly), in the gene AIMP1 that co-segregated with the phenotype in the respective families. Molecular modeling of the variants revealed deleterious effects on the protein structure that are predicted to result in reduced AIMP1 function. Our findings indicate that the clinical spectrum for AIMP1 defects is broader than witnessed so far. PMID:26173967

  10. Molecular evaluation of a novel missense mutation & an insertional truncating mutation in SUMF1 gene

    Directory of Open Access Journals (Sweden)

    Udhaya H Kotecha

    2014-01-01

    Full Text Available Background & objectives: Multiple suphphatase deficiency (MSD is an autosomal recessive disorder affecting the post translational activation of all enzymes of the sulphatase family. To date, approximately 30 different mutations have been identified in the causative gene, sulfatase modifying factor 1 (SUMF1. We describe here the mutation analysis of a case of MSD. Methods: The proband was a four year old boy with developmental delay followed by neuroregression. He had coarse facies, appendicular hypertonia, truncal ataxia and ichthyosis limited to both lower limbs. Radiographs showed dysostosis multiplex. Clinical suspicion of MSD was confirmed by enzyme analysis of four enzymes of the sulphatase group. Results: The patient was compound heterozygote for a c.451A>G (p.K151E substitution in exon 3 and a single base insertion mutation (c.690_691 InsT in exon 5 in the SUMF1 gene. The bioinformatic analysis of the missense mutation revealed no apparent effect on the overall structure. However, the mutated 151-amino acid residue was found to be adjacent to the substrate binding and the active site residues, thereby affecting the substrate binding and/or catalytic activity, resulting in almost complete loss of enzyme function. Conclusions: The two mutations identified in the present case were novel. This is perhaps the first report of an insertion mutation in SUMF1 causing premature truncation of the protein.

  11. Novel splice-site and missense mutations in the ALDH1A3 gene underlying autosomal recessive anophthalmia/microphthalmia.

    Science.gov (United States)

    Semerci, C Nur; Kalay, Ersan; Yıldırım, Cem; Dinçer, Tuba; Olmez, Akgün; Toraman, Bayram; Koçyiğit, Ali; Bulgu, Yunus; Okur, Volkan; Satıroğlu-Tufan, Lale; Akarsu, Nurten A

    2014-06-01

    This study aimed to identify the underlying genetic defect responsible for anophthalmia/microphthalmia. In total, two Turkish families with a total of nine affected individuals were included in the study. Affymetrix 250 K single nucleotide polymorphism genotyping and homozygosity mapping were used to identify the localisation of the genetic defect in question. Coding region of the ALDH1A3 gene was screened via direct sequencing. cDNA samples were generated from primary fibroblast cell cultures for expression analysis. Reverse transcriptase PCR (RT-PCR) analysis was performed using direct sequencing of the obtained fragments. The causative genetic defect was mapped to chromosome 15q26.3. A homozygous G>A substitution (c.666G>A) at the last nucleotide of exon 6 in the ALDH1A3 gene was identified in the first family. Further cDNA sequencing of ALDH1A3 showed that the c.666G>A mutation caused skipping of exon 6, which predicted in-frame loss of 43 amino acids (p.Trp180_Glu222del). A novel missense c.1398C>A mutation in exon 12 of ALDH1A3 that causes the substitution of a conserved asparagine by lysine at amino acid position 466 (p.Asn466Lys) was observed in the second family. No extraocular findings-except for nevus flammeus in one affected individual and a variant of Dandy-Walker malformation in another affected individual-were observed. Autistic-like behaviour and mental retardation were observed in three cases. In conclusion, novel ALDH1A3 mutations identified in the present study confirm the pivotal role of ALDH1A3 in human eye development. Autistic features, previously reported as an associated finding, were considered to be the result of social deprivation and inadequate parenting during early infancy in the presented families. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  12. Missense Variants in ATM in 26,101 Breast Cancer Cases and 29,842 Controls

    DEFF Research Database (Denmark)

    Fletcher, O.; Johnson, N.; Silva, Andreá Lema Da

    2010-01-01

    Background: Truncating mutations in ATM have been shown to increase the risk of breast cancer but the effect of missense variants remains contentious. Methods: We have genotyped five polymorphic (minor allele frequency, 0.9-2.6%) missense single nucleotide polymorphisms (SNP) in ATM (S49C, S707P, F...... for any of the SNPs with an overall trend OR of 1.06 (P-trend = 0.04). The trend OR among bilateral and familial cases was 1.12 (95% confidence interval, 1.02-1.23; P-trend = 0.02). Conclusions: In this large combined analysis, these five missense ATM SNPs were associated with a small increased risk...

  13. INTRODUCTION Previous reports have documented a high ...

    African Journals Online (AJOL)

    Conclusion: The positive effect of education on oral hygiene practices is highlighted in this study. However there is still need for proper health enlightenment in this population with regards to use of the available oral health care facilities. Keywords: Oral hygiene, Pregnancy, Nigeria. Annals of Ibadan Postgraduate Medicine.

  14. BRCA1/2 missense mutations and the value of in-silico analyses.

    Science.gov (United States)

    Sadowski, Carolin E; Kohlstedt, Daniela; Meisel, Cornelia; Keller, Katja; Becker, Kerstin; Mackenroth, Luisa; Rump, Andreas; Schröck, Evelin; Wimberger, Pauline; Kast, Karin

    2017-11-01

    The clinical implications of genetic variants in BRCA1/2 in healthy and affected individuals are considerable. Variant interpretation, however, is especially challenging for missense variants. The majority of them are classified as variants of unknown clinical significance (VUS). Computational (in-silico) predictive programs are easy to access, but represent only one tool out of a wide range of complemental approaches to classify VUS. With this single-center study, we aimed to evaluate the impact of in-silico analyses in a spectrum of different BRCA1/2 missense variants. We conducted mutation analysis of BRCA1/2 in 523 index patients with suspected hereditary breast and ovarian cancer (HBOC). Classification of the genetic variants was performed according to the German Consortium (GC)-HBOC database. Additionally, all missense variants were classified by the following three in-silico prediction tools: SIFT, Mutation Taster (MT2) and PolyPhen2 (PPH2). Overall 201 different variants, 68 of which constituted missense variants were ranked as pathogenic, neutral, or unknown. The classification of missense variants by in-silico tools resulted in a higher amount of pathogenic mutations (25% vs. 13.2%) compared to the GC-HBOC-classification. Altogether, more than fifty percent (38/68, 55.9%) of missense variants were ranked differently. Sensitivity of in-silico-tools for mutation prediction was 88.9% (PPH2), 100% (SIFT) and 100% (MT2). We found a relevant discrepancy in variant classification by using in-silico prediction tools, resulting in potential overestimation and/or underestimation of cancer risk. More reliable, notably gene-specific, prediction tools and functional tests are needed to improve clinical counseling. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  15. New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants

    DEFF Research Database (Denmark)

    Andreasen, Charlotte Hartig; Nielsen, Jonas B; Refsgaard, Lena

    2013-01-01

    Cardiomyopathies are a heterogeneous group of diseases with various etiologies. We focused on three genetically determined cardiomyopathies: hypertrophic (HCM), dilated (DCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC). Eighty-four genes have so far been associated with these card......Cardiomyopathies are a heterogeneous group of diseases with various etiologies. We focused on three genetically determined cardiomyopathies: hypertrophic (HCM), dilated (DCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC). Eighty-four genes have so far been associated...... with these cardiomyopathies, but the disease-causing effect of reported variants is often dubious. In order to identify possible false-positive variants, we investigated the prevalence of previously reported cardiomyopathy-associated variants in recently published exome data. We searched for reported missense and nonsense...... variants in the NHLBI-Go Exome Sequencing Project (ESP) containing exome data from 6500 individuals. In ESP, we identified 94 variants out of 687 (14%) variants previously associated with HCM, 58 out of 337 (17%) variants associated with DCM, and 38 variants out of 209 (18%) associated with ARVC...

  16. Femoral Component Revision with Use of Impaction Bone-Grafting and a Cemented Polished Stem: A Concise Follow-up, at Fifteen to Twenty Years, of a Previous Report*

    NARCIS (Netherlands)

    Te Stroet, M.A.; Gardeniers, J.W.M.; Verdonschot, N.J.; Rijnen, W.H.C.; Slooff, T.J.J.H.; Schreurs, B.W.

    2012-01-01

    We previously reported our results for thirty-three consecutive femoral component revisions with impaction bone-grafting, performed with the X-change femoral revision system and a cemented polished Exeter stem, at a minimum of eight years of follow-up. The present updated study shows the results

  17. BRCA2 hypomorphic missense variants confer moderate risks of breast cancer

    OpenAIRE

    Shimelis, Hermela; Mesman, Romy L.s.; Von Nicolai, Catharina; Ehlen, Asa; Guidugli, Lucia; Martin, Charlotte; Calleja, Fabienne Mgr; Meeks, Huong; Hallberg, Emily; Hinton, Jamie; Lilyquist, Jenna; Hu, Chunling; Aalfs, Cora M; Aittomaki, Kristiina; Andrulis, Irene L.

    2017-01-01

    Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case–control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ances...

  18. BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer.

    OpenAIRE

    Shimelis, Hermela; Mesman, Romy LS; Von, Nicolai Catharina; Ehlen, Asa; Guidugli, Lucia; Martin, Charlotte; Calléja, Fabienne MGR; Meeks, Huong; Hallberg, Emily; Hinton, Jamie; Lilyquist, Jenna; Hu, Chunling; Aalfs, Cora M; Aittomäki, Kristiina; Andrulis, Irene

    2017-01-01

    Breast cancer risks conferred by many germline missense variants in the $\\textit{BRCA1}$ and $\\textit{BRCA2}$ genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case-control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine ...

  19. A rat model of hypohidrotic ectodermal dysplasia carries a missense mutation in the Edaradd gene

    Science.gov (United States)

    2011-01-01

    Background Hypohidrotic ectodermal dysplasia (HED) is a congenital disorder characterized by sparse hair, oligodontia, and inability to sweat. It is caused by mutations in any of three Eda pathway genes: ectodysplasin (Eda), Eda receptor (Edar), and Edar-associated death domain (Edaradd), which encode ligand, receptor, and intracellular adaptor molecule, respectively. The Eda signaling pathway activates NF-κB, which is central to ectodermal differentiation. Although the causative genes and the molecular pathway affecting HED have been identified, no curative treatment for HED has been established. Previously, we found a rat spontaneous mutation that caused defects in hair follicles and named it sparse-and-wavy (swh). Here, we have established the swh rat as the first rat model of HED and successfully identified the swh mutation. Results The swh/swh rat showed sparse hair, abnormal morphology of teeth, and absence of sweat glands. The ectoderm-derived glands, meibomian, preputial, and tongue glands, were absent. We mapped the swh mutation to the most telomeric part of rat Chr 7 and found a Pro153Ser missense mutation in the Edaradd gene. This mutation was located in the death domain of EDARADD, which is crucial for signal transduction and resulted in failure to activate NF-κB. Conclusions These findings suggest that swh is a loss-of-function mutation in the rat Edaradd and indicate that the swh/swh rat would be an excellent animal model of HED that could be used to investigate the pathological basis of the disease and the development of new therapies. PMID:22013926

  20. Association of the Lipoprotein Receptor SCARB1 Common Missense Variant rs4238001 with Incident Coronary Heart Disease.

    Directory of Open Access Journals (Sweden)

    Ani Manichaikul

    Full Text Available Previous studies in mice and humans have implicated the lipoprotein receptor SCARB1 in association with atherosclerosis and lipid levels. In the current study, we sought to examine association of SCARB1 missense single nucleotide polymorphism (SNP rs4238001 with incident coronary heart disease (CHD.Genotypes for rs4238001 were imputed for 2,319 White, 1,570 African American, and 1,292 Hispanic-American MESA participants using the 1,000 Genomes reference set. Cox proportional hazards models were used to determine association of rs4238001 with incident CHD, with adjustments for age, sex, study site, principal components of ancestry, body mass index, diabetes status, serum creatinine, lipid levels, hypertension status, education and smoking exposure. Meta-analysis across race/ethnic groups within MESA showed statistically significant association of the T allele with higher risk of CHD under a consistent and formally adjudicated definition of CHD events in this contemporary cohort study (hazard ratio [HR] = 1.49, 95% CI [1.04, 2.14], P = 0.028. Analyses combining MESA with additional population-based cohorts expanded our samples in Whites (total n = 11,957 with 871 CHD events and African Americans (total n = 5,962 with 355 CHD events and confirmed an increased risk of CHD overall (HR of 1.19 with 95% CI [1.04, 1.37], P = 0.013, in African Americans (HR of 1.49 with 95% CI [1.07, 2.06], P = 0.019, in males (HR of 1.29 with 95% CI [1.08, 1.54], P = 4.91 x 10(-3 and in White males (HR of 1.24 with 95% CI [1.03, 1.51], P = 0.026.SCARB1 missense rs4238001 is statistically significantly associated with incident CHD across a large population of multiple race/ethnic groups.

  1. Profound, prelingual nonsyndromic deafness maps to chromosome 10q21 and is caused by a novel missense mutation in the Usher syndrome type IF gene PCDH15.

    Science.gov (United States)

    Doucette, Lance; Merner, Nancy D; Cooke, Sandra; Ives, Elizabeth; Galutira, Dante; Walsh, Vanessa; Walsh, Tom; MacLaren, Linda; Cater, Tracey; Fernandez, Bridget; Green, Jane S; Wilcox, Edward R; Shotland, Lawrence I; Shotland, Larry; Li, Xiaoyan Cindy; Li, X C; Lee, Ming; King, Mary-Claire; Young, Terry-Lynn

    2009-05-01

    We studied a consanguineous family (Family A) from the island of Newfoundland with an autosomal recessive form of prelingual, profound, nonsyndromic sensorineural hearing loss. A genome-wide scan mapped the deafness trait to 10q21-22 (max LOD score of 4.0; D10S196) and fine mapping revealed a 16 Mb ancestral haplotype in deaf relatives. The PCDH15 gene was mapped within the critical region and was an interesting candidate because truncating mutations cause Usher syndrome type IF (USH1F) and two missense mutations have been previously associated with isolated deafness (DFNB23). Sequencing of the PCDH15 gene revealed 33 sequencing variants. Three of these variants were homozygous exclusively in deaf siblings but only one of them was not seen in ethnically matched controls. This novel c.1583 T>A transversion predicts an amino-acid substitution of a valine with an aspartic acid at codon 528 (V528D). Like the two DFNB23 mutations, the V528D mutation in Family A occurs in a highly conserved extracellular cadherin (EC) domain of PCDH15 and is predicted to be more deleterious than the previously identified DFNB23 missense mutations (R134G and G262D). Physical assessment, vestibular and visual function testing in deaf adults ruled out syndromic deafness because of Usher syndrome. This study validates the DFNB23 designation and supports the hypothesis that missense mutations in conserved motifs of PCDH15 cause nonsyndromic hearing loss. This emerging genotype-phenotype correlation in USH1F is similar to that in several other USH1 genes and cautions against a prognosis of a dual sensory loss in deaf children found to be homozygous for hypomorphic mutations at the USH1F locus.

  2. Missense mutation in DISC1 C-terminal coiled-coil has GSK3β signaling and sex-dependent behavioral effects in mice

    Science.gov (United States)

    Dachtler, James; Elliott, Christina; Rodgers, R. John; Baillie, George S.; Clapcote, Steven J.

    2016-01-01

    Disrupted-in-Schizophrenia 1 (DISC1) is a risk factor for schizophrenia and affective disorders. The full-length DISC1 protein consists of an N-terminal ‘head’ domain and a C-terminal tail domain that contains several predicted coiled-coils, structural motifs involved in protein-protein interactions. To probe the in vivo effects of missense mutation of DISC1’s C-terminal tail, we tested mice carrying mutation D453G within a predicted α-helical coiled-coil region. We report that, relative to wild-type littermates, female DISC1D453G mice exhibited novelty-induced hyperlocomotion, an anxiogenic profile in the elevated plus-maze and open field tests, and reduced social exploration of unfamiliar mice. Male DISC1D453G mice displayed a deficit in passive avoidance, while neither males nor females exhibited any impairment in startle reactivity or prepulse inhibition. Whole brain homogenates showed normal levels of DISC1 protein, but decreased binding of DISC1 to GSK3β, decreased phospho-inhibition of GSK3β at serine 9, and decreased levels of β-catenin in DISC1D453G mice of either sex. Interrupted GSK3β signaling may thus be part of the mechanism underlying the behavioral phenotype associated with D453G, in common with the previously described N-terminal domain mutations Q31L and L100P in mice, and the schizophrenia risk-conferring variant R264Q in humans. PMID:26728762

  3. Abnormal fibrinogen Zlín (.gamma.Thr21Ile) with missense mutation causing hypofibrinogenemia

    Czech Academy of Sciences Publication Activity Database

    Riedelová-Reicheltová, Z.; Riedel, Tomáš; Májek, P.; Kotlín, R.; Geierová, V.; Suttnar, J.; Dyr, J. E.

    2014-01-01

    Roč. 132, č. 2 (2014), s. 140-143 ISSN 0001-5792 R&D Projects: GA ČR GBP205/12/G118 Institutional support: RVO:61389013 Keywords : fibrinogen * missense mutation * hypofibrinogenemia Subject RIV: BO - Biophysics Impact factor: 1.116, year: 2014

  4. Predicting the impact of Lynch syndrome-causing missense mutations from structural calculations

    DEFF Research Database (Denmark)

    Nielsen, Sofie V,; Stein, Amelie; Dinitzen, Alexander B.

    2017-01-01

    selected the human mismatch repair protein, MSH2, where missense variants are known to cause the hereditary cancer predisposition disease, known as Lynch syndrome. We show that the majority of disease-causing MSH2 mutations give rise to folding defects and proteasome-dependent degradation rather than...... and for diagnosis of Lynch syndrome, and perhaps other hereditary diseases....

  5. A novel missense Norrie disease mutation associated with a severe ocular phenotype.

    Science.gov (United States)

    Khan, Arif O; Shamsi, Farrukh A; Al-Saif, Amr; Kambouris, Marios

    2004-01-01

    Clinical findings and pedigree analysis led to the diagnosis of severe Norrie disease in two brothers. DNA sequencing demonstrated a novel missense mutation (703G>T) that significantly alters predicted protein structure. Less severe retinal developmental disease may be associated with milder mutations in the Norrie disease gene.

  6. A novel missense mutation in collagenous domain of EDA gene in a ...

    Indian Academy of Sciences (India)

    Supplementary data: A novel missense mutation in collagenous domain of EDA gene in a. Chinese family with X-linked hypohidrotic ectodermal dysplasia. Daxu Li, Ran Xu, Fumeng Huang, Biyuan Wang, Yu Tao, Zijian Jiang, Hairui Li, Jianfeng Yao,. Peng Xu, Xiaokang Wu, Le Ren, Rui Zhang, John R. Kelsoe and Jie Ma.

  7. Hypomyelinating leukodystrophy-associated missense mutation in HSPD1 blunts mitochondrial dynamics

    Energy Technology Data Exchange (ETDEWEB)

    Miyamoto, Yuki [Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535 (Japan); Eguchi, Takahiro [The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639 (Japan); Kawahara, Kazuko [Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535 (Japan); Hasegawa, Nanami [Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535 (Japan); Faculty of Pharmacy, Keio University, Minato, Tokyo 105-8512 (Japan); Nakamura, Kazuaki [Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535 (Japan); Funakoshi-Tago, Megumi [Faculty of Pharmacy, Keio University, Minato, Tokyo 105-8512 (Japan); Tanoue, Akito [Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535 (Japan); Tamura, Hiroomi [Faculty of Pharmacy, Keio University, Minato, Tokyo 105-8512 (Japan); Yamauchi, Junji, E-mail: yamauchi-j@ncchd.go.jp [Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535 (Japan); Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo, Tokyo 113-8510 (Japan)

    2015-07-03

    Myelin-forming glial cells undergo dynamic morphological changes in order to produce mature myelin sheaths with multiple layers. In the central nervous system (CNS), oligodendrocytes differentiate to insulate neuronal axons with myelin sheaths. Myelin sheaths play a key role in homeostasis of the nervous system, but their related disorders lead not only to dismyelination and repeated demyelination but also to severe neuropathies. Hereditary hypomyelinating leukodystrophies (HLDs) are a group of such diseases affecting oligodendrocytes and are often caused by missense mutations of the respective responsible genes. Despite increasing identification of gene mutations through advanced nucleotide sequencing technology, studies on the relationships between gene mutations and their effects on cellular and subcellular aberrance have not followed at the same rapid pace. In this study, we report that an HLD4-associated (Asp-29-to-Gly) mutant of mitochondrial heat shock 60-kDa protein 1 (HSPD1) causes short-length morphologies and increases the numbers of mitochondria due to their aberrant fission and fusion cycles. In experiments using a fluorescent dye probe, this mutation decreases the mitochondrial membrane potential. Also, mitochondria accumulate in perinuclear regions. HLD4-associated HSPD1 mutant blunts mitochondrial dynamics, probably resulting in oligodendrocyte malfunction. This study constitutes a first finding concerning the relationship between disease-associated HSPD1 mutation and mitochondrial dynamics, which may be similar to the relationship between another disease-associated HSPD1 mutation (MitCHAP-60 disease) and aberrant mitochondrial dynamics. - Highlights: • The HLD4 mutant of HSPD1 decreases mitochondrial fission frequency. • The HLD4 mutant decreases mitochondrial fusion frequency. • Mitochondria harboring the HLD4 mutant exhibit slow motility. • The HLD4 mutant of HSPD1 decreases mitochondrial membrane potential. • HLD4-related diseases may

  8. Hypomyelinating leukodystrophy-associated missense mutation in HSPD1 blunts mitochondrial dynamics

    International Nuclear Information System (INIS)

    Miyamoto, Yuki; Eguchi, Takahiro; Kawahara, Kazuko; Hasegawa, Nanami; Nakamura, Kazuaki; Funakoshi-Tago, Megumi; Tanoue, Akito; Tamura, Hiroomi; Yamauchi, Junji

    2015-01-01

    Myelin-forming glial cells undergo dynamic morphological changes in order to produce mature myelin sheaths with multiple layers. In the central nervous system (CNS), oligodendrocytes differentiate to insulate neuronal axons with myelin sheaths. Myelin sheaths play a key role in homeostasis of the nervous system, but their related disorders lead not only to dismyelination and repeated demyelination but also to severe neuropathies. Hereditary hypomyelinating leukodystrophies (HLDs) are a group of such diseases affecting oligodendrocytes and are often caused by missense mutations of the respective responsible genes. Despite increasing identification of gene mutations through advanced nucleotide sequencing technology, studies on the relationships between gene mutations and their effects on cellular and subcellular aberrance have not followed at the same rapid pace. In this study, we report that an HLD4-associated (Asp-29-to-Gly) mutant of mitochondrial heat shock 60-kDa protein 1 (HSPD1) causes short-length morphologies and increases the numbers of mitochondria due to their aberrant fission and fusion cycles. In experiments using a fluorescent dye probe, this mutation decreases the mitochondrial membrane potential. Also, mitochondria accumulate in perinuclear regions. HLD4-associated HSPD1 mutant blunts mitochondrial dynamics, probably resulting in oligodendrocyte malfunction. This study constitutes a first finding concerning the relationship between disease-associated HSPD1 mutation and mitochondrial dynamics, which may be similar to the relationship between another disease-associated HSPD1 mutation (MitCHAP-60 disease) and aberrant mitochondrial dynamics. - Highlights: • The HLD4 mutant of HSPD1 decreases mitochondrial fission frequency. • The HLD4 mutant decreases mitochondrial fusion frequency. • Mitochondria harboring the HLD4 mutant exhibit slow motility. • The HLD4 mutant of HSPD1 decreases mitochondrial membrane potential. • HLD4-related diseases may

  9. Missense mutations in ITPR1 cause autosomal dominant congenital nonprogressive spinocerebellar ataxia

    Directory of Open Access Journals (Sweden)

    Huang Lijia

    2012-09-01

    Full Text Available Abstract Background Congenital nonprogressive spinocerebellar ataxia is characterized by early gross motor delay, hypotonia, gait ataxia, mild dysarthria and dysmetria. The clinical presentation remains fairly stable and may be associated with cerebellar atrophy. To date, only a few families with autosomal dominant congenital nonprogressive spinocerebellar ataxia have been reported. Linkage to 3pter was demonstrated in one large Australian family and this locus was designated spinocerebellar ataxia type 29. The objective of this study is to describe an unreported Canadian family with autosomal dominant congenital nonprogressive spinocerebellar ataxia and to identify the underlying genetic causes in this family and the original Australian family. Methods and Results Exome sequencing was performed for the Australian family, resulting in the identification of a heterozygous mutation in the ITPR1 gene. For the Canadian family, genotyping with microsatellite markers and Sanger sequencing of ITPR1 gene were performed; a heterozygous missense mutation in ITPR1 was identified. Conclusions ITPR1 encodes inositol 1,4,5-trisphosphate receptor, type 1, a ligand-gated ion channel that mediates calcium release from the endoplasmic reticulum. Deletions of ITPR1 are known to cause spinocerebellar ataxia type 15, a distinct and very slowly progressive form of cerebellar ataxia with onset in adulthood. Our study demonstrates for the first time that, in addition to spinocerebellar ataxia type 15, alteration of ITPR1 function can cause a distinct congenital nonprogressive ataxia; highlighting important clinical heterogeneity associated with the ITPR1 gene and a significant role of the ITPR1-related pathway in the development and maintenance of the normal functions of the cerebellum.

  10. Habenular expression of rare missense variants of the β4 nicotinic receptor subunit alters nicotine consumption

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    Marta A Ślimak

    2014-01-01

    Full Text Available The CHRNA5-CHRNA3-CHRNB4 gene cluster, encoding the α5, α3 and β4 nicotinic acetylcholine receptor (nAChR subunits, has been linked to nicotine dependence. The habenulo-interpeduncular (Hb-IPN tract is particularly enriched in α3β4 nAChRs. We recently showed that modulation of these receptors in the medial habenula (MHb in mice altered nicotine consumption. Given that β4 is rate-limiting for receptor activity and that single nucleotide polymorphisms (SNPs in CHRNB4 have been linked to altered risk of nicotine dependence in humans, we were interested in determining the contribution of allelic variants of β4 to nicotine receptor activity in the MHb. We screened for missense SNPs with allele frequencies > 0.0005 and introduced the corresponding substitutions in Chrnb4. Fourteen variants were analyzed by co-expression with α3. We found that β4A90I and β4T374I variants, previously shown to associate with reduced risk of smoking, and an additional variant β4D447Y, significantly increased nicotine-evoked current amplitudes, while β4R348C, the mutation most frequently encountered in sporadic amyotrophic lateral sclerosis (sALS, showed reduced nicotine currents. We employed lentiviruses to express β4 or β4 variants in the MHb. Immunoprecipitation studies confirmed that β4 lentiviral-mediated expression leads to specific upregulation of α3β4 but not β2 nAChRs in the Mhb. Mice injected with the β4-containing virus showed pronounced aversion to nicotine as previously observed in transgenic Tabac mice overexpressing Chrnb4 at endogenous sites including the MHb. Habenular expression of the β4 gain-of-function allele T374I also resulted in strong aversion, while transduction with the β4 loss-of function allele R348C failed to induce nicotine aversion. Altogether, these data confirm the critical role of habenular β4 in nicotine consumption, and identify specific SNPs in CHRNB4 that modify nicotine-elicited currents and alter nicotine

  11. MAFA missense mutation causes familial insulinomatosis and diabetes mellitus

    NARCIS (Netherlands)

    Iacovazzo, D. (Donato); Flanagan, S.E. (Sarah E.); Walker, E. (Emily); Quezado, R. (Rosana); De Sousa Barros, F.A. (Fernando Antonio); Caswell, R. (Richard); Johnson, M.B. (Matthew B.); Wakeling, M. (Matthew); Brändle, M. (Michael); Guo, M. (Min); Dang, M.N. (Mary N.); Gabrovska, P. (Plamena); B. Niederle (Bruno); E. Christ (Emanuel); Jenni, S. (Stefan); Sipos, B. (Bence); Nieser, M. (Maike); A. Frilling (Andrea); Dhatariya, K. (Ketan); P. Chanson (Philippe); W.W. de Herder (Wouter); Konukiewitz, B. (Björn); Klöppel, G. (Günter); Stein, R. (Roland); M. Korbonits; S. Ellard (Sian)

    2018-01-01

    textabstractThe β-cell–enriched MAFA transcription factor plays a central role in regulating glucose-stimulated insulin secretion while also demonstrating oncogenic transformation potential in vitro. No disease-causing MAFA variants have been previously described. We investigated a large pedigree

  12. A missense mutation in ALDH18A1, encoding Delta1-pyrroline-5-carboxylate synthase (P5CS), causes an autosomal recessive neurocutaneous syndrome.

    Science.gov (United States)

    Bicknell, Louise S; Pitt, James; Aftimos, Salim; Ramadas, Ram; Maw, Marion A; Robertson, Stephen P

    2008-10-01

    There are several rare syndromes combining wrinkled, redundant skin and neurological abnormalities. Although phenotypic overlap between conditions has suggested that some might be allelic to one another, the aetiology for many of them remains unknown. A consanguineous New Zealand Maori family has been characterised that segregates an autosomal recessive connective tissue disorder (joint dislocations, lax skin) associated with neurological abnormalities (severe global developmental delay, choreoathetosis) without metabolic abnormalities in four affected children. A genome-screen performed under a hypothesis of homozygosity by descent for an ancestral mutation, identified a locus at 10q23 (Z = 3.63). One gene within the candidate interval, ALDH18A1, encoding Delta1-pyrroline-5-carboxylate synthase (P5CS), was considered a plausible disease gene since a missense mutation had previously been shown to cause progressive neurodegeneration, cataracts, skin laxity, joint dislocations and metabolic derangement in a consanguineous Algerian family. A missense mutation, 2350C>T, was identified in ALDH18A1, which predicts the substitution H784Y. H784 is invariant across all phyla and lies within a previously unrecognised, conserved C-terminal motif in P5CS. In an in vivo assay of flux through this metabolic pathway using dermal fibroblasts obtained from an affected individual, proline and ornithine biosynthetic activity of P5CS was not affected by the H784Y substitution. These data suggest that P5CS may possess additional uncharacterised functions that affect connective tissue and central nervous system function.

  13. Functional characterization of rare missense mutations in MLH1 and MSH2 identified in Danish colorectal cancer patients

    DEFF Research Database (Denmark)

    Christensen, Lise Lotte; Kariola, Reetta; Korhonen, Mari K

    2009-01-01

    Recently, we have performed a population based study to analyse the frequency of colorectal cancer related MLH1 and MSH2 missense mutations in the Danish population. Half of the analyzed mutations were rare and most likely only present in the families where they were identified originally. Some...... of the missense mutations were located in conserved regions in the MLH1 and MSH2 proteins indicating a relation to disease development. In the present study, we functionally characterized 10 rare missense mutations in MLH1 and MSH2 identified in 13 Danish CRC families. To elucidate the pathogenicity...

  14. Estimated carrier frequency of creatine transporter deficiency in females in the general population using functional characterization of novel missense variants in the SLC6A8 gene.

    Science.gov (United States)

    DesRoches, Caro-Lyne; Patel, Jaina; Wang, Peixiang; Minassian, Berge; Salomons, Gajja S; Marshall, Christian R; Mercimek-Mahmutoglu, Saadet

    2015-07-10

    Creatine transporter deficiency (CRTR-D) is an X-linked inherited disorder of creatine transport. All males and about 50% of females have intellectual disability or cognitive dysfunction. Creatine deficiency on brain proton magnetic resonance spectroscopy and elevated urinary creatine to creatinine ratio are important biomarkers. Mutations in the SLC6A8 gene occur de novo in 30% of males. Despite reports of high prevalence of CRTR-D in males with intellectual disability, there are no true prevalence studies in the general population. To determine carrier frequency of CRTR-D in the general population we studied the variants in the SLC6A8 gene reported in the Exome Variant Server database and performed functional characterization of missense variants. We also analyzed synonymous and intronic variants for their predicted pathogenicity using in silico analysis tools. Nine missense variants were functionally analyzed using transient transfection by site-directed mutagenesis with In-Fusion HD Cloning in HeLa cells. Creatine uptake was measured by liquid chromatography tandem mass spectrometry for creatine measurement. The c.1654G>T (p.Val552Leu) variant showed low residual creatine uptake activity of 35% of wild type transfected HeLa cells and was classified as pathogenic. Three variants (c.808G>A; p.Val270Met, c.942C>G; p.Phe314Leu and c.952G>A; p.Ala318Thr) were predicted to be pathogenic based on in silico analysis, but proved to be non-pathogenic by our functional analysis. The estimated carrier frequency of CRTR-D was 0.024% in females in the general population. We recommend functional studies for all novel missense variants by transient transfection followed by creatine uptake measurement by liquid chromatography tandem mass spectrometry as fast and cost effective method for the functional analysis of missense variants in the SLC6A8 gene. Crown Copyright © 2015. Published by Elsevier B.V. All rights reserved.

  15. Null missense ABCR (ABCA4) mutations in a family with stargardt disease and retinitis pigmentosa.

    Science.gov (United States)

    Shroyer, N F; Lewis, R A; Yatsenko, A N; Lupski, J R

    2001-11-01

    To determine the type of ABCR mutations that segregate in a family that manifests both Stargardt disease (STGD) and retinitis pigmentosa (RP), and the functional consequences of the underlying mutations. Direct sequencing of all 50 exons and flanking intronic regions of ABCR was performed for the STGD- and RP-affected relatives. RNA hybridization, Western blot analysis, and azido-adenosine triphosphate (ATP) labeling was used to determine the effect of disease-associated ABCR mutations in an in vitro assay system. Compound heterozygous missense mutations were identified in patients with STGD and RP. STGD-affected individual AR682-03 was compound heterozygous for the mutation 2588G-->C and a complex allele, [W1408R; R1640W]. RP-affected individuals AR682-04 and-05 were compound heterozygous for the complex allele [W1408R; R1640W] and the missense mutation V767D. Functional analysis of the mutation V767D by Western blot and ATP binding revealed a severe reduction in protein expression. In vitro analysis of ABCR protein with the mutations W1408R and R1640W showed a moderate effect of these individual mutations on expression and ATP-binding; the complex allele [W1408R; R1640W] caused a severe reduction in protein expression. These data reveal that missense ABCR mutations may be associated with RP. Functional analysis reveals that the RP-associated missense ABCR mutations are likely to be functionally null. These studies of the complex allele W1408R; R1640W suggest a synergistic effect of the individual mutations. These data are congruent with a model in which RP is associated with homozygous null mutations and with the notion that severity of retinal disease is inversely related to residual ABCR activity.

  16. A structural systems biology approach for quantifying the systemic consequences of missense mutations in proteins.

    Directory of Open Access Journals (Sweden)

    Tammy M K Cheng

    Full Text Available Gauging the systemic effects of non-synonymous single nucleotide polymorphisms (nsSNPs is an important topic in the pursuit of personalized medicine. However, it is a non-trivial task to understand how a change at the protein structure level eventually affects a cell's behavior. This is because complex information at both the protein and pathway level has to be integrated. Given that the idea of integrating both protein and pathway dynamics to estimate the systemic impact of missense mutations in proteins remains predominantly unexplored, we investigate the practicality of such an approach by formulating mathematical models and comparing them with experimental data to study missense mutations. We present two case studies: (1 interpreting systemic perturbation for mutations within the cell cycle control mechanisms (G2 to mitosis transition for yeast; (2 phenotypic classification of neuron-related human diseases associated with mutations within the mitogen-activated protein kinase (MAPK pathway. We show that the application of simplified mathematical models is feasible for understanding the effects of small sequence changes on cellular behavior. Furthermore, we show that the systemic impact of missense mutations can be effectively quantified as a combination of protein stability change and pathway perturbation.

  17. In silico investigation of molecular effects caused by missense mutations in creatine transporter protein

    Science.gov (United States)

    Zhang, Zhe; Schwatz, Charles; Alexov, Emil

    2011-03-01

    Creatine transporter (CT) protein, which is encoded by SLC6A8 gene, is essential for taking up the creatine in the cell, which in turn plays a key role in the spatial and temporal maintenance of energy in skeletal and cardiac muscle cells. It was shown that some missense mutations in CT cause mental retardation, while others are harmless non-synonymous single nucleoside polymorphism (nsSNP). Currently fifteen missense mutations in CT are known, among which twelve are disease-causing. Sequence analysis reveals that there is no clear trend distinguishing disease-causing from harmless missense mutations. Because of that, we built 3D model of the CT using highly homologous template and use the model to investigate the effects of mutations of CT stability and hydrogen bond network. It is demonstrated that disease-causing mutations affect the folding free energy and ionization states of titratable group in much greater extend as compared with harmless mutations. Supported by grants from NLM, NIH, grant numbers 1R03LM009748 and 1R03LM009748-S1.

  18. BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer

    DEFF Research Database (Denmark)

    Shimelis, Hermela; Mesman, Romy L S; Von Nicolai, Catharina

    2017-01-01

    Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk ......, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants. Cancer Res; 77(11); 2789-99. ©2017 AACR....... were investigated through a breast cancer case-control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR = 2.52; P = 0.04), and BRCA...... of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant...

  19. Functional consequences and rescue potential of pathogenic missense mutations in tripeptidyl peptidase I.

    Science.gov (United States)

    Walus, Mariusz; Kida, Elizabeth; Golabek, Adam A

    2010-06-01

    There are 35 missense mutations among 68 different mutations in the TPP1 gene, which encodes tripeptidyl peptidase I (TPPI), a lysosomal aminopeptidase associated with classic late-infantile neuronal ceroid lipofuscinosis (CLN2 disease). To elucidate the molecular mechanisms underlying TPPI deficiency in patients carrying missense mutations and to test the amenability of mutant proteins to chemical chaperones and permissive temperature treatment, we introduced individually 14 disease-associated missense mutations into human TPP1 cDNA and analyzed the cell biology of these TPPI variants expressed in Chinese hamster ovary cells. Most TPPI variants displayed obstructed transport to the lysosomes, prolonged half-life of the proenzyme, and residual or no enzymatic activity, indicating folding abnormalities. Protein misfolding was produced by mutations located in both the prosegment (p.Gly77Arg) and throughout the length of the mature enzyme. However, the routes of removal of misfolded proteins by the cells varied, ranging from their efficient degradation by the ubiquitin/proteasome system to abundant secretion. Two TPPI variants demonstrated enhanced processing in response to folding improvement treatment, and the activity of one of them, p.Arg447His, showed a fivefold increase under permissive temperature conditions, which suggests that folding improvement strategies may ameliorate the function of some misfolding TPPI mutant proteins.

  20. Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain.

    Directory of Open Access Journals (Sweden)

    Jeffrey C Lee

    2006-12-01

    Full Text Available Protein tyrosine kinases are important regulators of cellular homeostasis with tightly controlled catalytic activity. Mutations in kinase-encoding genes can relieve the autoinhibitory constraints on kinase activity, can promote malignant transformation, and appear to be a major determinant of response to kinase inhibitor therapy. Missense mutations in the EGFR kinase domain, for example, have recently been identified in patients who showed clinical responses to EGFR kinase inhibitor therapy.Encouraged by the promising clinical activity of epidermal growth factor receptor (EGFR kinase inhibitors in treating glioblastoma in humans, we have sequenced the complete EGFR coding sequence in glioma tumor samples and cell lines. We identified novel missense mutations in the extracellular domain of EGFR in 13.6% (18/132 of glioblastomas and 12.5% (1/8 of glioblastoma cell lines. These EGFR mutations were associated with increased EGFR gene dosage and conferred anchorage-independent growth and tumorigenicity to NIH-3T3 cells. Cells transformed by expression of these EGFR mutants were sensitive to small-molecule EGFR kinase inhibitors.Our results suggest extracellular missense mutations as a novel mechanism for oncogenic EGFR activation and may help identify patients who can benefit from EGFR kinase inhibitors for treatment of glioblastoma.

  1. HIV risk perception and testing behaviours among men having sex with men (MSM) reporting potential transmission risks in the previous 12 months from a large online sample of MSM living in Germany.

    Science.gov (United States)

    Marcus, Ulrich; Gassowski, Martyna; Drewes, Jochen

    2016-10-22

    HIV testing and serostatus awareness are essential to implement biomedical strategies (treatment as prevention; oral chemoprophylaxis), and for effective serostatus-based behaviours (HIV serosorting; strategic positioning). The analysis focuses on the associations between reported sexual risks, the perceived risk for HIV infection, and HIV testing behaviour in order to identify the most relevant barriers for HIV test uptake among MSM living in Germany. MSM were recruited to a nationwide anonymous online-survey in 2013 on MSM social networking/dating sites. Questions covered testing behaviours, reasons for testing decisions, and HIV risk perception (5-point scale). Additional questions addressed arguments in favour of home/ home collection testing (HT). Using descriptive statistics and logistic regression we compared men reporting recent HIV testing (RT; previous 12 month) with men never tested (NT) in a subsample not previously diagnosed with HIV and reporting ≥2 episodes of condomless anal intercourse (CLAI) with a non-steady partner of unknown HIV serostatus in the previous 12 months. The subsample consisted of 775 RT (13 % of RT) and 396 NT (7 % of NT). The number of CLAI episodes in the last 12 months with non-steady partners of unknown HIV status did not differ significantly between the groups, but RT reported significantly higher numbers of partners (>5 AI partners: 65 vs. 44 %). While perceived risks regarding last AI were comparable between the groups, 49vs. 30 % NT were risks (67 %) and routine testing (49 %) were the most common testing reasons for RT, while the strong belief not to be infected (59 %) and various worries (41 %) and fears of testing positive (35 %) were predominant reasons of NT. Greater anonymity (aOR 3.2; 2.4-4.4), less embarrassment, (aOR 2.8; 1.9-4.1), and avoiding discussions on sexual behaviour (aOR 1.6; 1.1-2.2) were emphasized in favour of HT by NT. Perceived partner knowledge and reasons reflecting perceived gay- and

  2. Successful adalimumab treatment of a psoriasis vulgaris patient with hemodialysis for renal failure: A case report and a review of the previous reports on biologic treatments for psoriasis patients with hemodialysis for renal failure.

    Science.gov (United States)

    Kusakari, Yoshiyuki; Yamasaki, Kenshi; Takahashi, Toshiya; Tsuchiyama, Kenichiro; Shimada-Omori, Ryoko; Nasu-Tamabuchi, Mei; Aiba, Setsuya

    2015-07-01

    The efficacy and safety of biologic treatments have been established in patients with moderate to severe psoriasis, but there are few reports on biologic therapy for patients with psoriasis complicated by end-stage renal failure on hemodialysis (HD). In this report, we demonstrated the efficacy and safety of adalimumab for patients with severe psoriasis on HD. A 46-year-old Japanese man with a 14-year history of psoriasis was referred to our clinic in September 2009. He had developed hypertension and renal failure during a 7-year history of cyclosporin treatment. With the infliximab treatment, he achieved 75% improvement of the Psoriasis Area and Severity Index (PASI) score within 3 months from the PASI of 42.3 before the treatment. However, his renal failure gradually deteriorated, and HD was initiated at 1 year after the introduction of infliximab. Because of hydration during the i.v. injection of infliximab, he developed pulmonary edema with every infliximab treatment after starting HD. We switched to ustekinumab treatment, but his psoriasis was not improved. Then, we switched to adalimumab and achieved a PASI-100 response within 2 months. The patient received adalimumab treatment for more than a year without any adverse effects. In addition to our case, five articles reported cases of psoriasis patients with renal failure on HD who were treated with biologics. The psoriatic lesions were improved by biologics in these cases, and no severe adverse effects on the renal function were reported. Thus, biologics are a reasonable treatment option for patients with severe psoriasis with renal failure on HD. © 2015 Japanese Dermatological Association.

  3. A Missense LRRK2 Variant Is a Risk Factor for Excessive Inflammatory Responses in Leprosy.

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    Vinicius M Fava

    2016-02-01

    Full Text Available Depending on the epidemiological setting, a variable proportion of leprosy patients will suffer from excessive pro-inflammatory responses, termed type-1 reactions (T1R. The LRRK2 gene encodes a multi-functional protein that has been shown to modulate pro-inflammatory responses. Variants near the LRRK2 gene have been associated with leprosy in some but not in other studies. We hypothesized that LRRK2 was a T1R susceptibility gene and that inconsistent association results might reflect different proportions of patients with T1R in the different sample settings. Hence, we evaluated the association of LRRK2 variants with T1R susceptibility.An association scan of the LRRK2 locus was performed using 156 single-nucleotide polymorphisms (SNPs. Evidence of association was evaluated in two family-based samples: A set of T1R-affected and a second set of T1R-free families. Only SNPs significant for T1R-affected families with significant evidence of heterogeneity relative to T1R-free families were considered T1R-specific. An expression quantitative trait locus (eQTL analysis was applied to evaluate the impact of T1R-specific SNPs on LRRK2 gene transcriptional levels.A total of 18 T1R-specific variants organized in four bins were detected. The core SNP capturing the T1R association was the LRRK2 missense variant M2397T (rs3761863 that affects LRRK2 protein turnover. Additionally, a bin of nine SNPs associated with T1R were eQTLs for LRRK2 in unstimulated whole blood cells but not after exposure to Mycobacterium leprae antigen.The results support a preferential association of LRRK2 variants with T1R. LRRK2 involvement in T1R is likely due to a pathological pro-inflammatory loop modulated by LRRK2 availability. Interestingly, the M2397T variant was reported in association with Crohn's disease with the same risk allele as in T1R suggesting common inflammatory mechanism in these two distinct diseases.

  4. Whole Exome Sequencing Leading to the Diagnosis of Dysferlinopathy with a Novel Missense Mutation (c.959G>C

    Directory of Open Access Journals (Sweden)

    Abhisek Swaika

    2016-01-01

    Full Text Available Dysferlinopathy is an uncommon, progressive muscular dystrophy that has a wide phenotypic variability and primarily supportive management (Nguyen et al., 2007; Narayanaswami et al., 2014. Amyloid myopathy is a distinct, rare disorder that can present similarly to inflammatory myopathies and requires a high clinical suspicion for early intervention to prolong survival. Amyloid myopathy is typically associated with other systemic manifestations of amyloidosis, but rare cases of isolated amyloid myopathy have been described (Mandl et al., 2000; Hull et al., 2001. Positive Congo red stains on tissue biopsy remain the gold standard for diagnosis (Spuler et al., 1998; Karacostas et al., 2005. A high clinical suspicion and meticulous diagnostic workup that includes novel techniques are necessary for identifying these rare disorders. We report a middle-aged man with progressive leg muscle weakness who was initially treated as having amyloid myopathy but was later diagnosed as having dysferlinopathy by Whole Exome Sequencing (WES analysis. We also report a novel missense mutation (c.959G>C to help correlate in any patient with presumed dysferlinopathy and to add to the already known genotype of this disorder.

  5. Avoiding dangerous missense: thermophiles display especially low mutation rates.

    Directory of Open Access Journals (Sweden)

    John W Drake

    2009-06-01

    Full Text Available Rates of spontaneous mutation have been estimated under optimal growth conditions for a variety of DNA-based microbes, including viruses, bacteria, and eukaryotes. When expressed as genomic mutation rates, most of the values were in the vicinity of 0.003-0.004 with a range of less than two-fold. Because the genome sizes varied by roughly 10(4-fold, the mutation rates per average base pair varied inversely by a similar factor. Even though the commonality of the observed genomic rates remains unexplained, it implies that mutation rates in unstressed microbes reach values that can be finely tuned by evolution. An insight originating in the 1920s and maturing in the 1960s proposed that the genomic mutation rate would reflect a balance between the deleterious effect of the average mutation and the cost of further reducing the mutation rate. If this view is correct, then increasing the deleterious impact of the average mutation should be countered by reducing the genomic mutation rate. It is a common observation that many neutral or nearly neutral mutations become strongly deleterious at higher temperatures, in which case they are called temperature-sensitive mutations. Recently, the kinds and rates of spontaneous mutations were described for two microbial thermophiles, a bacterium and an archaeon. Using an updated method to extrapolate from mutation-reporter genes to whole genomes reveals that the rate of base substitutions is substantially lower in these two thermophiles than in mesophiles. This result provides the first experimental support for the concept of an evolved balance between the total genomic impact of mutations and the cost of further reducing the basal mutation rate.

  6. HIV risk perception and testing behaviours among men having sex with men (MSM reporting potential transmission risks in the previous 12 months from a large online sample of MSM living in Germany

    Directory of Open Access Journals (Sweden)

    Ulrich Marcus

    2016-10-01

    Full Text Available Abstract Background HIV testing and serostatus awareness are essential to implement biomedical strategies (treatment as prevention; oral chemoprophylaxis, and for effective serostatus-based behaviours (HIV serosorting; strategic positioning. The analysis focuses on the associations between reported sexual risks, the perceived risk for HIV infection, and HIV testing behaviour in order to identify the most relevant barriers for HIV test uptake among MSM living in Germany. Methods MSM were recruited to a nationwide anonymous online-survey in 2013 on MSM social networking/dating sites. Questions covered testing behaviours, reasons for testing decisions, and HIV risk perception (5-point scale. Additional questions addressed arguments in favour of home/ home collection testing (HT. Using descriptive statistics and logistic regression we compared men reporting recent HIV testing (RT; previous 12 month with men never tested (NT in a subsample not previously diagnosed with HIV and reporting ≥2 episodes of condomless anal intercourse (CLAI with a non-steady partner of unknown HIV serostatus in the previous 12 months. Results The subsample consisted of 775 RT (13 % of RT and 396 NT (7 % of NT. The number of CLAI episodes in the last 12 months with non-steady partners of unknown HIV status did not differ significantly between the groups, but RT reported significantly higher numbers of partners (>5 AI partners: 65 vs. 44 %. While perceived risks regarding last AI were comparable between the groups, 49vs. 30 % NT were <30 years, lived more often in towns/villages <100,000 residents (60 vs. 39 %, were less out-particularly towards care providers-about being attracted to men (aOR 10.1; 6.9–14.8, more often identified as bisexual (aOR 3.5; 2.5–4.8, and reported lower testing intentions (aOR 0.08; 0.06–0.11. Perceived risks (67 % and routine testing (49 % were the most common testing reasons for RT, while the strong belief not to be infected

  7. A novel RUNX2 missense mutation predicted to disrupt DNA binding causes cleidocranial dysplasia in a large Chinese family with hyperplastic nails

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    Wang Xiaoqin

    2007-12-01

    Full Text Available Abstract Background Cleidocranial dysplasia (CCD is a dominantly inherited disease characterized by hypoplastic or absent clavicles, large fontanels, dental dysplasia, and delayed skeletal development. The purpose of this study is to investigate the genetic basis of Chinese family with CCD. Methods Here, a large Chinese family with CCD and hyperplastic nails was recruited. The clinical features displayed a significant intrafamilial variation. We sequenced the coding region of the RUNX2 gene for the mutation and phenotype analysis. Results The family carries a c.T407C (p.L136P mutation in the DNA- and CBFβ-binding Runt domain of RUNX2. Based on the crystal structure, we predict this novel missense mutation is likely to disrupt DNA binding by RUNX2, and at least locally affect the Runt domain structure. Conclusion A novel missense mutation was identified in a large Chinese family with CCD with hyperplastic nails. This report further extends the mutation spectrum and clinical features of CCD. The identification of this mutation will facilitate prenatal diagnosis and preimplantation genetic diagnosis.

  8. A missense mutation in the alpha-actinin 1 gene (ACTN1 is the cause of autosomal dominant macrothrombocytopenia in a large French family.

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    Paul Guéguen

    Full Text Available Inherited thrombocytopenia is a heterogeneous group of disorders characterized by a reduced number of blood platelets. Despite the identification of nearly 20 causative genes in the past decade, approximately half of all subjects with inherited thrombocytopenia still remain unexplained in terms of the underlying pathogenic mechanisms. Here we report a six-generation French pedigree with an autosomal dominant mode of inheritance and the identification of its genetic basis. Of the 55 subjects available for analysis, 26 were diagnosed with isolated macrothrombocytopenia. Genome-wide linkage analysis mapped a 10.9 Mb locus to chromosome 14 (14q22 with a LOD score of 7.6. Candidate gene analysis complemented by targeted next-generation sequencing identified a missense mutation (c.137GA; p.Arg46Gln in the alpha-actinin 1 gene (ACTN1 that segregated with macrothrombocytopenia in this large pedigree. The missense mutation occurred within actin-binding domain of alpha-actinin 1, a functionally critical domain that crosslinks actin filaments into bundles. The evaluation of cultured mutation-harboring megakaryocytes by electron microscopy and the immunofluorescence examination of transfected COS-7 cells suggested that the mutation causes disorganization of the cellular cytoplasm. Our study concurred with a recently published whole-exome sequence analysis of six small Japanese families with congenital macrothrombocytopenia, adding ACTN1 to the growing list of thrombocytopenia genes.

  9. Eight novel F13A1 gene missense mutations in patients with mild FXIII deficiency: in silico analysis suggests changes in FXIII-A subunit structure/function.

    Science.gov (United States)

    Biswas, Arijit; Ivaskevicius, Vytautas; Thomas, Anne; Varvenne, Michael; Brand, Brigitte; Rott, Hannelore; Haussels, Iris; Ruehl, Heiko; Scholz, Ute; Klamroth, Robert; Oldenburg, Johannes

    2014-10-01

    Mild FXIII deficiency is an under-diagnosed disorder because the carriers of this deficiency are often asymptomatic and reveal a phenotype only under special circumstances like surgery or induced trauma. Mutational reports from this type of deficiency have been rare. In this study, we present the phenotypic and genotypic data of nine patients showing mild FXIII-A deficiency caused by eight novel heterozygous missense mutations (Pro166Leu, Arg171Gln, His342Tyr, Gln415Arg, Leu529Pro, Gln601Lys, Arg703Gln and Arg715Gly) in the F13A1 gene. None of these variants were seen in 200 healthy controls. In silico structural analysis of the local wild-type protein structures (activated and non-activated) from X-ray crystallographic models downloaded from the protein databank identified potential structural/functional effects for the identified mutations. The missense mutations in the core domain are suggested to be directly influencing the catalytic triad. Mutations on other domains might influence other critical factors such as activation peptide cleavage or the barrel domain integrity. In vitro expression and subsequent biochemical studies in the future will be able to confirm the pathophysiological mechanisms proposed for the mutations in this article.

  10. Structure-Function Correlation Analysis of Connexin50 Missense Mutations Causing Congenital Cataract: Electrostatic Potential Alteration Could Determine Intracellular Trafficking Fate of Mutants

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    Devroop Sarkar

    2014-01-01

    Full Text Available Connexin50 (Cx50 mutations are reported to cause congenital cataract probably through the disruption of intercellular transport in the lens. Cx50 mutants that undergo mistrafficking have generally been associated with failure to form functional gap junction channels; however, sometimes even properly trafficked mutants were found to undergo similar consequences. We hereby wanted to elucidate any structural bases of the varied functional consequences of Cx50 missense mutations through in silico approach. Computational studies have been done based on a Cx50 homology model to assess conservation, solvent accessibility, and 3-dimensional localization of mutated residues as well as mutation-induced changes in surface electrostatic potential, H-bonding, and steric clash. This was supplemented with meta-analysis of published literature on the functional properties of connexin missense mutations. Analyses revealed that the mutation-induced critical alterations of surface electrostatic potential in Cx50 mutants could determine their fate in intracellular trafficking. A similar pattern was observed in case of mutations involving corresponding conserved residues in other connexins also. Based on these results the trafficking fates of 10 uncharacterized Cx50 mutations have been predicted. Further experimental analyses are needed to validate the observed correlation.

  11. E2-EPF UCP regulates stability and functions of missense mutant pVHL via ubiquitin mediated proteolysis.

    Science.gov (United States)

    Park, Kyeong-Su; Kim, Ju Hee; Shin, Hee Won; Chung, Kyung-Sook; Im, Dong-Soo; Lim, Jung Hwa; Jung, Cho-Rok

    2015-10-26

    Missense mutation of VHL gene is frequently detected in type 2 VHL diseases and linked to a wide range of pVHL functions and stability. Certain mutant pVHLs retain ability to regulate HIFs but lose their function by instability. In this case, regulating of degradation of mutant pVHLs, can be postulated as therapeutic method. The stability and cellular function of missense mutant pVHLs were determine in HEK293T transient expressing cell and 786-O stable cell line. Ubiquitination assay of mutant VHL proteins was performed in vitro system. Anticancer effect of adenovirus mediated shUCP expressing was evaluated using ex vivo mouse xenograft assay. Three VHL missense mutants (V155A, L158Q, and Q164R) are directly ubiquitinated by E2-EPF UCP (UCP) in vitro. Mutant pVHLs are more unstable than wild type in cell. Missense mutant pVHLs interact with UCP directly in both in vitro and cellular systems. Lacking all of lysine residues of pVHL result in resistance to ubiquitination thereby increase its stability. Missense mutant pVHLs maintained the function of E3 ligase to ubiquitinate HIF-1α in vitro. In cells expressing mutant pVHLs, Glut-1 and VEGF were relatively upregulated compared to their levels in cells expressing wild-type. Depletion of UCP restored missense mutant pVHLs levels and inhibited cell growth. Adenovirus-mediated shUCP RNA delivery inhibited tumor growth in ex vivo mouse xenograft model. These data suggest that targeting of UCP can be one of therapeutic method in type 2 VHL disease caused by unstable but functional missense mutant pVHL.

  12. A Single Missense Mutation in 77% of Prostate Cancer Bone Metastases: Novel Opportunity for Genetic Biomarker and Novel Therapeutic Mitochondrial Target

    Science.gov (United States)

    2017-10-01

    goal of this application is to identify targets for the treatment of androgen receptor null castration-resistant prostate cancer in in vitro and pre...AWARD NUMBER: W81XWH-16-1-0584 TITLE : A Single Missense Mutation in 77% of Prostate Cancer Bone Metastases: Novel Opportunity for Genetic...Missense Mutation in 77% of Prostate Cancer Bone Metastases: 5a. CONTRACT NUMBER A Single Missense Mutation in 77% of Prostate Cancer Bone Metastases

  13. In silico analysis of a novel MKRN3 missense mutation in familial central precocious puberty.

    Science.gov (United States)

    Neocleous, Vassos; Shammas, Christos; Phelan, Marie M; Nicolaou, Stella; Phylactou, Leonidas A; Skordis, Nicos

    2016-01-01

    The onset of puberty is influenced by the interplay of stimulating and restraining factors, many of which have a genetic origin. Premature activation of the GnRH secretion in central precocious puberty (CPP) may arise either from gain-of-function mutations of the KISS1 and KISS1R genes or from loss-of-function manner mutations of the MKRN3 gene leading to MKRN3 deficiency. To explore the genetic causes responsible for CPP and the potential role of the RING finger protein 3 (MKRN3) gene. We investigated potential sequence variations in the intronless MKRN3 gene by Sanger sequencing of the entire 507 amino acid coding region of exon 1 in a family with two affected girls presented with CPP at the age of 6 and 5·7 years, respectively. A novel heterozygous g.Gly312Asp missense mutation in the MKRN3 gene was identified in these siblings. The imprinted MKRN3 missense mutation was also identified as expected in the unaffected father and followed as expected an imprinted mode of inheritance. In silico analysis of the altered missense variant using the computational algorithms Polyphen2, SIFT and Mutation Taster predicted a damage and pathogenic alteration causing CPP. The pathogenicity of the alteration at the protein level via an in silico structural model is also explored. A novel mutation in the MKRN3 gene in two sisters with CPP was identified, supporting the fundamental role of this gene in the suppression of the hypothalamic GnRH neurons. © 2015 John Wiley & Sons Ltd.

  14. Validation of previously reported predictors for radiation-induced hypothyroidism in nasopharyngeal cancer patients treated with intensity-modulated radiation therapy, a post hoc analysis from a Phase III randomized trial.

    Science.gov (United States)

    Lertbutsayanukul, Chawalit; Kitpanit, Sarin; Prayongrat, Anussara; Kannarunimit, Danita; Netsawang, Buntipa; Chakkabat, Chakkapong

    2018-05-10

    This study aimed to validate previously reported dosimetric parameters, including thyroid volume, mean dose, and percentage thyroid volume, receiving at least 40, 45 and 50 Gy (V40, V45 and V50), absolute thyroid volume spared (VS) from 45, 50 and 60 Gy (VS45, VS50 and VS60), and clinical factors affecting the development of radiation-induced hypothyroidism (RHT). A post hoc analysis was performed in 178 euthyroid nasopharyngeal cancer (NPC) patients from a Phase III study comparing sequential versus simultaneous-integrated boost intensity-modulated radiation therapy. RHT was determined by increased thyroid-stimulating hormone (TSH) with or without reduced free thyroxin, regardless of symptoms. The median follow-up time was 42.5 months. The 1-, 2- and 3-year freedom from RHT rates were 78.4%, 56.4% and 43.4%, respectively. The median latency period was 21 months. The thyroid gland received a median mean dose of 53.5 Gy. Female gender, smaller thyroid volume, higher pretreatment TSH level (≥1.55 μU/ml) and VS60 treatment planning.

  15. Previously unknown species of Aspergillus.

    Science.gov (United States)

    Gautier, M; Normand, A-C; Ranque, S

    2016-08-01

    The use of multi-locus DNA sequence analysis has led to the description of previously unknown 'cryptic' Aspergillus species, whereas classical morphology-based identification of Aspergillus remains limited to the section or species-complex level. The current literature highlights two main features concerning these 'cryptic' Aspergillus species. First, the prevalence of such species in clinical samples is relatively high compared with emergent filamentous fungal taxa such as Mucorales, Scedosporium or Fusarium. Second, it is clearly important to identify these species in the clinical laboratory because of the high frequency of antifungal drug-resistant isolates of such Aspergillus species. Matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) has recently been shown to enable the identification of filamentous fungi with an accuracy similar to that of DNA sequence-based methods. As MALDI-TOF MS is well suited to the routine clinical laboratory workflow, it facilitates the identification of these 'cryptic' Aspergillus species at the routine mycology bench. The rapid establishment of enhanced filamentous fungi identification facilities will lead to a better understanding of the epidemiology and clinical importance of these emerging Aspergillus species. Based on routine MALDI-TOF MS-based identification results, we provide original insights into the key interpretation issues of a positive Aspergillus culture from a clinical sample. Which ubiquitous species that are frequently isolated from air samples are rarely involved in human invasive disease? Can both the species and the type of biological sample indicate Aspergillus carriage, colonization or infection in a patient? Highly accurate routine filamentous fungi identification is central to enhance the understanding of these previously unknown Aspergillus species, with a vital impact on further improved patient care. Copyright © 2016 European Society of Clinical Microbiology and

  16. WDR73 missense mutation causes infantile onset intellectual disability and cerebellar hypoplasia in a consanguineous family.

    Science.gov (United States)

    Jiang, Chen; Gai, Nan; Zou, Yongyi; Zheng, Yu; Ma, Ruiyu; Wei, Xianda; Liang, Desheng; Wu, Lingqian

    2017-01-01

    Galloway-Mowat syndrome (GMS) is a very rare autosomal-recessive disorder characterized by nephrotic syndrome associated with microcephaly, and various central nervous system abnormalities, mostly cerebral hypoplasia or cerebellar atrophy, intellectual disability and neural-migration defects. WDR73 is the only gene known to cause GMS, and has never been implicated in other disease. Here we present a Chinese consanguineous family with infantile onset intellectual disability and cerebellar hypoplasia but no microcephaly. Whole exome sequencing identified a WDR73 p.W371G missense mutation. The mutation is confirmed to be segregated in this family by Sanger sequencing according to a recessive inheritance pattern. It is predicted to be deleterious by multiple algorithms and affect highly conserved site. Structural modeling revealed conformational differences between the wild type protein and the p.W371G protein. Real-time PCR and Western blotting revealed altered mRNA and protein levels in mutated samples. Our study indicates the novel WDR73 p.W371G missense mutation causes infantile onset intellectual disability and cerebellar hypoplasia in recessive mode of inheritance. Our findings imply that microcephaly is a variable phenotype in WDR73-related disease, suggest WDR73 to be a candidate gene of severe intellectual disability and cerebellar hypoplasia, and expand the molecular spectrum of WDR73-related disease. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Hereditary thrombophilia: identification of nonsense and missense mutations in the protein C gene

    International Nuclear Information System (INIS)

    Romeo, G.; Hassan, H.J.; Staempfli, S.

    1987-01-01

    The structure of the gene for protein C, an anticoagulant serine protease, was analyzed in 29 unrelated patients with hereditary thrombophilia and protein C deficiency. Gene deletion(s) or gross rearrangement(s) was not demonstrable by Southern blot hybridization to cDNA probes. However, two unrelated patients showed a variant restriction pattern after Pvu II or BamHi digestion, due to mutations in the last exon: analysis of their pedigrees, including three or seven heterozygotes, respectively, with ∼50% reduction of both enzymatic and antigen level, showed the abnormal restriction pattern in all heterozygous individuals, but not in normal relatives. Cloning of protein C gene and sequencing of the last exon allowed the authors to identify a nonsense and a missense mutation, respectively. In the first case, codon 306 (CGA, arginine) is mutated to an inframe stop codon, thus generating a new Pvu II recognition site. In the second case, a missense mutation in the BamHI palindrome (GGATCC → GCATCC) leads to substitution of a key amino acid (a tryptophan to cysteine substitution at position 402), invariantly conserved in eukaryotic serine proteases. These point mutations may explain the protein C-deficiency phenotype of heterozygotes in the two pedigrees

  18. Nonketotic hyperglycinemia: Functional assessment of missense variants in GLDC to understand phenotypes of the disease.

    Science.gov (United States)

    Bravo-Alonso, Irene; Navarrete, Rosa; Arribas-Carreira, Laura; Perona, Almudena; Abia, David; Couce, María Luz; García-Cazorla, Angels; Morais, Ana; Domingo, Rosario; Ramos, María Antonia; Swanson, Michael A; Van Hove, Johan L K; Ugarte, Magdalena; Pérez, Belén; Pérez-Cerdá, Celia; Rodríguez-Pombo, Pilar

    2017-06-01

    The rapid analysis of genomic data is providing effective mutational confirmation in patients with clinical and biochemical hallmarks of a specific disease. This is the case for nonketotic hyperglycinemia (NKH), a Mendelian disorder causing seizures in neonates and early-infants, primarily due to mutations in the GLDC gene. However, understanding the impact of missense variants identified in this gene is a major challenge for the application of genomics into clinical practice. Herein, a comprehensive functional and structural analysis of 19 GLDC missense variants identified in a cohort of 26 NKH patients was performed. Mutant cDNA constructs were expressed in COS7 cells followed by enzymatic assays and Western blot analysis of the GCS P-protein to assess the residual activity and mutant protein stability. Structural analysis, based on molecular modeling of the 3D structure of GCS P-protein, was also performed. We identify hypomorphic variants that produce attenuated phenotypes with improved prognosis of the disease. Structural analysis allows us to interpret the effects of mutations on protein stability and catalytic activity, providing molecular evidence for clinical outcome and disease severity. Moreover, we identify an important number of mutants whose loss-of-functionality is associated with instability and, thus, are potential targets for rescue using folding therapeutic approaches. © 2017 Wiley Periodicals, Inc.

  19. Prefoldin Promotes Proteasomal Degradation of Cytosolic Proteins with Missense Mutations by Maintaining Substrate Solubility.

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    Sophie A Comyn

    2016-07-01

    Full Text Available Misfolded proteins challenge the ability of cells to maintain protein homeostasis and can accumulate into toxic protein aggregates. As a consequence, cells have adopted a number of protein quality control pathways to prevent protein aggregation, promote protein folding, and target terminally misfolded proteins for degradation. In this study, we employed a thermosensitive allele of the yeast Guk1 guanylate kinase as a model misfolded protein to investigate degradative protein quality control pathways. We performed a flow cytometry based screen to identify factors that promote proteasomal degradation of proteins misfolded as the result of missense mutations. In addition to the E3 ubiquitin ligase Ubr1, we identified the prefoldin chaperone subunit Gim3 as an important quality control factor. Whereas the absence of GIM3 did not impair proteasomal function or the ubiquitination of the model substrate, it led to the accumulation of the poorly soluble model substrate in cellular inclusions that was accompanied by delayed degradation. We found that Gim3 interacted with the Guk1 mutant allele and propose that prefoldin promotes the degradation of the unstable model substrate by maintaining the solubility of the misfolded protein. We also demonstrated that in addition to the Guk1 mutant, prefoldin can stabilize other misfolded cytosolic proteins containing missense mutations.

  20. Quantitative Missense Variant Effect Prediction Using Large-Scale Mutagenesis Data.

    Science.gov (United States)

    Gray, Vanessa E; Hause, Ronald J; Luebeck, Jens; Shendure, Jay; Fowler, Douglas M

    2018-01-24

    Large datasets describing the quantitative effects of mutations on protein function are becoming increasingly available. Here, we leverage these datasets to develop Envision, which predicts the magnitude of a missense variant's molecular effect. Envision combines 21,026 variant effect measurements from nine large-scale experimental mutagenesis datasets, a hitherto untapped training resource, with a supervised, stochastic gradient boosting learning algorithm. Envision outperforms other missense variant effect predictors both on large-scale mutagenesis data and on an independent test dataset comprising 2,312 TP53 variants whose effects were measured using a low-throughput approach. This dataset was never used for hyperparameter tuning or model training and thus serves as an independent validation set. Envision prediction accuracy is also more consistent across amino acids than other predictors. Finally, we demonstrate that Envision's performance improves as more large-scale mutagenesis data are incorporated. We precompute Envision predictions for every possible single amino acid variant in human, mouse, frog, zebrafish, fruit fly, worm, and yeast proteomes (https://envision.gs.washington.edu/). Copyright © 2017 Elsevier Inc. All rights reserved.

  1. A missense change in the ATG4D gene links aberrant autophagy to a neurodegenerative vacuolar storage disease.

    Directory of Open Access Journals (Sweden)

    Kaisa Kyöstilä

    2015-04-01

    Full Text Available Inherited neurodegenerative disorders are debilitating diseases that occur across different species. We have performed clinical, pathological and genetic studies to characterize a novel canine neurodegenerative disease present in the Lagotto Romagnolo dog breed. Affected dogs suffer from progressive cerebellar ataxia, sometimes accompanied by episodic nystagmus and behavioral changes. Histological examination revealed unique pathological changes, including profound neuronal cytoplasmic vacuolization in the nervous system, as well as spheroid formation and cytoplasmic aggregation of vacuoles in secretory epithelial tissues and mesenchymal cells. Genetic analyses uncovered a missense change, c.1288G>A; p.A430T, in the autophagy-related ATG4D gene on canine chromosome 20 with a highly significant disease association (p = 3.8 x 10-136 in a cohort of more than 2300 Lagotto Romagnolo dogs. ATG4D encodes a poorly characterized cysteine protease belonging to the macroautophagy pathway. Accordingly, our histological analyses indicated altered autophagic flux in affected tissues. The knockdown of the zebrafish homologue atg4da resulted in a widespread developmental disturbance and neurodegeneration in the central nervous system. Our study describes a previously unknown canine neurological disease with particular pathological features and implicates the ATG4D protein as an important autophagy mediator in neuronal homeostasis. The canine phenotype serves as a model to delineate the disease-causing pathological mechanism(s and ATG4D function, and can also be used to explore treatment options. Furthermore, our results reveal a novel candidate gene for human neurodegeneration and enable the development of a genetic test for veterinary diagnostic and breeding purposes.

  2. Urine screening for patients with developmental disabilities detected a patient with creatine transporter deficiency due to a novel missense mutation in SLC6A8.

    Science.gov (United States)

    Kato, Hidekazu; Miyake, Fuyu; Shimbo, Hiroko; Ohya, Makoto; Sugawara, Hidenori; Aida, Noriko; Anzai, Rie; Takagi, Mariko; Okuda, Mitsuko; Takano, Kyoko; Wada, Takahito; Iai, Mizue; Yamashita, Sumimasa; Osaka, Hitoshi

    2014-08-01

    Creatine transporter deficiency (CTD) is an example of X-linked intellectual disability syndromes, caused by mutations in SLC6A8 on Xq28. Although this is the second most frequent genetic cause of intellectual disabilities in Europe or America after Fragile X syndrome, information on the morbidity of this disease is limited in Japan. Using the HPLC screening method we have established recently, we examined samples of urine of 105 patients (73 males and 32 females) with developmental disabilities at our medical center. And we have found a family with three ID boys with a novel missense mutation in SLC6A8. This is the second report of a Japanese family case of CTD. A systematic diagnostic system of this syndrome should be established in Japan to enable us to estimate its frequency and treatment. Copyright © 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  3. A Missense Mutation of G257A at Exon 3 in PEX7 CDS Was Responsible for the Incidence of Rhizomelic Chondrodysplasia Punctata Type 1

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    Marziyeh Alamatsaz

    2018-02-01

    Full Text Available Background Rhizomelic chondrodysplasia punctata (RCDP type 1 is among of the rare autosomal recessive peroxisome biogenesis disorders caused by mutations in the PEX7 gene. RCDP patients with the classic form of RCDP1 do not live more than 10- year. Materials and Methods In the present study, a two-year-old girl with skeletal abnormalities and dysmorphic facial appearance is reported to be suffered from RCDP. The patient's parents were second cousins and healthy and there was no similar case in the parents’ family. PEX7 gene was sequenced in the patient and her parents. Results A homozygous mutation, G257A, was identified PEX7 in the genome of patient while the parents were compound heterozygous. Conclusion Taken together, clinical presentation and peroxisome profile of the patient suggested a missense mutation led to formation of a pathogenic PEX7, responsible for incidence of RCDP.

  4. Severe fluoropyrimidine toxicity due to novel and rare DPYD missense mutations, deletion and genomic amplification affecting DPD activity and mRNA splicing

    DEFF Research Database (Denmark)

    van Kuilenburg, André B P; Meijer, Judith; Maurer, Dirk

    2017-01-01

    Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5FU). Genetic variations in DPD have emerged as predictive risk factors for severe fluoropyrimidine toxicity. Here, we report novel and rare genetic variants underlying DPD deficiency...... in 9 cancer patients presenting with severe fluoropyrimidine-associated toxicity. All patients possessed a strongly reduced DPD activity, ranging from 9 to 53% of controls. Analysis of the DPD gene (DPYD) showed the presence of 21 variable sites including 4 novel and 4 very rare aberrations: 3 missense...... of exon 4 immediately upstream of the mutated splice-donor site in the process of DPD pre-mRNA splicing. A lethal toxicity in two DPD patients suggests that fluoropyrimidines combined with other therapies such as radiotherapy might be particularly toxic for DPD deficient patients. Our study advocates...

  5. Determining the role of missense mutations in the POU domain of HNF1A that reduce the DNA-binding affinity: A computational approach.

    Directory of Open Access Journals (Sweden)

    Sneha P

    Full Text Available Maturity-onset diabetes of the young type 3 (MODY3 is a non-ketotic form of diabetes associated with poor insulin secretion. Over the past years, several studies have reported the association of missense mutations in the Hepatocyte Nuclear Factor 1 Alpha (HNF1A with MODY3. Missense mutations in the POU homeodomain (POUH of HNF1A hinder binding to the DNA, thereby leading to a dysfunctional protein. Missense mutations of the HNF1A were retrieved from public databases and subjected to a three-step computational mutational analysis to identify the underlying mechanism. First, the pathogenicity and stability of the mutations were analyzed to determine whether they alter protein structure and function. Second, the sequence conservation and DNA-binding sites of the mutant positions were assessed; as HNF1A protein is a transcription factor. Finally, the biochemical properties of the biological system were validated using molecular dynamic simulations in Gromacs 4.6.3 package. Two arginine residues (131 and 203 in the HNF1A protein are highly conserved residues and contribute to the function of the protein. Furthermore, the R131W, R131Q, and R203C mutations were predicted to be highly deleterious by in silico tools and showed lower binding affinity with DNA when compared to the native protein using the molecular docking analysis. Triplicate runs of molecular dynamic (MD simulations (50ns revealed smaller changes in patterns of deviation, fluctuation, and compactness, in complexes containing the R131Q and R131W mutations, compared to complexes containing the R203C mutant complex. We observed reduction in the number of intermolecular hydrogen bonds, compactness, and electrostatic potential, as well as the loss of salt bridges, in the R203C mutant complex. Substitution of arginine with cysteine at position 203 decreases the affinity of the protein for DNA, thereby destabilizing the protein. Based on our current findings, the MD approach is an important

  6. Genetic and bioinformatics analysis of four novel GCK missense variants detected in Caucasian families with GCK-MODY phenotype.

    Science.gov (United States)

    Costantini, S; Malerba, G; Contreas, G; Corradi, M; Marin Vargas, S P; Giorgetti, A; Maffeis, C

    2015-05-01

    Heterozygous loss-of-function mutations in the glucokinase (GCK) gene cause maturity-onset diabetes of the young (MODY) subtype GCK (GCK-MODY/MODY2). GCK sequencing revealed 16 distinct mutations (13 missense, 1 nonsense, 1 splice site, and 1 frameshift-deletion) co-segregating with hyperglycaemia in 23 GCK-MODY families. Four missense substitutions (c.718A>G/p.Asn240Asp, c.757G>T/p.Val253Phe, c.872A>C/p.Lys291Thr, and c.1151C>T/p.Ala384Val) were novel and a founder effect for the nonsense mutation (c.76C>T/p.Gln26*) was supposed. We tested whether an accurate bioinformatics approach could strengthen family-genetic evidence for missense variant pathogenicity in routine diagnostics, where wet-lab functional assays are generally unviable. In silico analyses of the novel missense variants, including orthologous sequence conservation, amino acid substitution (AAS)-pathogenicity predictors, structural modeling and splicing predictors, suggested that the AASs and/or the underlying nucleotide changes are likely to be pathogenic. This study shows how a careful bioinformatics analysis could provide effective suggestions to help molecular-genetic diagnosis in absence of wet-lab validations. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. Integrating population variation and protein structural analysis to improve clinical interpretation of missense variation: application to the WD40 domain.

    Science.gov (United States)

    Laskowski, Roman A; Tyagi, Nidhi; Johnson, Diana; Joss, Shelagh; Kinning, Esther; McWilliam, Catherine; Splitt, Miranda; Thornton, Janet M; Firth, Helen V; Wright, Caroline F

    2016-03-01

    We present a generic, multidisciplinary approach for improving our understanding of novel missense variants in recently discovered disease genes exhibiting genetic heterogeneity, by combining clinical and population genetics with protein structural analysis. Using six new de novo missense diagnoses in TBL1XR1 from the Deciphering Developmental Disorders study, together with population variation data, we show that the β-propeller structure of the ubiquitous WD40 domain provides a convincing way to discriminate between pathogenic and benign variation. Children with likely pathogenic mutations in this gene have severely delayed language development, often accompanied by intellectual disability, autism, dysmorphology and gastrointestinal problems. Amino acids affected by likely pathogenic missense mutations are either crucial for the stability of the fold, forming part of a highly conserved symmetrically repeating hydrogen-bonded tetrad, or located at the top face of the β-propeller, where 'hotspot' residues affect the binding of β-catenin to the TBLR1 protein. In contrast, those altered by population variation are significantly less likely to be spatially clustered towards the top face or to be at buried or highly conserved residues. This result is useful not only for interpreting benign and pathogenic missense variants in this gene, but also in other WD40 domains, many of which are associated with disease. © The Author 2016. Published by Oxford University Press.

  8. A novel COL11A1 missense mutation in siblings with non-ocular Stickler syndrome.

    Science.gov (United States)

    Kohmoto, Tomohiro; Tsuji, Atsumi; Morita, Kei-Ichi; Naruto, Takuya; Masuda, Kiyoshi; Kashimada, Kenichi; Enomoto, Keisuke; Morio, Tomohiro; Harada, Hiroyuki; Imoto, Issei

    2016-01-01

    Stickler syndrome (STL) is an autosomal, dominantly inherited, clinically variable and genetically heterogeneous connective tissue disorder characterized by ocular, auditory, orofacial and skeletal abnormalities. We conducted targeted resequencing using a next-generation sequencer for molecular diagnosis of a 2-year-old girl who was clinically suspected of having STL with Pierre Robin sequence. We detected a novel heterozygous missense mutation, NM_001854.3:n.4838G>A [NM_001854.3 (COL11A1_v001):c.4520G>A], in COL11A1, resulting in a Gly to Asp substitution at position 1507 [NM_001854.3(COL11A1_i001)] within one of the collagen-like domains of the triple helical region. The same mutation was detected in her 4-year-old brother with cleft palate and high-frequency sensorineural hearing loss.

  9. Brittle Cornea Syndrome Associated with a Missense Mutation in the Zinc-Finger 469 Gene

    DEFF Research Database (Denmark)

    Christensen, Anne Elisabeth; Knappskog, Per Morten; Midtbø, Marit

    2010-01-01

    Purpose: To investigate the diverse clinical manifestations, identify the causative mutation and explain the association with red hair in a family with brittle cornea syndrome (BCS). Methods: Eight family members in three generations underwent ophthalmic, dental, and general medical examination...... mapping with SNP markers, DNA sequencing, and MC1R genotyping. Results: At 42 and 48 years of age, respectively, both affected individuals were blind due to retinal detachment and secondary glaucoma. They had extremely thin and bulging corneas, velvety skin, chestnut colored hair, scoliosis, reduced BMD......, dental anomalies, hearing loss and minor cardiac defects. The morphologies of the skin biopsies were normal except that in some areas slightly thinner collagen fibrils were seen in one of the affected individuals. Molecular genetic analysis revealed a novel missense mutation of ZNF469, c.10016G...

  10. A de novo missense mutation of FGFR2 causes facial dysplasia syndrome in Holstein cattle

    DEFF Research Database (Denmark)

    Agerholm, Jørgen Steen; McEvoy, Fintan; Heegaard, Steffen

    2017-01-01

    was suspected as all recorded cases were progeny of the same sire. Detailed investigations were performed to characterize the syndrome and to reveal its cause. Results Seven malformed calves were submitted examination. All cases shared a common morphology with the most striking lesions being severe facial...... chromosome 26 where whole genome sequencing of a case-parent trio revealed two de novo variants perfectly associated with the disease: an intronic SNP in the DMBT1 gene and a single non-synonymous variant in the FGFR2 gene. This FGFR2 missense variant (c.927G>T) affects a gene encoding a member...... of the fibroblast growth factor receptor family, where amino acid sequence is highly conserved between members and across species. It is predicted to change an evolutionary conserved tryptophan into a cysteine residue (p.Trp309Cys). Both variant alleles were proven to result from de novo mutation events...

  11. cDNA sequencing improves the detection of P53 missense mutations in colorectal cancer

    International Nuclear Information System (INIS)

    Szybka, Malgorzata; Kordek, Radzislaw; Zakrzewska, Magdalena; Rieske, Piotr; Pasz-Walczak, Grazyna; Kulczycka-Wojdala, Dominika; Zawlik, Izabela; Stawski, Robert; Jesionek-Kupnicka, Dorota; Liberski, Pawel P

    2009-01-01

    Recently published data showed discrepancies beteween P53 cDNA and DNA sequencing in glioblastomas. We hypothesised that similar discrepancies may be observed in other human cancers. To this end, we analyzed 23 colorectal cancers for P53 mutations and gene expression using both DNA and cDNA sequencing, real-time PCR and immunohistochemistry. We found P53 gene mutations in 16 cases (15 missense and 1 nonsense). Two of the 15 cases with missense mutations showed alterations based only on cDNA, and not DNA sequencing. Moreover, in 6 of the 15 cases with a cDNA mutation those mutations were difficult to detect in the DNA sequencing, so the results of DNA analysis alone could be misinterpreted if the cDNA sequencing results had not also been available. In all those 15 cases, we observed a higher ratio of the mutated to the wild type template by cDNA analysis, but not by the DNA analysis. Interestingly, a similar overexpression of P53 mRNA was present in samples with and without P53 mutations. In terms of colorectal cancer, those discrepancies might be explained under three conditions: 1, overexpression of mutated P53 mRNA in cancer cells as compared with normal cells; 2, a higher content of cells without P53 mutation (normal cells and cells showing K-RAS and/or APC but not P53 mutation) in samples presenting P53 mutation; 3, heterozygous or hemizygous mutations of P53 gene. Additionally, for heterozygous mutations unknown mechanism(s) causing selective overproduction of mutated allele should also be considered. Our data offer new clues for studying discrepancy in P53 cDNA and DNA sequencing analysis

  12. Functional analysis of HNPCC-related missense mutations in MSH2

    Energy Technology Data Exchange (ETDEWEB)

    Luetzen, Anne [Department of Science, Systems and Models, Roskilde University, DK-4000 Roskilde (Denmark); Wind, Niels de; Georgijevic, Dubravka [Department of Toxicogenetics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden (Netherlands); Nielsen, Finn Cilius [Department of Clinical Biochemistry, Rigshospitalet, DK-2100 Copenhagen (Denmark); Rasmussen, Lene Juel [Department of Science, Systems and Models, Roskilde University, DK-4000 Roskilde (Denmark)], E-mail: ljr@ruc.dk

    2008-10-14

    Hereditary nonpolyposis colorectal cancer (HNPCC) is associated with germline mutations in the human DNA mismatch repair (MMR) genes, most frequently MSH2 and MLH1. The majority of HNPCC mutations cause truncations and thus loss of function of the affected polypeptide. However, a significant proportion of MMR mutations found in HNPCC patients are single amino acid substitutions and the functional consequences of many of these mutations in DNA repair are unclear. We have examined the consequences of seven MSH2 missense mutations found in HNPCC families by testing the MSH2 mutant proteins in functional assays as well as by generating equivalent missense mutations in Escherichia coli MutS and analyzing the phenotypes of these mutants. Here we show that two mutant proteins, MSH2-P622L and MSH2-C697F confer multiple biochemical defects, namely in mismatch binding, in vivo interaction with MSH6 and EXO1, and in nuclear localization in the cell. Mutation G674R, located in the ATP-binding region of MSH2, appears to confer resistance to ATP-dependent mismatch release. Mutations D167H and H639R show reduced mismatch binding. Results of in vivo experiments in E. coli with MutS mutants show that one additional mutant, equivalent of MSH2-A834T that do not show any defects in MSH2 assays, is repair deficient. In conclusion, all mutant proteins (except for MSH2-A305T) have defects; either in mismatch binding, ATP-release, mismatch repair activity, subcellular localization or protein-protein interactions.

  13. Prediction of phenotypes of missense mutations in human proteins from biological assemblies.

    Science.gov (United States)

    Wei, Qiong; Xu, Qifang; Dunbrack, Roland L

    2013-02-01

    Single nucleotide polymorphisms (SNPs) are the most frequent variation in the human genome. Nonsynonymous SNPs that lead to missense mutations can be neutral or deleterious, and several computational methods have been presented that predict the phenotype of human missense mutations. These methods use sequence-based and structure-based features in various combinations, relying on different statistical distributions of these features for deleterious and neutral mutations. One structure-based feature that has not been studied significantly is the accessible surface area within biologically relevant oligomeric assemblies. These assemblies are different from the crystallographic asymmetric unit for more than half of X-ray crystal structures. We find that mutations in the core of proteins or in the interfaces in biological assemblies are significantly more likely to be disease-associated than those on the surface of the biological assemblies. For structures with more than one protein in the biological assembly (whether the same sequence or different), we find the accessible surface area from biological assemblies provides a statistically significant improvement in prediction over the accessible surface area of monomers from protein crystal structures (P = 6e-5). When adding this information to sequence-based features such as the difference between wildtype and mutant position-specific profile scores, the improvement from biological assemblies is statistically significant but much smaller (P = 0.018). Combining this information with sequence-based features in a support vector machine leads to 82% accuracy on a balanced dataset of 50% disease-associated mutations from SwissVar and 50% neutral mutations from human/primate sequence differences in orthologous proteins. Copyright © 2012 Wiley Periodicals, Inc.

  14. Functional analysis of HNPCC-related missense mutations in MSH2

    International Nuclear Information System (INIS)

    Luetzen, Anne; Wind, Niels de; Georgijevic, Dubravka; Nielsen, Finn Cilius; Rasmussen, Lene Juel

    2008-01-01

    Hereditary nonpolyposis colorectal cancer (HNPCC) is associated with germline mutations in the human DNA mismatch repair (MMR) genes, most frequently MSH2 and MLH1. The majority of HNPCC mutations cause truncations and thus loss of function of the affected polypeptide. However, a significant proportion of MMR mutations found in HNPCC patients are single amino acid substitutions and the functional consequences of many of these mutations in DNA repair are unclear. We have examined the consequences of seven MSH2 missense mutations found in HNPCC families by testing the MSH2 mutant proteins in functional assays as well as by generating equivalent missense mutations in Escherichia coli MutS and analyzing the phenotypes of these mutants. Here we show that two mutant proteins, MSH2-P622L and MSH2-C697F confer multiple biochemical defects, namely in mismatch binding, in vivo interaction with MSH6 and EXO1, and in nuclear localization in the cell. Mutation G674R, located in the ATP-binding region of MSH2, appears to confer resistance to ATP-dependent mismatch release. Mutations D167H and H639R show reduced mismatch binding. Results of in vivo experiments in E. coli with MutS mutants show that one additional mutant, equivalent of MSH2-A834T that do not show any defects in MSH2 assays, is repair deficient. In conclusion, all mutant proteins (except for MSH2-A305T) have defects; either in mismatch binding, ATP-release, mismatch repair activity, subcellular localization or protein-protein interactions

  15. Homozygous missense mutation in the LMAN2L gene segregates with intellectual disability in a large consanguineous Pakistani family.

    Science.gov (United States)

    Rafiullah, Rafiullah; Aslamkhan, Muhammad; Paramasivam, Nagarajan; Thiel, Christian; Mustafa, Ghulam; Wiemann, Stefan; Schlesner, Matthias; Wade, Rebecca C; Rappold, Gudrun A; Berkel, Simone

    2016-02-01

    Intellectual disability (ID) is a neurodevelopmental disorder affecting 1%-3% of the population worldwide. It is characterised by high phenotypic and genetic heterogeneity and in most cases the underlying cause of the disorder is unknown. In our study we investigated a large consanguineous family from Baluchistan, Pakistan, comprising seven affected individuals with a severe form of autosomal recessive ID (ARID) and epilepsy, to elucidate a putative genetic cause. Whole exome sequencing (WES) of a trio, including a child with ID and epilepsy and its healthy parents that were part of this large family, revealed a homozygous missense variant p.R53Q in the lectin mannose-binding 2-like (LMAN2L) gene. This homozygous variant was co-segregating in the family with the phenotype of severe ID and infantile epilepsy; unaffected family members were heterozygous variant carriers. The variant was predicted to be pathogenic by five different in silico programmes and further three-dimensional structure modelling of the protein suggests that variant p.R53Q may impair protein-protein interaction. LMAN2L (OMIM: 609552) encodes for the lectin, mannose-binding 2-like protein which is a cargo receptor in the endoplasmic reticulum important for glycoprotein transport. Genome-wide association studies have identified an association of LMAN2L to different neuropsychiatric disorders. This is the first report linking LMAN2L to a phenotype of severe ARID and seizures, indicating that the deleterious homozygous p.R53Q variant very likely causes the disorder. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  16. Missense Variant in MAPK Inactivator PTPN5 Is Associated with Decreased Severity of Post-Burn Hypertrophic Scarring.

    Directory of Open Access Journals (Sweden)

    Ravi F Sood

    Full Text Available Hypertrophic scarring (HTS is hypothesized to have a genetic mechanism, yet its genetic determinants are largely unknown. The mitogen-activated protein kinase (MAPK pathways are important mediators of inflammatory signaling, and experimental evidence implicates MAPKs in HTS formation. We hypothesized that single-nucleotide polymorphisms (SNPs in MAPK-pathway genes would be associated with severity of post-burn HTS.We analyzed data from a prospective-cohort genome-wide association study of post-burn HTS. We included subjects with deep-partial-thickness burns admitted to our center who provided blood for genotyping and had at least one Vancouver Scar Scale (VSS assessment. After adjusting for HTS risk factors and population stratification, we tested MAPK-pathway gene SNPs for association with the four VSS variables in a joint regression model. In addition to individual-SNP analysis, we performed gene-based association testing.Our study population consisted of 538 adults (median age 40 years who were predominantly White (76% males (71% admitted to our center from 2007-2014 with small-to-moderate-sized burns (median burn size 6% total body surface area. Of 2,146 SNPs tested, a rare missense variant in the PTPN5 gene (rs56234898; minor allele frequency 1.5% was significantly associated with decreased severity of post-burn HTS (P = 1.3×10-6. In gene-based analysis, PTPN5 (P = 1.2×10-5 showed a significant association and BDNF (P = 9.5×10-4 a borderline-significant association with HTS severity.We report PTPN5 as a novel genetic locus associated with HTS severity. PTPN5 is a MAPK inhibitor expressed in neurons, suggesting a potential role for neurotrophic factors and neuroinflammatory signaling in HTS pathophysiology.

  17. Allele frequencies of hemojuvelin gene (HJV I222N and G320V missense mutations in white and African American subjects from the general Alabama population

    Directory of Open Access Journals (Sweden)

    Bohannon Sean B

    2004-12-01

    Full Text Available Abstract Background Homozygosity or compound heterozygosity for coding region mutations of the hemojuvelin gene (HJV in whites is a cause of early age-of-onset iron overload (juvenile hemochromatosis, and of hemochromatosis phenotypes in some young or middle-aged adults. HJV coding region mutations have also been identified recently in African American primary iron overload and control subjects. Primary iron overload unexplained by typical hemochromatosis-associated HFE genotypes is common in white and black adults in Alabama, and HJV I222N and G320V were detected in a white Alabama juvenile hemochromatosis index patient. Thus, we estimated the frequency of the HJV missense mutations I222N and G320V in adult whites and African Americans from Alabama general population convenience samples. Methods We evaluated the genomic DNA of 241 Alabama white and 124 African American adults who reported no history of hemochromatosis or iron overload to detect HJV missense mutations I222N and G320V using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP technique. Analysis for HJV I222N was performed in 240 whites and 124 African Americans. Analysis for HJV G320V was performed in 241 whites and 118 African Americans. Results One of 240 white control subjects was heterozygous for HJV I222N; she was also heterozygous for HFE C282Y, but had normal serum iron measures and bone marrow iron stores. HJV I222N was not detected in 124 African American subjects. HJV G320V was not detected in 241 white or 118 African American subjects. Conclusions HJV I222N and G320V are probably uncommon causes or modifiers of primary iron overload in adult whites and African Americans in Alabama. Double heterozygosity for HJV I222N and HFE C282Y may not promote increased iron absorption.

  18. A missense mutation in the CRBN gene that segregates with intellectual disability and self-mutilating behaviour in a consanguineous Saudi family.

    Science.gov (United States)

    Sheereen, Atia; Alaamery, Manal; Bawazeer, Shahad; Al Yafee, Yusra; Massadeh, Salam; Eyaid, Wafaa

    2017-04-01

    Autosomal-recessive non-syndromic intellectual disability (ARNS-ID) is an aetiologically heterogeneous disorder. Although little is known about the function of human cereblon (CRBN), its relationship to mild cognitive deficits suggests that it is involved in the basic processes of human memory and learning. We aim to identify the genetic cause of intellectual disability and self-mutilation in a consanguineous Saudi family with five affected members. Clinical whole-exome sequencing was performed on the proband patient, and Sanger sequencing was done to validate and confirm segregation in other family members. A missense variant (c. 1171T>C) in the CRBN gene was identified in five individuals with severe intellectual disability (ID) in a consanguineous Saudi family. The homozygous variant was co-segregating in the family with the phenotype of severe ID, seizures and self-mutilating behaviour. The missense mutation (p.C391R) reported here results in the replacement of a conserved cysteine residue by an arginine in the CULT (cereblon domain of unknown activity, binding cellular ligands and thalidomide) domain of CRBN, which contains a zinc-binding site. These findings thus contribute to a growing list of ID disorders caused by CRBN mutations, broaden the spectrum of phenotypes attributable to ARNS-ID and provide new insight into genotype-phenotype correlations between CRBN mutations and the aetiology of ARNS-ID. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  19. A novel rasopathy caused by recurrent de novo missense mutations in PPP1CB closely resembles Noonan syndrome with loose anagen hair.

    Science.gov (United States)

    Gripp, Karen W; Aldinger, Kimberly A; Bennett, James T; Baker, Laura; Tusi, Jessica; Powell-Hamilton, Nina; Stabley, Deborah; Sol-Church, Katia; Timms, Andrew E; Dobyns, William B

    2016-09-01

    Noonan syndrome is a rasopathy caused by mutations in multiple genes encoding components of the RAS/MAPK pathway. Despite its variable phenotype, limited genotype-phenotype correlations exist. Noonan syndrome with loose anagen hair (NS-LAH) is characterized by its distinctive hair anomalies, developmental differences, and structural brain abnormalities and is caused by a single recurrent missense SHOC2 mutation. SHOC2 forms a complex with protein phosphatase 1 (PP1C). Protein phosphatases counterbalance kinases and control activation of signaling proteins, such as the mitogen-activated protein kinases of the RAS/MAPK pathway. Here we report four patients with de novo missense mutations in protein phosphatase one catalytic subunit beta (PPP1CB), sharing a recognizable phenotype. Three individuals had the recurrent PPP1CB c.146G>C, p.Pro49Arg mutation, the fourth had a c.166G>C, p.Ala56Pro change. All had relative or absolute macrocephaly, low-set and posteriorly angulated ears, and developmental delay. Slow growing and/or sparse hair and/or an unruly hair texture was present in all. Three individuals had feeding difficulties requiring feeding tubes. One of two males had cryptorchidism, another had pectus excavatum. Short stature was present in three. A female with the recurrent mutation had a Dandy-Walker malformation and optic nerve hypoplasia. Mild ventriculomegaly occurred in all, cerebellar tonsillar ectopia was seen in two and progressed to Chiari 1 malformation in one individual. Based on the combination of phenotypic findings and PPP1CB's effect on RAF dephosphorylation within the RAS/MAPK pathway, this novel condition can be considered a rasopathy, most similar to NS-LAH. Collectively, these mutations meet the standardized criteria for pathogenicity. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  20. Defective nucleolar localization and dominant interfering properties of a parafibromin L95P missense mutant causing the hyperparathyroidism-jaw tumor syndrome

    Science.gov (United States)

    Panicker, Leelamma M.; Zhang, Jian-Hua; Dagur, Pradeep K.; Gastinger, Matthew J.; Simonds, William F.

    2011-01-01

    The hyperparathyroidism-jaw tumor syndrome (HPT-JT) is a familial cancer syndrome that can result from germline inactivation of HRPT2/CDC73, a putative tumor suppressor gene that encodes parafibromin, a component of the transcriptional regulatory PAF1 complex with homology to the yeast protein Cdc73p. The vast majority of HRPT2/CDC73 germline mutations identified have been truncation or frameshift mutations, and loss-of-function due to missense mutation is rare. We report here a kindred with HPT-JT due to a germline L95P missense mutation in parafibromin. The mutant parafibromin was studied in vitro to understand the basis of its presumed loss-of-function. When transfected in cultured cells the L95P mutant was expressed to a lower level than wild-type parafibromin, a difference that was not overcome by inhibition of the proteasome degradation pathway. The L95P mutant parafibromin retained the ability to assemble with endogenous PAF1 complex components as evidenced by co-immunoprecipitation. Analysis of subcellular localization showed that the L95P mutant was markedly deficient in nucleolar localization compared to the wild-type, an impairment likely resulting from disruption of a putative nucleolar localization signal immediately upstream of the L95P mutation. Transfection of the L95P parafibromin mutant, but not the wild type, enhanced cell-cycle progression and increased cell survival in NIH-3T3 and HEK 293 cells, resulting apparently from dominant interference with endogenous parafibromin action. The simultaneous loss of nucleolar localization and acquisition of a growth stimulatory phenotype with the L95P mutation raise the possibility that parafibromin must interact with targets in the nucleolus to fully execute its tumor suppressor functions. PMID:20304979

  1. Subsequent childbirth after a previous traumatic birth.

    Science.gov (United States)

    Beck, Cheryl Tatano; Watson, Sue

    2010-01-01

    Nine percent of new mothers in the United States who participated in the Listening to Mothers II Postpartum Survey screened positive for meeting the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for posttraumatic stress disorder after childbirth. Women who have had a traumatic birth experience report fewer subsequent children and a longer length of time before their second baby. Childbirth-related posttraumatic stress disorder impacts couples' physical relationship, communication, conflict, emotions, and bonding with their children. The purpose of this study was to describe the meaning of women's experiences of a subsequent childbirth after a previous traumatic birth. Phenomenology was the research design used. An international sample of 35 women participated in this Internet study. Women were asked, "Please describe in as much detail as you can remember your subsequent pregnancy, labor, and delivery following your previous traumatic birth." Colaizzi's phenomenological data analysis approach was used to analyze the stories of the 35 women. Data analysis yielded four themes: (a) riding the turbulent wave of panic during pregnancy; (b) strategizing: attempts to reclaim their body and complete the journey to motherhood; (c) bringing reverence to the birthing process and empowering women; and (d) still elusive: the longed-for healing birth experience. Subsequent childbirth after a previous birth trauma has the potential to either heal or retraumatize women. During pregnancy, women need permission and encouragement to grieve their prior traumatic births to help remove the burden of their invisible pain.

  2. Evolutionary Analysis Predicts Sensitive Positions of MMP20 and Validates Newly- and Previously-Identified MMP20 Mutations Causing Amelogenesis Imperfecta.

    Science.gov (United States)

    Gasse, Barbara; Prasad, Megana; Delgado, Sidney; Huckert, Mathilde; Kawczynski, Marzena; Garret-Bernardin, Annelyse; Lopez-Cazaux, Serena; Bailleul-Forestier, Isabelle; Manière, Marie-Cécile; Stoetzel, Corinne; Bloch-Zupan, Agnès; Sire, Jean-Yves

    2017-01-01

    Amelogenesis imperfecta (AI) designates a group of genetic diseases characterized by a large range of enamel disorders causing important social and health problems. These defects can result from mutations in enamel matrix proteins or protease encoding genes. A range of mutations in the enamel cleavage enzyme matrix metalloproteinase-20 gene ( MMP20 ) produce enamel defects of varying severity. To address how various alterations produce a range of AI phenotypes, we performed a targeted analysis to find MMP20 mutations in French patients diagnosed with non-syndromic AI. Genomic DNA was isolated from saliva and MMP20 exons and exon-intron boundaries sequenced. We identified several homozygous or heterozygous mutations, putatively involved in the AI phenotypes. To validate missense mutations and predict sensitive positions in the MMP20 sequence, we evolutionarily compared 75 sequences extracted from the public databases using the Datamonkey webserver. These sequences were representative of mammalian lineages, covering more than 150 million years of evolution. This analysis allowed us to find 324 sensitive positions (out of the 483 MMP20 residues), pinpoint functionally important domains, and build an evolutionary chart of important conserved MMP20 regions. This is an efficient tool to identify new- and previously-identified mutations. We thus identified six functional MMP20 mutations in unrelated families, finding two novel mutated sites. The genotypes and phenotypes of these six mutations are described and compared. To date, 13 MMP20 mutations causing AI have been reported, making these genotypes and associated hypomature enamel phenotypes the most frequent in AI.

  3. A de novo missense mutation of FGFR2 causes facial dysplasia syndrome in Holstein cattle.

    Science.gov (United States)

    Agerholm, Jørgen S; McEvoy, Fintan J; Heegaard, Steffen; Charlier, Carole; Jagannathan, Vidhya; Drögemüller, Cord

    2017-08-02

    Surveillance for bovine genetic diseases in Denmark identified a hitherto unreported congenital syndrome occurring among progeny of a Holstein sire used for artificial breeding. A genetic aetiology due to a dominant inheritance with incomplete penetrance or a mosaic germline mutation was suspected as all recorded cases were progeny of the same sire. Detailed investigations were performed to characterize the syndrome and to reveal its cause. Seven malformed calves were submitted examination. All cases shared a common morphology with the most striking lesions being severe facial dysplasia and complete prolapse of the eyes. Consequently the syndrome was named facial dysplasia syndrome (FDS). Furthermore, extensive brain malformations, including microencephaly, hydrocephalus, lobation of the cerebral hemispheres and compression of the brain were present. Subsequent data analysis of progeny of the sire revealed that around 0.5% of his offspring suffered from FDS. High density single nucleotide polymorphism (SNP) genotyping data of the seven cases and their parents were used to map the defect in the bovine genome. Significant genetic linkage was obtained for three regions, including chromosome 26 where whole genome sequencing of a case-parent trio revealed two de novo variants perfectly associated with the disease: an intronic SNP in the DMBT1 gene and a single non-synonymous variant in the FGFR2 gene. This FGFR2 missense variant (c.927G>T) affects a gene encoding a member of the fibroblast growth factor receptor family, where amino acid sequence is highly conserved between members and across species. It is predicted to change an evolutionary conserved tryptophan into a cysteine residue (p.Trp309Cys). Both variant alleles were proven to result from de novo mutation events in the germline of the sire. FDS is a novel genetic disorder of Holstein cattle. Mutations in the human FGFR2 gene are associated with various dominant inherited craniofacial dysostosis syndromes. Given

  4. Unique spectrum of SPAST variants in Estonian HSP patients: presence of benign missense changes but lack of exonic rearrangements

    Directory of Open Access Journals (Sweden)

    Gross-Paju Katrin

    2010-03-01

    Full Text Available Abstract Background Hereditary spastic paraplegia (HSP is a clinically and genetically heterogeneous disorder that can be an autosomal-dominant, autosomal-recessive, or X-linked disease. The most common autosomal-dominant form of the disease derives from mutations in the SPAST gene. Methods The aim of this study was to analyze 49 patients diagnosed with HSP from the Estonian population for sequence variants of the SPAST gene and to describe the associated phenotypes. Healthy control individuals (n = 100 with no family history of HSP were also analyzed. All patient samples were screened using denaturing high performance liquid chromatography (DHPLC and multiplex ligation-dependent probe amplification (MLPA assay. Samples with abnormal DHPLC and MLPA profiles were sequenced, with the same regions sequenced in control samples. Results Sequence variants of SPAST were identified in 19/49 HSP patients (38.8%, twelve among them had pathogenic mutations. Within the latter group there was one sporadic case. Eight patients had pure, and four - complex HSP. The twelve variants were identified: seven pathogenic (c.1174-1G>C, c.1185delA, c.1276C>T, c.1352_1356delGAGAA, c.1378C>A, c.1518_1519insTC, c.1841_1842insA and five non-pathogenic (c.131C>T, c.484G>A, c.685A>G, c.1245+202delG, c.1245+215G>C. Only 2 of these mutations had previously been described (c.131C>T, c.1245+202delG. Three mutations, c.1174-1G>C, c.1276 C>T, c.1378C>A, showed intrafamilial segregation. Conclusion This study identified new variants of the SPAST gene which included benign missense variants and short insertions/deletions. No large rearrangements were found. Based on these data, 7 new pathogenic variants of HSP are associated with clinical phenotypes.

  5. Systemic vascular phenotypes of Loeys-Dietz syndrome in a child carrying a de novo R381P mutation in TGFBR2: a case report

    OpenAIRE

    Uike, Kiyoshi; Matsushita, Yuki; Sakai, Yasunari; Togao, Osamu; Nagao, Michinobu; Ishizaki, Yoshito; Nagata, Hazumu; Yamamura, Kenichiro; Torisu, Hiroyuki; Hara, Toshiro

    2013-01-01

    Background Loeys?Dietz syndrome, also known as Marfan syndrome type II, is a rare connective tissue disorder caused by dominant mutations in transforming growth factor-beta receptors (TGFBR1 and 2). Case presentation We report a 7-year-old Japanese boy with Loeys?Dietz syndrome who carried a novel, de novo missense mutation in TGFBR2 (c.1142g?>?c, R381P). He showed dysmorphic faces and skeletal malformations that were typical in previous cases with Loeys-Dietz syndrome. The cardiac studies di...

  6. Identification of missense mutations in the Norrie disease gene associated with advanced retinopathy of prematurity.

    Science.gov (United States)

    Shastry, B S; Pendergast, S D; Hartzer, M K; Liu, X; Trese, M T

    1997-05-01

    Retinopathy of prematurity (ROP) is a retinal vascular disease occurring in infants with short gestational age and low birth weight and can lead to retinal detachment (ROP stages 4 and 5). X-linked familial exudative vitreoretinopathy is phenotypically similar to ROP and has been associated with mutations in the Norrie disease (ND) gene in some cases. To determine if similar mutations in the ND gene may play a role in the development of advanced ROP. Clinical examination and molecular genetic analysis were performed on 16 children, including 2 dizygotic and 1 monozygotic twin pairs, and their parents from 13 families. Sequencing of the amplified products revealed missense mutations (R121W and L108P) in the third exon of the ND gene in 4 patients. These mutations were not present in an unaffected premature twin, 2 children with regressed stage 3 ROP, the parents, or in 50 unrelated healthy control subjects. These findings suggest that mutations in the ND gene may play a role in the development of severe ROP in premature infants.

  7. EnsembleGASVR: A novel ensemble method for classifying missense single nucleotide polymorphisms

    KAUST Repository

    Rapakoulia, Trisevgeni

    2014-04-26

    Motivation: Single nucleotide polymorphisms (SNPs) are considered the most frequently occurring DNA sequence variations. Several computational methods have been proposed for the classification of missense SNPs to neutral and disease associated. However, existing computational approaches fail to select relevant features by choosing them arbitrarily without sufficient documentation. Moreover, they are limited to the problem ofmissing values, imbalance between the learning datasets and most of them do not support their predictions with confidence scores. Results: To overcome these limitations, a novel ensemble computational methodology is proposed. EnsembleGASVR facilitates a twostep algorithm, which in its first step applies a novel evolutionary embedded algorithm to locate close to optimal Support Vector Regression models. In its second step, these models are combined to extract a universal predictor, which is less prone to overfitting issues, systematizes the rebalancing of the learning sets and uses an internal approach for solving the missing values problem without loss of information. Confidence scores support all the predictions and the model becomes tunable by modifying the classification thresholds. An extensive study was performed for collecting the most relevant features for the problem of classifying SNPs, and a superset of 88 features was constructed. Experimental results show that the proposed framework outperforms well-known algorithms in terms of classification performance in the examined datasets. Finally, the proposed algorithmic framework was able to uncover the significant role of certain features such as the solvent accessibility feature, and the top-scored predictions were further validated by linking them with disease phenotypes. © The Author 2014.

  8. Risk of cancer by ATM missense mutations in the general population

    DEFF Research Database (Denmark)

    Dombernowsky, Sarah Louise; Weischer, Maren; Allin, Kristine Højgaard

    2008-01-01

    PURPOSE: Truncating and missense mutations in the ATM gene, which cause insufficient DNA damage surveillance, allow damaged cells to proceed into mitosis, which eventually results in increased cancer susceptibility. We tested the hypotheses that ATM Ser49Cys and ATM Ser707Pro heterozygosity......: Multifactorially adjusted hazard ratios for ATM Ser49Cys heterozygotes versus noncarriers were 1.2 (95% CI, 0.9 to 1.5) for cancer overall, 0.8 (95% CI, 0.3 to 2.0) for breast cancer, 4.8 (95% CI, 2.2 to 11) for melanoma, 2.3 (95% CI, 1.1 to 5.0) for prostate cancer, and 3.4 (95% CI, 1.1 to 11) for cancer...... of the oral cavity/pharynx. Multifactorially adjusted hazard ratios for ATM Ser707Pro heterozygotes versus noncarriers were 0.8 (95% CI, 0.6 to 1.2) for cancer overall, 0.6 (95% CI, 0.2 to 1.6) for breast cancer, 10 (95% CI, 1.1 to 93) for thyroid/other endocrine tumors, and 2.7 (95% CI, 1.0 to 7...

  9. A Novel Missense Mutation in Oncostatin M Receptor Beta Causing Primary Localized Cutaneous Amyloidosis

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    Marjan Saeedi

    2014-01-01

    Full Text Available Primary localized cutaneous amyloidosis (PLCA is a chronic skin disorder, caused by amyloid material deposition in the upper dermis. Autosomal dominant PLCA has been mapped earlier to pathogenic missense mutations in the OSMR gene, which encodes the oncostatin M receptor ß subunit (OSMRß. OSMRß is interleukin-6 family cytokine receptors and possesses two ligands, oncostatin M and interleukin-31, which both have biologic roles in inflammation and keratinocyte cell proliferation, differentiation, and apoptosis. Here, we identified a new OSMR mutation in a Kurdish family for the first time. Blood samples were taken from all the affected individuals in the family. DNA extraction was performed using salting out technique. Primers were designed for intron flanking individual exons of OSMR gene which were subjected to direct sequencing after PCR amplification for each sample. Sequencing showed a C/T substitution at position 613 in the proband. This mutation results in an L613S (leucine 613 to serine amino acid change. The identified mutation was observed in all affected family members but not in 100 ethnically matched healthy controls. Elucidating the molecular basis of familial PLCA provides new insight into mechanisms of itch in human skin and may lead to new therapeutic targets for pruritus.

  10. Predicting the impact of Lynch syndrome-causing missense mutations from structural calculations.

    Directory of Open Access Journals (Sweden)

    Sofie V Nielsen

    2017-04-01

    Full Text Available Accurate methods to assess the pathogenicity of mutations are needed to fully leverage the possibilities of genome sequencing in diagnosis. Current data-driven and bioinformatics approaches are, however, limited by the large number of new variations found in each newly sequenced genome, and often do not provide direct mechanistic insight. Here we demonstrate, for the first time, that saturation mutagenesis, biophysical modeling and co-variation analysis, performed in silico, can predict the abundance, metabolic stability, and function of proteins inside living cells. As a model system, we selected the human mismatch repair protein, MSH2, where missense variants are known to cause the hereditary cancer predisposition disease, known as Lynch syndrome. We show that the majority of disease-causing MSH2 mutations give rise to folding defects and proteasome-dependent degradation rather than inherent loss of function, and accordingly our in silico modeling data accurately identifies disease-causing mutations and outperforms the traditionally used genetic disease predictors. Thus, in conclusion, in silico biophysical modeling should be considered for making genotype-phenotype predictions and for diagnosis of Lynch syndrome, and perhaps other hereditary diseases.

  11. The NRG1 exon 11 missense variant is not associated with autism in the Central Valley of Costa Rica

    Directory of Open Access Journals (Sweden)

    Fallas Marietha

    2007-05-01

    Full Text Available Abstract Background We are conducting a genetic study of autism in the isolated population of the Central Valley of Costa Rica (CVCR. A novel Neuregulin 1 (NRG1 missense variant (exon 11 G>T was recently associated with psychosis and schizophrenia (SCZ in the same population isolate. Methods We genotyped the NRG1 exon 11 missense variant in 146 cases with autism, or autism spectrum disorder, with CVCR ancestry, and both parents when available (N = 267 parents from 143 independent families. Additional microsatellites were genotyped to examine haplotypes bearing the exon 11 variant. Results The NRG1 exon 11 G>T variant was found in 4/146 cases including one de novo occurrence. The frequency of the variant in case chromosomes was 0.014 and 0.045 in the parental non-transmitted chromosomes. At least 6 haplotypes extending 0.229 Mb were associated with the T allele. Three independent individuals, with no personal or family history of psychiatric disorder, shared at least a 1 megabase haplotype 5' to the T allele. Conclusion The NRG1 exon 11 missense variant is not associated with autism in the CVCR.

  12. Usher syndrome type 1 due to missense mutations on both CDH23 alleles: investigation of mRNA splicing.

    Science.gov (United States)

    Becirovic, Elvir; Ebermann, Inga; Nagy, Ditta; Zrenner, Eberhart; Seeliger, Mathias Wolfgang; Bolz, Hanno Jörn

    2008-03-01

    Usher syndrome (USH) is an autosomal recessive condition characterized by sensorineural hearing loss, vestibular dysfunction, and visual impairment due to retinitis pigmentosa. Truncating mutations in the cadherin-23 gene (CDH23) result in Usher syndrome type 1D (USH1D), whereas missense mutations affecting strongly conserved motifs of the CDH23 protein cause non-syndromic deafness (DFNB12). Four missense mutations constitute an exception from this genotype-phenotype correlation: they have been described in USH1 patients in homozygous state. Using a minigene assay, we have investigated these changes (c.1450G>C, p.A484P; c.3625A>G, p.T1209A; c.4520G>A, p.R1507Q; and c.5237G>A, p.R1746Q) for a possible impact on mRNA splicing which could explain the syndromic phenotype. While in silico analysis suggested impairment of splicing in all four cases, we found aberrant splicing for only one mutation, p.R1746Q. However, splicing was normal in case of p.A484P, p.T1209A and p.R1507Q. These three latter CDH23 missense mutations could interfere with functions of both, the auditory and the visual system. Alternatively, they could represent rare non-pathogenic polymorphisms.

  13. A case report of percutaneous endoscopic gastrostomy left-side gastropexy to resolve a recurrent gastric dilatation in a dog previously treated with right-side gastropexy for gastric dilatation volvulus.

    Science.gov (United States)

    Spinella, Giuseppe; Cinti, Filippo; Pietra, Marco; Capitani, Ombretta; Valentini, Simona

    2014-12-01

    A 6-year-old, large-breed, female dog was evaluated for gastric dilatation (GD). The dog was affected by GD volvulus, which had been surgically treated with gastric derotation and right incisional gastropexy. Recurrence of GD appeared 36 hours after surgery. The dilatation was immediately treated with an orogastric probe but still recurred 4 times. Therefore, a left-side gastropexy by percutaneous endoscopic gastrostomy (PEG) was performed to prevent intermittent GD. After PEG tube placement, the patient recovered rapidly without side effects. Several techniques of gastropexy have been described as a prophylactic method for gastric dilatation volvulus, but to the authors' knowledge, this is the first report of left-sided PEG gastropexy performed in a case of canine GD recurrence after an incisional right gastropexy. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. A novel homozygous Arg222Trp missense mutation in WNT7A in two sisters with severe Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome.

    Science.gov (United States)

    Kantaputra, Piranit N; Mundlos, Stefan; Sripathomsawat, Warissara

    2010-11-01

    Al-Awadi/Raas-Rothschild/Schinzel phocomelia (AARRS) syndrome, a rare autosomal recessive disorder, comprises malformations of upper and lower limbs with severely hypoplastic pelvis and abnormal genitalia. Mutations in WNT7A have been reported as cause of the syndrome. We report on two sisters in a Thai family with short and malformed long bones, absent fibulae, flexion contracture of digits, and a/hypoplastic nails. Fusion between severely malformed femora and slender tibiae has never been reported in patients with WNT7A mutations. Lower limbs were more severely malformed than the upper ones and the pelvis was also severely affected. Multiple fusions of long bones and of the femoral heads to the acetabula were evident. A novel homozygous missense mutation in coding exon 4 of the WNT7A was detected in both affected daughters (c.664C > T) leading to an amino acid exchange from arginine to tryptophan (p.Arg222Trp; R222W). The phenotype is likely to result from an abnormality of all three signaling centers in the developing limb resulting in ventralization with a loss of dorsal structures (aplasia/hypoplasia of nails) a loss of anterior-posterior identity (single distal bones in lower limb without polarity) and an outgrowth defect resulting in distal truncations. © 2010 Wiley-Liss, Inc.

  15. A novel missense mutation in the HECT domain of NEDD4L identified in a girl with periventricular nodular heterotopia, polymicrogyria and cleft palate.

    Science.gov (United States)

    Kato, Koji; Miya, Fuyuki; Hori, Ikumi; Ieda, Daisuke; Ohashi, Kei; Negishi, Yutaka; Hattori, Ayako; Okamoto, Nobuhiko; Kato, Mitsuhiro; Tsunoda, Tatsuhiko; Yamasaki, Mami; Kanemura, Yonehiro; Kosaki, Kenjiro; Saitoh, Shinji

    2017-09-01

    We identified a novel de novo heterozygous missense mutation in the NEDD4L gene (NM_015277: c.2617G>A; p.Glu873Lys) through whole-exome sequencing in a 3-year-old girl showing severe global developmental delay, infantile spasms, cleft palate, periventricular nodular heterotopia and polymicrogyria. Mutations in the HECT domain of NEDD4L have been reported in patients with a neurodevelopmental disorder along with similar brain malformations. All patients reported with NEDD4L HECT domain mutations showed periventricular nodular heterotopia, and most had seizures, cortex anomalies, cleft palate and syndactyly. The unique constellation of clinical features in patients with NEDD4L mutations might help clinically distinguish them from patients with other genetic mutations including FLNA, which is a well-known causative gene of periventricular nodular heterotopia. Although mutations in the HECT domain of NEDD4L that lead to AKT-mTOR pathway deregulation in forced expression system were reported, our western blot analysis did not show an increased level of AKT-mTOR activity in lymphoblastoid cell lines (LCLs) derived from the patient. In contrast to the forced overexpression system, AKT-mTOR pathway deregulation in LCLs derived from our patient seems to be subtle.

  16. Characterisation of the novel deleterious RAD51C p.Arg312Trp variant and prioritisation criteria for functional analysis of RAD51C missense changes.

    Science.gov (United States)

    Gayarre, Javier; Martín-Gimeno, Paloma; Osorio, Ana; Paumard, Beatriz; Barroso, Alicia; Fernández, Victoria; de la Hoya, Miguel; Rojo, Alejandro; Caldés, Trinidad; Palacios, José; Urioste, Miguel; Benítez, Javier; García, María J

    2017-09-26

    Despite a high prevalence of deleterious missense variants, most studies of RAD51C ovarian cancer susceptibility gene only provide in silico pathogenicity predictions of missense changes. We identified a novel deleterious RAD51C missense variant (p.Arg312Trp) in a high-risk family, and propose a criteria to prioritise RAD51C missense changes qualifying for functional analysis. To evaluate pathogenicity of p.Arg312Trp variant we used sequence homology, loss of heterozygosity (LOH) and segregation analysis, and a comprehensive functional characterisation. To define a functional-analysis prioritisation criteria, we used outputs for the known functionally confirmed deleterious and benign RAD51C missense changes from nine pathogenicity prediction algorithms. The p.Arg312Trp variant failed to correct mitomycin and olaparib hypersensitivity and to complement abnormal RAD51C foci formation according to functional assays, which altogether with LOH and segregation data demonstrated deleteriousness. Prioritisation criteria were based on the number of predictors providing a deleterious output, with a minimum of 5 to qualify for testing and a PredictProtein score greater than 33 to assign high-priority indication. Our study points to a non-negligible number of RAD51C missense variants likely to impair protein function, provides a guideline to prioritise and encourage their selection for functional analysis and anticipates that reference laboratories should have available resources to conduct such assays.

  17. Underestimation of Severity of Previous Whiplash Injuries

    Science.gov (United States)

    Naqui, SZH; Lovell, SJ; Lovell, ME

    2008-01-01

    INTRODUCTION We noted a report that more significant symptoms may be expressed after second whiplash injuries by a suggested cumulative effect, including degeneration. We wondered if patients were underestimating the severity of their earlier injury. PATIENTS AND METHODS We studied recent medicolegal reports, to assess subjects with a second whiplash injury. They had been asked whether their earlier injury was worse, the same or lesser in severity. RESULTS From the study cohort, 101 patients (87%) felt that they had fully recovered from their first injury and 15 (13%) had not. Seventy-six subjects considered their first injury of lesser severity, 24 worse and 16 the same. Of the 24 that felt the violence of their first accident was worse, only 8 had worse symptoms, and 16 felt their symptoms were mainly the same or less than their symptoms from their second injury. Statistical analysis of the data revealed that the proportion of those claiming a difference who said the previous injury was lesser was 76% (95% CI 66–84%). The observed proportion with a lesser injury was considerably higher than the 50% anticipated. CONCLUSIONS We feel that subjects may underestimate the severity of an earlier injury and associated symptoms. Reasons for this may include secondary gain rather than any proposed cumulative effect. PMID:18201501

  18. A missense mutation in the agouti signaling protein gene (ASIP) is associated with the no light points coat phenotype in donkeys.

    Science.gov (United States)

    Abitbol, Marie; Legrand, Romain; Tiret, Laurent

    2015-04-08

    Seven donkey breeds are recognized by the French studbook and are characterized by a black, bay or grey coat colour including light cream-to-white points (LP). Occasionally, Normand bay donkeys give birth to dark foals that lack LP and display the no light points (NLP) pattern. This pattern is more frequent and officially recognized in American miniature donkeys. The LP (or pangare) phenotype resembles that of the light bellied agouti pattern in mouse, while the NLP pattern resembles that of the mammalian recessive black phenotype; both phenotypes are associated with the agouti signaling protein gene (ASIP). We used a panel of 127 donkeys to identify a recessive missense c.349 T > C variant in ASIP that was shown to be in complete association with the NLP phenotype. This variant results in a cysteine to arginine substitution at position 117 in the ASIP protein. This cysteine is highly-conserved among vertebrate ASIP proteins and was previously shown by mutagenesis experiments to lie within a functional site. Altogether, our results strongly support that the identified mutation is causative of the NLP phenotype. Thus, we propose to name the c.[349 T > C] allele in donkeys, the a(nlp) allele, which enlarges the panel of coat colour alleles in donkeys and ASIP recessive loss-of-function alleles in animals.

  19. Neonatal High Bone Mass With First Mutation of the NF-κB Complex: Heterozygous De Novo Missense (p.Asp512Ser) RELA (Rela/p65).

    Science.gov (United States)

    Frederiksen, Anja L; Larsen, Martin J; Brusgaard, Klaus; Novack, Deborah V; Knudsen, Peter Juel Thiis; Schrøder, Henrik Daa; Qiu, Weimin; Eckhardt, Christina; McAlister, William H; Kassem, Moustapha; Mumm, Steven; Frost, Morten; Whyte, Michael P

    2016-01-01

    Heritable disorders that feature high bone mass (HBM) are rare. The etiology is typically a mutation(s) within a gene that regulates the differentiation and function of osteoblasts (OBs) or osteoclasts (OCs). Nevertheless, the molecular basis is unknown for approximately one-fifth of such entities. NF-κB signaling is a key regulator of bone remodeling and acts by enhancing OC survival while impairing OB maturation and function. The NF-κB transcription complex comprises five subunits. In mice, deletion of the p50 and p52 subunits together causes osteopetrosis (OPT). In humans, however, mutations within the genes that encode the NF-κB complex, including the Rela/p65 subunit, have not been reported. We describe a neonate who died suddenly and unexpectedly and was found at postmortem to have HBM documented radiographically and by skeletal histopathology. Serum was not available for study. Radiographic changes resembled malignant OPT, but histopathological investigation showed morphologically normal OCs and evidence of intact bone resorption excluding OPT. Furthermore, mutation analysis was negative for eight genes associated with OPT or HBM. Instead, accelerated bone formation appeared to account for the HBM. Subsequently, trio-based whole exome sequencing revealed a heterozygous de novo missense mutation (c.1534_1535delinsAG, p.Asp512Ser) in exon 11 of RELA encoding Rela/p65. The mutation was then verified using bidirectional Sanger sequencing. Lipopolysaccharide stimulation of patient fibroblasts elicited impaired NF-κB responses compared with healthy control fibroblasts. Five unrelated patients with unexplained HBM did not show a RELA defect. Ours is apparently the first report of a mutation within the NF-κB complex in humans. The missense change is associated with neonatal osteosclerosis from in utero increased OB function rather than failed OC action. These findings demonstrate the importance of the Rela/p65 subunit within the NF-κB pathway for human

  20. Quality of life with palbociclib plus fulvestrant in previously treated hormone receptor-positive, HER2-negative metastatic breast cancer: patient-reported outcomes from the PALOMA-3 trial.

    Science.gov (United States)

    Harbeck, N; Iyer, S; Turner, N; Cristofanilli, M; Ro, J; André, F; Loi, S; Verma, S; Iwata, H; Bhattacharyya, H; Puyana Theall, K; Bartlett, C H; Loibl, S

    2016-06-01

    In the PALOMA-3 study, palbociclib plus fulvestrant demonstrated improved progression-free survival compared with fulvestrant plus placebo in hormone receptor-positive, HER2- endocrine-resistant metastatic breast cancer (MBC). This analysis compared patient-reported outcomes (PROs) between the two treatment groups. Patients were randomized 2 : 1 to receive palbociclib 125 mg/day orally for 3 weeks followed by 1 week off (n = 347) plus fulvestrant (500 mg i.m. per standard of care) or placebo plus fulvestrant (n = 174). PROs were assessed on day 1 of cycles 1-4 and of every other subsequent cycle starting with cycle 6 using the EORTC QLQ-C30 and its breast cancer module, QLQ-BR23. High scores (range 0-100) could indicate better functioning/quality of life (QoL) or worse symptom severity. Repeated-measures mixed-effect analyses were carried out to compare on-treatment overall scores and changes from baseline between treatment groups while controlling for baseline. Between-group comparisons of time to deterioration in global QoL and pain were made using an unstratified log-rank test and Cox proportional hazards model. Questionnaire completion rates were high at baseline and during treatment (from baseline to cycle 14, ≥95.8% in each group completed ≥1 question on the EORTC QLQ-C30). On treatment, estimated overall global QoL scores significantly favored the palbociclib plus fulvestrant group [66.1, 95% confidence interval (CI) 64.5-67.7 versus 63.0, 95% CI 60.6-65.3; P = 0.0313]. Significantly greater improvement from baseline in pain was also observed in this group (-3.3, 95% CI -5.1 to -1.5 versus 2.0, 95% CI -0.6 to 4.6; P = 0.0011). No significant differences were observed for other QLQ-BR23 functioning domains, breast or arm symptoms. Treatment with palbociclib plus fulvestrant significantly delayed deterioration in global QoL (P < 0.025) and pain (P < 0.001) compared with fulvestrant alone. Palbociclib plus fulvestrant allowed patients to maintain good Qo

  1. Identification of A Novel Missense Mutation in The Norrie Disease Gene: The First Molecular Genetic Analysis and Prenatal Diagnosis of Norrie Disease in An Iranian Family.

    Science.gov (United States)

    Talebi, Farah; Ghanbari Mardasi, Farideh; Mohammadi Asl, Javad; Lashgari, Ali; Farhadi, Freidoon

    2018-07-01

    Norrie disease (ND) is a rare X-linked recessive disorder, which is characterized by congenital blindness and, in several cases, accompanied with mental retardation and deafness. ND is caused by mutations in NDP, located on the proximal short arm of the X chromosome (Xp11.3). The disease has been observed in many ethnic groups worldwide, however, no such case has been reported from Iran. In this study, we present the molecular analysis of two patients with ND and the subsequent prenatal diagnosis. Screening of NDP identified a hemizygous missense mutation (p.Ser133Cys) in the affected male siblings of the family. The mother was the carrier for the mutation (p.Ser133Cys). In a subsequent chorionic amniotic pregnancy, we carried out prenatal diagnosis by sequencing NDP in the chorionic villi sample at 11 weeks of gestation. The fetus was carrying the mutation and thus unaffected. This is the first mutation report and prenatal diagnosis of an Iranian family with ND, and highlights the importance of prenatal diagnostic screening of this congenital disorder and relevant genetic counseling. Copyright© by Royan Institute. All rights reserved.

  2. SDS, a structural disruption score for assessment of missense variant deleteriousness

    Directory of Open Access Journals (Sweden)

    Thanawadee ePreeprem

    2014-04-01

    Full Text Available We have developed a novel structure-based evaluation for missense variants that explicitly models protein structure and amino acid properties to predict the likelihood that a variant disrupts protein function. A structural disruption score (SDS is introduced as a measure to depict the likelihood that a case variant is functional. The score is constructed using characteristics that distinguish between causal and neutral variants within a group of proteins. The SDS score is correlated with standard sequence-based deleteriousness, but shows promise for improving discrimination between neutral and causal variants at less conserved sites.The prediction was performed on 3-dimentional structures of 57 gene products whose homozygous SNPs were identified as case-exclusive variants in an exome sequencing study of epilepsy disorders. We contrasted the candidate epilepsy variants with scores for likely benign variants found in the EVS database, and for positive control variants in the same genes that are suspected to promote a range of diseases. To derive a characteristic profile of damaging SNPs, we transformed continuous scores into categorical variables based on the score distribution of each measurement, collected from all possible SNPs in this protein set, where extreme measures were assumed to be deleterious. A second epilepsy dataset was used to replicate the findings. Causal variants tend to receive higher sequence-based deleterious scores, induce larger physico-chemical changes between amino acid pairs, locate in protein domains, buried sites or on conserved protein surface clusters, and cause protein destabilization, relative to negative controls. These measures were agglomerated for each variant. A list of nine high-priority putative functional variants for epilepsy was generated. Our newly developed SDS protocol facilitates SNP prioritization for experimental validation.

  3. Increased missense mutation burden of Fatty Acid metabolism related genes in nunavik inuit population.

    Science.gov (United States)

    Zhou, Sirui; Xiong, Lan; Xie, Pingxing; Ambalavanan, Amirthagowri; Bourassa, Cynthia V; Dionne-Laporte, Alexandre; Spiegelman, Dan; Turcotte Gauthier, Maude; Henrion, Edouard; Diallo, Ousmane; Dion, Patrick A; Rouleau, Guy A

    2015-01-01

    Nunavik Inuit (northern Quebec, Canada) reside along the arctic coastline where for generations their daily energy intake has mainly been derived from animal fat. Given this particular diet it has been hypothesized that natural selection would lead to population specific allele frequency differences and unique variants in genes related to fatty acid metabolism. A group of genes, namely CPT1A, CPT1B, CPT1C, CPT2, CRAT and CROT, encode for three carnitine acyltransferases that are important for the oxidation of fatty acids, a critical step in their metabolism. Exome sequencing and SNP array genotyping were used to examine the genetic variations in the six genes encoding for the carnitine acyltransferases in 113 Nunavik Inuit individuals. Altogether ten missense variants were found in genes CPT1A, CPT1B, CPT1C, CPT2 and CRAT, including three novel variants and one Inuit specific variant CPT1A p.P479L (rs80356779). The latter has the highest frequency (0.955) compared to other Inuit populations. We found that by comparison to Asians or Europeans, the Nunavik Inuit have an increased mutation burden in CPT1A, CPT2 and CRAT; there is also a high level of population differentiation based on carnitine acyltransferase gene variations between Nunavik Inuit and Asians. The increased number and frequency of deleterious variants in these fatty acid metabolism genes in Nunavik Inuit may be the result of genetic adaptation to their diet and/or the extremely cold climate. In addition, the identification of these variants may help to understand some of the specific health risks of Nunavik Inuit.

  4. Seizure is a rare presentation for acute hemolysis due to G6PD deficiency. We report a previously healthy boy who presented initially with seizure and cyanosis and subsequently acute hemolysis, due to glucose-6-phosphate dehydrogenase deficiency (G6PD) an

    OpenAIRE

    Afshin FAYYAZI; Ali KHAJEH; Hosein ESFAHANI

    2012-01-01

    Seizure is a rare presentation for acute hemolysis due to G6PD deficiency. We report a previously healthy boy who presented initially with seizure and cyanosis and subsequently acute hemolysis, due to glucose-6-phosphate dehydrogenase deficiency (G6PD) and probably secondary methemoglobinemia, following the ingestion of fava beans.

  5. The influence of previous low back trouble, general health, and working conditions on future sick-listing because of low back trouble. A 15-year follow-up study of risk indicators for self-reported sick-listing caused by low back trouble.

    Science.gov (United States)

    Müller, C F; Monrad, T; Biering-Sørensen, F; Darre, E; Deis, A; Kryger, P

    1999-08-01

    A 15-year follow-up study. To find risk indicators for self-reported sick-listing because of low back trouble and to evaluate which variables were the most important indicators of work incapacity resulting from low back trouble during the follow-up period of 15 years. The initial data were obtained from a health survey conducted in a general population from the Municipality of Glostrup, Denmark. The follow-up data included information from the Central Person Register, the Early Retirement Pension Register, and a postal questionnaire regarding self-reported sick-listing because of low back trouble. An epidemiologic study, in which logistic regression analyses were used for evaluation of the data. The model used consisted of the variable in question, age, gender, and previous experience of low back trouble, along with interactions. It was found that 22 of 37 variables were risk indicators for later self-reported sick-listing because of low back trouble during the preceding year or the 7 years before the date of follow-up evaluation. In analyzing the most significant variables simultaneously, it was found that information from the initial investigation about sick-listing in general during the previous 10 years, sciatic pain, use of analgesics for low back trouble, previous sick-listing because of low back trouble, and occupation were the most important risk indicators for self-reported work incapacity resulting from low back trouble during the follow-up period of 15 years. Findings showed that the strongest prognostic indicators of later sick-listing because of low back trouble involve information from the person about previous sick-listing behavior in general and previous experience of low back trouble episodes, especially if these had been accompanied by sciatic pain, use of analgesics, or previous low back trouble sick-listing.

  6. Structural Effects of Some Relevant Missense Mutations on the MECP2-DNA Binding: A MD Study Analyzed by Rescore+, a Versatile Rescoring Tool of the VEGA ZZ Program.

    Science.gov (United States)

    Pedretti, Alessandro; Granito, Cinzia; Mazzolari, Angelica; Vistoli, Giulio

    2016-09-01

    DNA methylation plays key roles in mammalian cells and is modulated by a set of proteins which recognize symmetrically methylated nucleotides. Among them, the protein MECP2 shows multifunctional roles repressing and/or activating genes by binding to both methylated and unmethylated regions of the genome. The interest for this protein markedly increased from the observation that its mutations are the primary cause of Rett syndrome, a neurodevelopmental disorder which causes mental retardation in young females. Thus, the present study is aimed to investigate the effects of some of these known pathogenic missense mutations (i.e. R106Q, R106W, R111G, R133C and R133H) on the MECP2 folding and DNA binding by molecular dynamics simulations. The effects of the simulated mutations are also parameterized by using a here proposed new tool, named Rescore+, implemented in the VEGA ZZ suite of programs, which calculates a set of scoring functions on all frames of a trajectory or on all complexes contained in a database thus allowing an easy rescoring of results coming from MD or docking simulations. The obtained results revealed that the reported loss of the MECP2 function induced by the simulated mutations can be ascribed to both stabilizing and destabilizing effect on DNA binding. The study confirms that MD simulations are particularly useful to rationalize and predict the mutation effects offering insightful information for diagnostics and drug design. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. Functional PMS2 hybrid alleles containing a pseudogene-specific missense variant trace back to a single ancient intrachromosomal recombination event.

    Science.gov (United States)

    Ganster, Christina; Wernstedt, Annekatrin; Kehrer-Sawatzki, Hildegard; Messiaen, Ludwine; Schmidt, Konrad; Rahner, Nils; Heinimann, Karl; Fonatsch, Christa; Zschocke, Johannes; Wimmer, Katharina

    2010-05-01

    Sequence exchange between PMS2 and its pseudogene PMS2CL, embedded in an inverted duplication on chromosome 7p22, has been reported to be an ongoing process that leads to functional PMS2 hybrid alleles containing PMS2- and PMS2CL-specific sequence variants at the 5'-and the 3'-end, respectively. The frequency of PMS2 hybrid alleles, their biological significance, and the mechanisms underlying their formation are largely unknown. Here we show that overall hybrid alleles account for one-third of 384 PMS2 alleles analyzed in individuals of different ethnic backgrounds. Depending on the population, 14-60% of hybrid alleles carry PMS2CL-specific sequences in exons 13-15, the remainder only in exon 15. We show that exons 13-15 hybrid alleles, named H1 hybrid alleles, constitute different haplotypes but trace back to a single ancient intrachromosomal recombination event with crossover. Taking advantage of an ancestral sequence variant specific for all H1 alleles we developed a simple gDNA-based polymerase chain reaction (PCR) assay that can be used to identify H1-allele carriers with high sensitivity and specificity (100 and 99%, respectively). Because H1 hybrid alleles harbor missense variant p.N775S of so far unknown functional significance, we assessed the H1-carrier frequency in 164 colorectal cancer patients. So far, we found no indication that the variant plays a major role with regard to cancer susceptibility. (c) 2010 Wiley-Liss, Inc.

  8. Mice with missense and nonsense NF1 mutations display divergent phenotypes compared with human neurofibromatosis type I

    Directory of Open Access Journals (Sweden)

    Kairong Li

    2016-07-01

    Full Text Available Neurofibromatosis type 1 (NF1 is a common genetic disorder characterized by the occurrence of nerve sheath tumors and considerable clinical heterogeneity. Some translational studies have been limited by the lack of animal models available for assessing patient-specific mutations. In order to test therapeutic approaches that might restore function to the mutated gene or gene product, we developed mice harboring NF1 patient-specific mutations including a nonsense mutation (c.2041C>T; p.Arg681* and a missense mutation (c.2542G>C; p.Gly848Arg. The latter is associated with the development of multiple plexiform neurofibromas along spinal nerve roots. We demonstrate that the human nonsense NF1Arg681* and missense NF1Gly848Arg mutations have different effects on neurofibromin expression in the mouse and each recapitulates unique aspects of the NF1 phenotype, depending upon the genetic context when assessed in the homozygous state or when paired with a conditional knockout allele. Whereas the missense Nf1Gly848Arg mutation fails to produce an overt phenotype in the mouse, animals homozygous for the nonsense Nf1Arg681* mutation are not viable. Mice with one Nf1Arg681* allele in combination with a conditional floxed Nf1 allele and the DhhCre transgene (Nf14F/Arg681*; DhhCre display disorganized nonmyelinating axons and neurofibromas along the spinal column, which leads to compression of the spinal cord and paralysis. This model will be valuable for preclinical testing of novel nonsense suppression therapies using drugs to target in-frame point mutations that create premature termination codons in individuals with NF1.

  9. Three-dimensional spatial analysis of missense variants in RTEL1 identifies pathogenic variants in patients with Familial Interstitial Pneumonia.

    Science.gov (United States)

    Sivley, R Michael; Sheehan, Jonathan H; Kropski, Jonathan A; Cogan, Joy; Blackwell, Timothy S; Phillips, John A; Bush, William S; Meiler, Jens; Capra, John A

    2018-01-23

    Next-generation sequencing of individuals with genetic diseases often detects candidate rare variants in numerous genes, but determining which are causal remains challenging. We hypothesized that the spatial distribution of missense variants in protein structures contains information about function and pathogenicity that can help prioritize variants of unknown significance (VUS) and elucidate the structural mechanisms leading to disease. To illustrate this approach in a clinical application, we analyzed 13 candidate missense variants in regulator of telomere elongation helicase 1 (RTEL1) identified in patients with Familial Interstitial Pneumonia (FIP). We curated pathogenic and neutral RTEL1 variants from the literature and public databases. We then used homology modeling to construct a 3D structural model of RTEL1 and mapped known variants into this structure. We next developed a pathogenicity prediction algorithm based on proximity to known disease causing and neutral variants and evaluated its performance with leave-one-out cross-validation. We further validated our predictions with segregation analyses, telomere lengths, and mutagenesis data from the homologous XPD protein. Our algorithm for classifying RTEL1 VUS based on spatial proximity to pathogenic and neutral variation accurately distinguished 7 known pathogenic from 29 neutral variants (ROC AUC = 0.85) in the N-terminal domains of RTEL1. Pathogenic proximity scores were also significantly correlated with effects on ATPase activity (Pearson r = -0.65, p = 0.0004) in XPD, a related helicase. Applying the algorithm to 13 VUS identified from sequencing of RTEL1 from patients predicted five out of six disease-segregating VUS to be pathogenic. We provide structural hypotheses regarding how these mutations may disrupt RTEL1 ATPase and helicase function. Spatial analysis of missense variation accurately classified candidate VUS in RTEL1 and suggests how such variants cause disease. Incorporating

  10. A case report of novel mutation in PRF1 gene, which causes familial autosomal recessive hemophagocytic lymphohistiocytosis.

    Science.gov (United States)

    Bordbar, Mohammad Reza; Modarresi, Farzaneh; Farazi Fard, Mohammad Ali; Dastsooz, Hassan; Shakib Azad, Nader; Faghihi, Mohammad Ali

    2017-05-03

    Hemophagocytic Lymphohistiocytosis (HLH) is a life-threatening immunodeficiency and multi-organ disease that affects people of all ages and ethnic groups. Common symptoms and signs of this disease are high fever, hepatosplenomegaly, and cytopenias. Familial form of HLH disease, which is an autosomal recessive hematological disorder is due to disease-causing mutations in several genes essential for NK and T-cell granule-mediated cytotoxic function. For an effective cytotoxic response from cytotoxic T lymphocyte or NK cell encountering an infected cell or tumor cell, different processes are required, including trafficking, docking, priming, membrane fusion, and entry of cytotoxic granules into the target cell leading to apoptosis. Therefore, genes involved in these steps play important roles in the pathogenesis of HLH disease which include PRF1, UNC13D (MUNC13-4), STX11, and STXBP2 (MUNC18-2). Here, we report a novel missense mutation in an 8-year-old boy suffered from hepatosplenomegaly, hepatitis, epilepsy and pancytopenia. The patient was born to a first-cousin parents with no previous documented disease in his parents. To identify mutated gene in the proband, Whole Exome Sequencing (WES) utilizing next generation sequencing was used on an Illumina HiSeq 2000 platform on DNA sample from the patient. Results showed a novel deleterious homozygous missense mutation in PRF1 gene (NM_001083116: exon3: c. 1120 T > G, p.W374G) in the patient and then using Sanger sequencing it was confirmed in the proband and his parents. Since his parents were heterozygous for the identified mutation, autosomal recessive pattern of inheritance was confirmed in the family. Our study identified a rare new pathogenic missense mutation in PRF1 gene in patient with HLH disease and it is the first report of mutation in PRF1 in Iranian patients with this disease.

  11. Preoperative screening: value of previous tests.

    Science.gov (United States)

    Macpherson, D S; Snow, R; Lofgren, R P

    1990-12-15

    To determine the frequency of tests done in the year before elective surgery that might substitute for preoperative screening tests and to determine the frequency of test results that change from a normal value to a value likely to alter perioperative management. Retrospective cohort analysis of computerized laboratory data (complete blood count, sodium, potassium, and creatinine levels, prothrombin time, and partial thromboplastin time). Urban tertiary care Veterans Affairs Hospital. Consecutive sample of 1109 patients who had elective surgery in 1988. At admission, 7549 preoperative tests were done, 47% of which duplicated tests performed in the previous year. Of 3096 previous results that were normal as defined by hospital reference range and done closest to the time of but before admission (median interval, 2 months), 13 (0.4%; 95% CI, 0.2% to 0.7%), repeat values were outside a range considered acceptable for surgery. Most of the abnormalities were predictable from the patient's history, and most were not noted in the medical record. Of 461 previous tests that were abnormal, 78 (17%; CI, 13% to 20%) repeat values at admission were outside a range considered acceptable for surgery (P less than 0.001, frequency of clinically important abnormalities of patients with normal previous results with those with abnormal previous results). Physicians evaluating patients preoperatively could safely substitute the previous test results analyzed in this study for preoperative screening tests if the previous tests are normal and no obvious indication for retesting is present.

  12. Missense Mutations Allow a Sequence-Blind Mutant of SpoIIIE to Successfully Translocate Chromosomes during Sporulation.

    Science.gov (United States)

    Bose, Baundauna; Reed, Sydney E; Besprozvannaya, Marina; Burton, Briana M

    2016-01-01

    SpoIIIE directionally pumps DNA across membranes during Bacillus subtilis sporulation and vegetative growth. The sequence-reading domain (γ domain) is required for directional DNA transport, and its deletion severely impairs sporulation. We selected suppressors of the spoIIIEΔγ sporulation defect. Unexpectedly, many suppressors were intragenic missense mutants, and some restore sporulation to near-wild-type levels. The mutant proteins are likely not more abundant, faster at translocating DNA, or sequence-sensitive, and rescue does not involve the SpoIIIE homolog SftA. Some mutants behave differently when co-expressed with spoIIIEΔγ, consistent with the idea that some, but not all, variants may form mixed oligomers. In full-length spoIIIE, these mutations do not affect sporulation, and yet the corresponding residues are rarely found in other SpoIIIE/FtsK family members. The suppressors do not rescue chromosome translocation defects during vegetative growth, indicating that the role of the γ domain cannot be fully replaced by these mutations. We present two models consistent with our findings: that the suppressors commit to transport in one arbitrarily-determined direction or delay spore development. It is surprising that missense mutations somehow rescue loss of an entire domain with a complex function, and this raises new questions about the mechanism by which SpoIIIE pumps DNA and the roles SpoIIIE plays in vivo.

  13. A novel missense mutation of the paired box 3 gene in a Turkish family with Waardenburg syndrome type 1.

    Science.gov (United States)

    Hazan, Filiz; Ozturk, A Taylan; Adibelli, Hamit; Unal, Nurettin; Tukun, Ajlan

    2013-01-01

    Screening of mutations in the paired box 3 (PAX3) gene in three generations of a Turkish family with Waardenburg syndrome type 1 (WS1). WS1 was diagnosed in a 13-month-old girl according to the WS Consortium criteria. Detailed family history of the proband revealed eight affected members in three generations. Routine clinical and audiological examination and ophthalmologic evaluation were performed on eight affected and five healthy members of the study family. Dystopia canthorum was detected in all affected patients; however, a brilliant blue iris was present in five patients who also had mild retinal hypopigmentation. Genomic DNA was extracted from the peripheral blood of affected and unaffected individuals in the family as well as 50 unrelated healthy volunteers. All coding exons and adjacent intronic regions of PAX3 were sequenced directly. A novel missense heterozygous c.788T>G mutation was identified in eight patients. This nucleotide alteration was not found in unaffected members of the study family or in the 50 unrelated control subjects. The mutation causes V263G amino-acid substitution in the homeodomain of the PAX3 protein, which represents the 45(th) residue of helix 3. We identified a novel missense c.788T>G mutation in PAX3 in a family with Waardenburg syndrome with intrafamilial phenotypic heterogeneity.

  14. Missense Mutations Allow a Sequence-Blind Mutant of SpoIIIE to Successfully Translocate Chromosomes during Sporulation.

    Directory of Open Access Journals (Sweden)

    Baundauna Bose

    Full Text Available SpoIIIE directionally pumps DNA across membranes during Bacillus subtilis sporulation and vegetative growth. The sequence-reading domain (γ domain is required for directional DNA transport, and its deletion severely impairs sporulation. We selected suppressors of the spoIIIEΔγ sporulation defect. Unexpectedly, many suppressors were intragenic missense mutants, and some restore sporulation to near-wild-type levels. The mutant proteins are likely not more abundant, faster at translocating DNA, or sequence-sensitive, and rescue does not involve the SpoIIIE homolog SftA. Some mutants behave differently when co-expressed with spoIIIEΔγ, consistent with the idea that some, but not all, variants may form mixed oligomers. In full-length spoIIIE, these mutations do not affect sporulation, and yet the corresponding residues are rarely found in other SpoIIIE/FtsK family members. The suppressors do not rescue chromosome translocation defects during vegetative growth, indicating that the role of the γ domain cannot be fully replaced by these mutations. We present two models consistent with our findings: that the suppressors commit to transport in one arbitrarily-determined direction or delay spore development. It is surprising that missense mutations somehow rescue loss of an entire domain with a complex function, and this raises new questions about the mechanism by which SpoIIIE pumps DNA and the roles SpoIIIE plays in vivo.

  15. A Case of Inflammatory Generalized Type of Peeling Skin Syndrome Possibly Caused by a Homozygous Missense Mutation of CDSN.

    Science.gov (United States)

    Kawakami, Hiroshi; Uchiyama, Masaki; Maeda, Tatsuo; Tsunoda, Takahiko; Mitsuhashi, Yoshihiko; Tsuboi, Ryoji

    2014-09-01

    A 54-year-old Japanese woman had repetitive superficial skin peeling and ensuing erythematous changes in the sites since infancy. Her parents had a consanguineous marriage, and she was the only individual affected in her family tree. The erythematous changes seemed to worsen in the summer. Histologically, hyperkeratosis and splitting of the epidermis within the stratum corneum was noted, and electron microscopy revealed shedding of corneal cells in the horny layer and normal-looking corneodesmosomes. Gene analysis revealed a homozygous missense mutation at c.1358G>A in CDSN. Electron microscopic examination of the length and number of corneodesmosomes revealed statistically significant shortness and sparsity in the affected individual (mean ± SD 386.2 ± 149.5 nm) compared with that of an age- and site-matched control (406.6 ± 182.3 nm). We speculate that this size shrinkage of corneodesmosomes might be the result of a missense mutation of CDSN and that this could be one of the factors contributing to the pathological process of skin peeling.

  16. A Case of Inflammatory Generalized Type of Peeling Skin Syndrome Possibly Caused by a Homozygous Missense Mutation of CDSN

    Directory of Open Access Journals (Sweden)

    Hiroshi Kawakami

    2014-10-01

    Full Text Available A 54-year-old Japanese woman had repetitive superficial skin peeling and ensuing erythematous changes in the sites since infancy. Her parents had a consanguineous marriage, and she was the only individual affected in her family tree. The erythematous changes seemed to worsen in the summer. Histologically, hyperkeratosis and splitting of the epidermis within the stratum corneum was noted, and electron microscopy revealed shedding of corneal cells in the horny layer and normal-looking corneodesmosomes. Gene analysis revealed a homozygous missense mutation at c.1358G>A in CDSN. Electron microscopic examination of the length and number of corneodesmosomes revealed statistically significant shortness and sparsity in the affected individual (mean ± SD 386.2 ± 149.5 nm compared with that of an age- and site-matched control (406.6 ± 182.3 nm. We speculate that this size shrinkage of corneodesmosomes might be the result of a missense mutation of CDSN and that this could be one of the factors contributing to the pathological process of skin peeling.

  17. Automatic electromagnetic valve for previous vacuum

    International Nuclear Information System (INIS)

    Granados, C. E.; Martin, F.

    1959-01-01

    A valve which permits the maintenance of an installation vacuum when electric current fails is described. It also lets the air in the previous vacuum bomb to prevent the oil ascending in the vacuum tubes. (Author)

  18. Common pathogenic effects of missense mutations in the P-type ATPase ATP13A2 (PARK9) associated with early-onset parkinsonism.

    Science.gov (United States)

    Podhajska, Agata; Musso, Alessandra; Trancikova, Alzbeta; Stafa, Klodjan; Moser, Roger; Sonnay, Sarah; Glauser, Liliane; Moore, Darren J

    2012-01-01

    Mutations in the ATP13A2 gene (PARK9) cause autosomal recessive, juvenile-onset Kufor-Rakeb syndrome (KRS), a neurodegenerative disease characterized by parkinsonism. KRS mutations produce truncated forms of ATP13A2 with impaired protein stability resulting in a loss-of-function. Recently, homozygous and heterozygous missense mutations in ATP13A2 have been identified in subjects with early-onset parkinsonism. The mechanism(s) by which missense mutations potentially cause parkinsonism are not understood at present. Here, we demonstrate that homozygous F182L, G504R and G877R missense mutations commonly impair the protein stability of ATP13A2 leading to its enhanced degradation by the proteasome. ATP13A2 normally localizes to endosomal and lysosomal membranes in neurons and the F182L and G504R mutations disrupt this vesicular localization and promote the mislocalization of ATP13A2 to the endoplasmic reticulum. Heterozygous T12M, G533R and A746T mutations do not obviously alter protein stability or subcellular localization but instead impair the ATPase activity of microsomal ATP13A2 whereas homozygous missense mutations disrupt the microsomal localization of ATP13A2. The overexpression of ATP13A2 missense mutants in SH-SY5Y neural cells does not compromise cellular viability suggesting that these mutant proteins lack intrinsic toxicity. However, the overexpression of wild-type ATP13A2 may impair neuronal integrity as it causes a trend of reduced neurite outgrowth of primary cortical neurons, whereas the majority of disease-associated missense mutations lack this ability. Finally, ATP13A2 overexpression sensitizes cortical neurons to neurite shortening induced by exposure to cadmium or nickel ions, supporting a functional interaction between ATP13A2 and heavy metals in post-mitotic neurons, whereas missense mutations influence this sensitizing effect. Collectively, our study provides support for common loss-of-function effects of homozygous and heterozygous missense

  19. A homozygous missense variant in VWA2, encoding an interactor of the Fraser-complex, in a patient with vesicoureteral reflux.

    Directory of Open Access Journals (Sweden)

    Amelie T van der Ven

    Full Text Available Congenital anomalies of the kidney and urinary tract (CAKUT are the most common cause (40-50% of chronic kidney disease (CKD in children. About 40 monogenic causes of CAKUT have so far been discovered. To date less than 20% of CAKUT cases can be explained by mutations in these 40 genes. To identify additional monogenic causes of CAKUT, we performed whole exome sequencing (WES and homozygosity mapping (HM in a patient with CAKUT from Indian origin and consanguineous descent. We identified a homozygous missense mutation (c.1336C>T, p.Arg446Cys in the gene Von Willebrand factor A domain containing 2 (VWA2. With immunohistochemistry studies on kidneys of newborn (P1 mice, we show that Vwa2 and Fraser extracellular matrix complex subunit 1 (Fras1 co-localize in the nephrogenic zone of the renal cortex. We identified a pronounced expression of Vwa2 in the basement membrane of the ureteric bud (UB and derivatives of the metanephric mesenchyme (MM. By applying in vitro assays, we demonstrate that the Arg446Cys mutation decreases translocation of monomeric VWA2 protein and increases translocation of aggregated VWA2 protein into the extracellular space. This is potentially due to the additional, unpaired cysteine residue in the mutated protein that is used for intermolecular disulfide bond formation. VWA2 is a known, direct interactor of FRAS1 of the Fraser-Complex (FC. FC-encoding genes and interacting proteins have previously been implicated in the pathogenesis of syndromic and/or isolated CAKUT phenotypes in humans. VWA2 therefore constitutes a very strong candidate in the search for novel CAKUT-causing genes. Our results from in vitro experiments indicate a dose-dependent neomorphic effect of the Arg446Cys homozygous mutation in VWA2.

  20. Dominant Red Coat Color in Holstein Cattle Is Associated with a Missense Mutation in the Coatomer Protein Complex, Subunit Alpha (COPA Gene.

    Directory of Open Access Journals (Sweden)

    Ben Dorshorst

    Full Text Available Coat color in Holstein dairy cattle is primarily controlled by the melanocortin 1 receptor (MC1R gene, a central determinant of black (eumelanin vs. red/brown pheomelanin synthesis across animal species. The major MC1R alleles in Holsteins are Dominant Black (MC1RD and Recessive Red (MC1Re. A novel form of dominant red coat color was first observed in an animal born in 1980. The mutation underlying this phenotype was named Dominant Red and is epistatic to the constitutively activated MC1RD. Here we show that a missense mutation in the coatomer protein complex, subunit alpha (COPA, a gene with previously no known role in pigmentation synthesis, is completely associated with Dominant Red in Holstein dairy cattle. The mutation results in an arginine to cysteine substitution at an amino acid residue completely conserved across eukaryotes. Despite this high level of conservation we show that both heterozygotes and homozygotes are healthy and viable. Analysis of hair pigment composition shows that the Dominant Red phenotype is similar to the MC1R Recessive Red phenotype, although less effective at reducing eumelanin synthesis. RNA-seq data similarly show that Dominant Red animals achieve predominantly pheomelanin synthesis by downregulating genes normally required for eumelanin synthesis. COPA is a component of the coat protein I seven subunit complex that is involved with retrograde and cis-Golgi intracellular coated vesicle transport of both protein and RNA cargo. This suggests that Dominant Red may be caused by aberrant MC1R protein or mRNA trafficking within the highly compartmentalized melanocyte, mimicking the effect of the Recessive Red loss of function MC1R allele.

  1. Previously unreported abnormalities in Wolfram Syndrome Type 2.

    Science.gov (United States)

    Akturk, Halis Kaan; Yasa, Seda

    2017-01-01

    Wolfram syndrome (WFS) is a rare autosomal recessive disease with non-autoimmune childhood onset insulin dependent diabetes and optic atrophy. WFS type 2 (WFS2) differs from WFS type 1 (WFS1) with upper intestinal ulcers, bleeding tendency and the lack ofdiabetes insipidus. Li-fespan is short due to related comorbidities. Only a few familieshave been reported with this syndrome with the CISD2 mutation. Here we report two siblings with a clinical diagnosis of WFS2, previously misdiagnosed with type 1 diabetes mellitus and diabetic retinopathy-related blindness. We report possible additional clinical and laboratory findings that have not been pre-viously reported, such as asymptomatic hypoparathyroidism, osteomalacia, growth hormone (GH) deficiency and hepatomegaly. Even though not a requirement for the diagnosis of WFS2 currently, our case series confirm hypogonadotropic hypogonadism to be also a feature of this syndrome, as reported before. © Polish Society for Pediatric Endocrinology and Diabetology.

  2. Evolutionary Analysis Predicts Sensitive Positions of MMP20 and Validates Newly- and Previously-Identified MMP20 Mutations Causing Amelogenesis Imperfecta

    Directory of Open Access Journals (Sweden)

    Barbara Gasse

    2017-06-01

    Full Text Available Amelogenesis imperfecta (AI designates a group of genetic diseases characterized by a large range of enamel disorders causing important social and health problems. These defects can result from mutations in enamel matrix proteins or protease encoding genes. A range of mutations in the enamel cleavage enzyme matrix metalloproteinase-20 gene (MMP20 produce enamel defects of varying severity. To address how various alterations produce a range of AI phenotypes, we performed a targeted analysis to find MMP20 mutations in French patients diagnosed with non-syndromic AI. Genomic DNA was isolated from saliva and MMP20 exons and exon-intron boundaries sequenced. We identified several homozygous or heterozygous mutations, putatively involved in the AI phenotypes. To validate missense mutations and predict sensitive positions in the MMP20 sequence, we evolutionarily compared 75 sequences extracted from the public databases using the Datamonkey webserver. These sequences were representative of mammalian lineages, covering more than 150 million years of evolution. This analysis allowed us to find 324 sensitive positions (out of the 483 MMP20 residues, pinpoint functionally important domains, and build an evolutionary chart of important conserved MMP20 regions. This is an efficient tool to identify new- and previously-identified mutations. We thus identified six functional MMP20 mutations in unrelated families, finding two novel mutated sites. The genotypes and phenotypes of these six mutations are described and compared. To date, 13 MMP20 mutations causing AI have been reported, making these genotypes and associated hypomature enamel phenotypes the most frequent in AI.

  3. 77 FR 70176 - Previous Participation Certification

    Science.gov (United States)

    2012-11-23

    ... participants' previous participation in government programs and ensure that the past record is acceptable prior... information is designed to be 100 percent automated and digital submission of all data and certifications is... government programs and ensure that the past record is acceptable prior to granting approval to participate...

  4. On the Tengiz petroleum deposit previous study

    International Nuclear Information System (INIS)

    Nysangaliev, A.N.; Kuspangaliev, T.K.

    1997-01-01

    Tengiz petroleum deposit previous study is described. Some consideration about structure of productive formation, specific characteristic properties of petroleum-bearing collectors are presented. Recommendation on their detail study and using of experience on exploration and development of petroleum deposit which have analogy on most important geological and industrial parameters are given. (author)

  5. Subsequent pregnancy outcome after previous foetal death

    NARCIS (Netherlands)

    Nijkamp, J. W.; Korteweg, F. J.; Holm, J. P.; Timmer, A.; Erwich, J. J. H. M.; van Pampus, M. G.

    Objective: A history of foetal death is a risk factor for complications and foetal death in subsequent pregnancies as most previous risk factors remain present and an underlying cause of death may recur. The purpose of this study was to evaluate subsequent pregnancy outcome after foetal death and to

  6. A Novel Missense Mutation in SLC5A5 Gene in a Sudanese Family with Congenital Hypothyroidism.

    Science.gov (United States)

    Watanabe, Yui; Ebrhim, Reham Shareef; Abdullah, Mohamed A; Weiss, Roy E

    2018-05-15

    Thyroid hormone synthesis requires the presence of iodide. The sodium iodide symporter (NIS) is a glycoprotein which mediates the active uptake of iodide from the blood stream into the thyroid grand. NIS defects due to SLC5A5 gene mutations are known to cause congenital hypothyroidism (CH). The proposita is a 28-year-old female whose origin is the North Sudan where neonatal screening for CH is not available. She presented with severe constipation and a goiter at the age of 40 days. Laboratory testing confirmed CH and she was started on levothyroxine (L-T4). Presumably due to the delayed treatment the patient developed mental retardation. Her younger sister presented with a goiter, tongue protrusion and umbilical hernia and the youngest brother was also diagnosed with CH based on the TSH >100 µIU/mL at the age of 22 days and 8 days, respectively. Two siblings were treated with L-T4 and had normal development. Their consanguineous parents had no history of thyroid disorders. We performed whole exome sequencing (WES) on the proposita. WES identified a novel homozygous missense mutation in the SLC5A5 gene: c.1042T>G, p.Tyr348Asp, which was subsequently confirmed by Sanger sequencing. All affected children were homozygous for the same mutation and their unaffected mother was heterozygous. The NIS protein is composed of 13 transmembrane segments (TMS), an extracellular amino-terminus and an intracellular carboxyl terminus. The mutation is located in the TMS IX which has the most β-OH group-containing amino acids (serine and threonine) which is implicated in Na+ binding and translocation. In conclusion, a novel homozygous missense mutation in the SLC5A5 gene was identified in the Sudanese family with CH. The mutation is located in the TMS IX of the NIS protein which is essential for NIS function. Low iodine intake in Sudan is considered to affect severity of hypothyroidism in the patients.

  7. Recurrent missense mutations in TMEM43 (ARVD5) due to founder effects cause arrhythmogenic cardiomyopathies in the UK and Canada

    KAUST Repository

    Haywood, Annika

    2012-11-15

    AimsAutosomal dominant arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) (in the group of arrhythmogenic cardiomyopathies) is a common cause of sudden cardiac death in young adults. It is both clinically and genetically heterogeneous, with 12 loci (ARVC/D1-12) and eight genes identified, the majority of which encode structural proteins of cardiac desmosomes. The most recent gene identified, TMEM43, causes disease due to a missense mutation in a non-desmosomal gene (p.S358L) in 15 extended families from Newfoundland, Canada. To determine whether mutations in TMEM43 cause ARVC/D and arrhythmogenic cardiomyopathy in other populations, we fully re-sequenced TMEM43 on 143 ARVC/D probands (families) from the UK and 55 probands (from 55 families) from Newfoundland.Methods and resultsBidirectional sequencing of TMEM43 including intron-exon boundaries revealed 33 variants, the majority located in non-coding regions of TMEM43. For the purpose of validation, families of probands with rare, potentially deleterious coding variants were subjected to clinical and molecular follow-up. Three missense variants of uncertain significance (p.R28W, p.E142K, p.R312W) were located in highly conserved regions of the TMEM43 protein. One variant (p.R312W) also co-segregated with relatives showing clinical signs of disease. Genotyping and expansion of the disease-associated haplotype in subjects with the p.R312W variant from Newfoundland, Canada, and the UK suggest common ancestry.ConclusionAlthough the p.R312W variant was found in controls (3/378), identification of an ancestral disease p R312W haplotype suggests that the p.R312W variant is a pathogenic founder mutation. © 2012 The Author.

  8. Recurrent missense mutations in TMEM43 (ARVD5) due to founder effects cause arrhythmogenic cardiomyopathies in the UK and Canada

    KAUST Repository

    Haywood, Annika; Merner, Nancy D.; Hodgkinson, Kathy A.; Houston, Jim; Syrris, Petros; Booth, Valerie; Connors, Sean; Pantazis, Antonios; Quarta, Giovanni; Elliott, Perry; McKenna, William; Young, Terry Lynn

    2012-01-01

    AimsAutosomal dominant arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) (in the group of arrhythmogenic cardiomyopathies) is a common cause of sudden cardiac death in young adults. It is both clinically and genetically heterogeneous, with 12 loci (ARVC/D1-12) and eight genes identified, the majority of which encode structural proteins of cardiac desmosomes. The most recent gene identified, TMEM43, causes disease due to a missense mutation in a non-desmosomal gene (p.S358L) in 15 extended families from Newfoundland, Canada. To determine whether mutations in TMEM43 cause ARVC/D and arrhythmogenic cardiomyopathy in other populations, we fully re-sequenced TMEM43 on 143 ARVC/D probands (families) from the UK and 55 probands (from 55 families) from Newfoundland.Methods and resultsBidirectional sequencing of TMEM43 including intron-exon boundaries revealed 33 variants, the majority located in non-coding regions of TMEM43. For the purpose of validation, families of probands with rare, potentially deleterious coding variants were subjected to clinical and molecular follow-up. Three missense variants of uncertain significance (p.R28W, p.E142K, p.R312W) were located in highly conserved regions of the TMEM43 protein. One variant (p.R312W) also co-segregated with relatives showing clinical signs of disease. Genotyping and expansion of the disease-associated haplotype in subjects with the p.R312W variant from Newfoundland, Canada, and the UK suggest common ancestry.ConclusionAlthough the p.R312W variant was found in controls (3/378), identification of an ancestral disease p R312W haplotype suggests that the p.R312W variant is a pathogenic founder mutation. © 2012 The Author.

  9. Previously undiagnosed hemophilia patient with intracerebral hemorrhage

    Directory of Open Access Journals (Sweden)

    Eray Atalay

    2015-09-01

    Full Text Available Intracranial bleeding in hemophilia patients is a rare but a mortal complication. Diagnosis of hemophilia in adulthood is an uncommon occurrence. In this case report an adult patient with intracranial hemorrhage is presented.

  10. Association between Two Common Missense Substitutions, Thr6Lys and Val81Ile, in MC3R Gene and Childhood Obesity: A Meta-Analysis.

    Science.gov (United States)

    Koya, Charita; Yu, Tsung; Strong, Carol; Tsai, Meng-Che

    2018-04-24

    Two common missense variants in the melanocortin-3 receptor (MC3R) gene, Thr6Lys (T6K) and Val81Ile (V81I), are presumably correlated with pediatric obesity. This meta-analysis aimed to examine and synthesize evidence on the association between these two common MC3R polymorphisms and the development of childhood obesity. A combination of words relevant to the research question was searched on PubMed, EMBASE, Scopus, and the Cochrane database. Results were restricted to human studies, specifically child and adolescent populations. Articles were excluded based on accessibility of full online texts and availability of pertinent data. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random effects model to determine the association of the polymorphisms with obesity. Searches on the databases using the keywords identified 65 potentially relevant reports. Among them, 32 studies were excluded due to irrelevance, and 28 studies excluded due to lack of access, insufficient data, and investigation of other variants. A final set of five studies included in this meta-analysis found that the risk of overweight/obesity increased by 46.1% per K allele and 21.7% per I allele. Only homozygous genotypes for T6K were associated with a 3.10-fold (95% CI: 1.29-7.43) increased risk of overweight/obesity in children. Data were insufficient to examine if homozygosity for both rare alleles further increases risk. Our results supported a recessive inheritance model for MC3R gene as a potential cause of childhood obesity. High clinical heterogeneity existed among studies and thus requires more research of larger participation for future integration of data.

  11. Novel missense mutations in PNPLA2 causing late onset and clinical heterogeneity of neutral lipid storage disease with myopathy in three siblings.

    Science.gov (United States)

    Missaglia, Sara; Tasca, Elisabetta; Angelini, Corrado; Moro, Laura; Tavian, Daniela

    2015-01-01

    Neutral lipid storage disease with myopathy (NLSD-M) is a rare autosomal recessive disorder characterised by an abnormal accumulation of triacylglycerol into cytoplasmic lipid droplets (LDs). NLSD-M patients are mainly affected by progressive myopathy, cardiomyopathy and hepatomegaly. Mutations in the PNPLA2 gene cause variable phenotypes of NLSD-M. PNPLA2 codes for adipose triglyceride lipase (ATGL), an enzyme that hydrolyses fatty acids from triacylglycerol. This report outlines the clinical and genetic findings in a NLSD-M Italian family with three affected members. In our patients, we identified two novel PNPLA2 missense mutations (p.L56R and p.I193F). Functional data analysis demonstrated that these mutations caused the production of ATGL proteins able to bind to LDs, but with decreased lipase activity. The oldest brother, at the age of 38, had weakness and atrophy of the right upper arm and kyphosis. Now he is 61 years old and is unable to raise arms in the horizontal position. The second brother, from the age of 44, had exercise intolerance, cramps and pain in lower limbs. He is currently 50 years old and has an asymmetric distal amyotrophy. One of the two sisters, 58 years old, presents the same PNPLA2 mutations, but she is still oligo-symptomatic on neuromuscular examination with slight triceps muscle involvement. She suffered from diabetes and liver steatosis. This NLSD-M family shows a wide range of intra-familial phenotypic variability in subjects carrying the same mutations, both in terms of target-organs and in terms of rate of disease progression. Copyright © 2015. Published by Elsevier Inc.

  12. A pathogenic S250F missense mutation results in a mouse model of mild aromatic l-amino acid decarboxylase (AADC) deficiency.

    Science.gov (United States)

    Caine, Charlotte; Shohat, Meytal; Kim, Jeong-Ki; Nakanishi, Koki; Homma, Shunichi; Mosharov, Eugene V; Monani, Umrao R

    2017-11-15

    Homozygous mutations in the aromatic l-amino acid decarboxylase (AADC) gene result in a severe depletion of its namesake protein, triggering a debilitating and often fatal form of infantile Parkinsonism known as AADC deficiency. AADC deficient patients fail to produce normal levels of the monoamine neurotransmitters dopamine and serotonin, and suffer a multi-systemic disorder characterized by movement abnormalities, developmental delay and autonomic dysfunction; an absolute loss of dopamine is generally considered incompatible with life. There is no optimal treatment for AADC deficiency and few truly good models in which to investigate disease mechanisms or develop and refine therapeutic strategies. In this study, we introduced a relatively frequently reported but mildly pathogenic S250F missense mutation into the murine Aadc gene. We show that mutants homozygous for the mutation are viable and express a stable but minimally active form of the AADC protein. Although the low enzymatic activity of the protein resulted in only modestly reduced concentrations of brain dopamine, serotonin levels were markedly diminished, and this perturbed behavior as well as autonomic function in mutant mice. Still, we found no evidence of morphologic abnormalities of the dopaminergic cells in mutant brains. The striatum as well as substantia nigra appeared normal and no loss of dopamine expressing cells in the latter was detected. We conclude that even minute levels of active AADC are sufficient to allow for substantial amounts of dopamine to be produced in model mice harboring the S250F mutation. Such mutants represent a novel, mild model of human AADC deficiency. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  13. A novel missense KIT mutation causing piebaldism in one Chinese family associated with café-au-lait macules and intertriginous freckling

    Directory of Open Access Journals (Sweden)

    Jia WX

    2015-04-01

    Full Text Available Wei-Xue Jia,1,2 Xue-Min Xiao,1,2 Jian-Bing Wu,1,2 Yi-Ping Ma,1,2 Yi-Ping Ge,1,2 Qi Li,1,2 Qiu-Xia Mao,1,2 Cheng-Rang Li1,2 1Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, Jiangsu, China; 2Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Nanjing, Jiangsu, China Abstract: Piebaldism is a rare autosomal dominant genodermatosis, manifesting as congenital and stable depigmentation of the skin and white forelock. It has been found to be associated with mutations in the KIT or SLUG genes. We report a Chinese piebaldism family including a 28-year-old woman and her 3-year-old son with characteristics of white patches and forelock associated with numerous brown macules and patches. Genomic DNA samples of the proband and her son were extracted from their peripheral blood. One hundred unrelated healthy individuals were used as controls. All coding regions of KIT, SLUG, and NF1 genes were amplified by polymerase chain reaction using exon flanking intronic primers and Sanger sequencings were performed. DNA sequencing revealed heterozygous missense c.2431T>G mutation in exon 17 of the KIT gene in the proband and the affected son. No potentially pathogenic variant was identified in SLUG or NF1 genes. The nucleotide substitution was not found in 100 unrelated control individuals. This study reveals a novel KIT mutation in piebaldism, and it further supports that café-au-lait macules and intertriginous freckling of piebaldism are parts of pigmented anomaly in piebaldism, which does not necessarily represent coexistence of neurofibromatosis type 1 (NF1. Keywords: novel mutation, KIT gene, neurofibromatosis type 1 

  14. Haemophilus influenzae type f meningitis in a previously healthy boy

    DEFF Research Database (Denmark)

    Ronit, Andreas; Berg, Ronan M G; Bruunsgaard, Helle

    2013-01-01

    Non-serotype b strains of Haemophilus influenzae are extremely rare causes of acute bacterial meningitis in immunocompetent individuals. We report a case of acute bacterial meningitis in a 14-year-old boy, who was previously healthy and had been immunised against H influenzae serotype b (Hib...

  15. Process cells dismantling of EUREX pant: previous activities

    International Nuclear Information System (INIS)

    Gili, M.

    1998-01-01

    In the '98-'99 period some process cells of the EUREX pant will be dismantled, in order to place there the liquid wastes conditioning plant 'CORA'. This report resumes the previous activities (plant rinsing campaigns and inactive Cell 014 dismantling), run in the past three years and the drawn experience [it

  16. Mouse models of two missense mutations in actin-binding domain 1 of dystrophin associated with Duchenne or Becker muscular dystrophy.

    Science.gov (United States)

    McCourt, Jackie L; Talsness, Dana M; Lindsay, Angus; Arpke, Robert W; Chatterton, Paul D; Nelson, D'anna M; Chamberlain, Christopher M; Olthoff, John T; Belanto, Joseph J; McCourt, Preston M; Kyba, Michael; Lowe, Dawn A; Ervasti, James M

    2018-02-01

    Missense mutations in the dystrophin protein can cause Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD) through an undefined pathomechanism. In vitro studies suggest that missense mutations in the N-terminal actin-binding domain (ABD1) cause protein instability, and cultured myoblast studies reveal decreased expression levels that can be restored to wild-type with proteasome inhibitors. To further elucidate the pathophysiology of missense dystrophin in vivo, we generated two transgenic mdx mouse lines expressing L54R or L172H mutant dystrophin, which correspond to missense mutations identified in human patients with DMD or BMD, respectively. Our biochemical, histologic and physiologic analysis of the L54R and L172H mice show decreased levels of dystrophin which are proportional to the phenotypic severity. Proteasome inhibitors were ineffective in both the L54R and L172H mice, yet mice homozygous for the L172H transgene were able to express even higher levels of dystrophin which caused further improvements in muscle histology and physiology. Given that missense dystrophin is likely being degraded by the proteasome but whole body proteasome inhibition was not possible, we screened for ubiquitin-conjugating enzymes involved in targeting dystrophin to the proteasome. A myoblast cell line expressing L54R mutant dystrophin was screened with an siRNA library targeting E1, E2 and E3 ligases which identified Amn1, FBXO33, Zfand5 and Trim75. Our study establishes new mouse models of dystrophinopathy and identifies candidate E3 ligases that may specifically regulate dystrophin protein turnover in vivo. © The Author(s) 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  17. Diffuse reticuloendothelial system involvement in type IV glycogen storage disease with a novel GBE1 mutation: a case report and review.

    Science.gov (United States)

    Magoulas, Pilar L; El-Hattab, Ayman W; Roy, Angshumoy; Bali, Deeksha S; Finegold, Milton J; Craigen, William J

    2012-06-01

    Glycogen storage disease type IV is a rare autosomal recessive disorder of glycogen metabolism caused by mutations in the GBE1 gene that encodes the 1,4-alpha-glucan-branching enzyme 1. Its clinical presentation is variable, with the most common form presenting in early childhood with primary hepatic involvement. Histologic manifestations in glycogen storage disease type IV typically consist of intracytoplasmic non-membrane-bound inclusions containing abnormally branched glycogen (polyglucosan bodies) within hepatocytes and myocytes. We report a female infant with classic hepatic form of glycogen storage disease type IV who demonstrated diffuse reticuloendothelial system involvement with the spleen, bone marrow, and lymph nodes infiltrated by foamy histiocytes with intracytoplasmic polyglucosan deposits. Sequence analysis of the GBE1 gene revealed compound heterozygosity for a previously described frameshift mutation (c.1239delT) and a novel missense mutation (c.1279G>A) that is predicted to alter a conserved glycine residue. GBE enzyme analysis revealed no detectable activity. A review of the literature for glycogen storage disease type IV patients with characterized molecular defects and deficient enzyme activity reveals most GBE1 mutations to be missense mutations clustering in the catalytic enzyme domain. Individuals with the classic hepatic form of glycogen storage disease type IV tend to be compound heterozygotes for null and missense mutations. Although the extensive reticuloendothelial system involvement that was observed in our patient is not typical of glycogen storage disease type IV, it may be associated with severe enzymatic deficiency and a poor outcome. Copyright © 2012 Elsevier Inc. All rights reserved.

  18. Books average previous decade of economic misery.

    Science.gov (United States)

    Bentley, R Alexander; Acerbi, Alberto; Ormerod, Paul; Lampos, Vasileios

    2014-01-01

    For the 20(th) century since the Depression, we find a strong correlation between a 'literary misery index' derived from English language books and a moving average of the previous decade of the annual U.S. economic misery index, which is the sum of inflation and unemployment rates. We find a peak in the goodness of fit at 11 years for the moving average. The fit between the two misery indices holds when using different techniques to measure the literary misery index, and this fit is significantly better than other possible correlations with different emotion indices. To check the robustness of the results, we also analysed books written in German language and obtained very similar correlations with the German economic misery index. The results suggest that millions of books published every year average the authors' shared economic experiences over the past decade.

  19. Books Average Previous Decade of Economic Misery

    Science.gov (United States)

    Bentley, R. Alexander; Acerbi, Alberto; Ormerod, Paul; Lampos, Vasileios

    2014-01-01

    For the 20th century since the Depression, we find a strong correlation between a ‘literary misery index’ derived from English language books and a moving average of the previous decade of the annual U.S. economic misery index, which is the sum of inflation and unemployment rates. We find a peak in the goodness of fit at 11 years for the moving average. The fit between the two misery indices holds when using different techniques to measure the literary misery index, and this fit is significantly better than other possible correlations with different emotion indices. To check the robustness of the results, we also analysed books written in German language and obtained very similar correlations with the German economic misery index. The results suggest that millions of books published every year average the authors' shared economic experiences over the past decade. PMID:24416159

  20. Previous Experience a Model of Practice UNAE

    OpenAIRE

    Ormary Barberi Ruiz; María Dolores Pesántez Palacios

    2017-01-01

    The statements presented in this article represents a preliminary version of the proposed model of pre-professional practices (PPP) of the National University of Education (UNAE) of Ecuador, an urgent institutional necessity is revealed in the descriptive analyzes conducted from technical support - administrative (reports, interviews, testimonials), pedagogical foundations of UNAE (curricular directionality, transverse axes in practice, career plan, approach and diagnostic examination as subj...

  1. Secondary recurrent miscarriage is associated with previous male birth.

    LENUS (Irish Health Repository)

    Ooi, Poh Veh

    2012-01-31

    Secondary recurrent miscarriage (RM) is defined as three or more consecutive pregnancy losses after delivery of a viable infant. Previous reports suggest that a firstborn male child is associated with less favourable subsequent reproductive potential, possibly due to maternal immunisation against male-specific minor histocompatibility antigens. In a retrospective cohort study of 85 cases of secondary RM we aimed to determine if secondary RM was associated with (i) gender of previous child, maternal age, or duration of miscarriage history, and (ii) increased risk of pregnancy complications. Fifty-three women (62.0%; 53\\/85) gave birth to a male child prior to RM compared to 32 (38.0%; 32\\/85) who gave birth to a female child (p=0.002). The majority (91.7%; 78\\/85) had uncomplicated, term deliveries and normal birth weight neonates, with one quarter of the women previously delivered by Caesarean section. All had routine RM investigations and 19.0% (16\\/85) had an abnormal result. Fifty-seven women conceived again and 33.3% (19\\/57) miscarried, but there was no significant difference in failure rates between those with a previous male or female child (13\\/32 vs. 6\\/25, p=0.2). When patients with abnormal results were excluded, or when women with only one previous child were considered, there was still no difference in these rates. A previous male birth may be associated with an increased risk of secondary RM but numbers preclude concluding whether this increases recurrence risk. The suggested association with previous male birth provides a basis for further investigations at a molecular level.

  2. Secondary recurrent miscarriage is associated with previous male birth.

    LENUS (Irish Health Repository)

    Ooi, Poh Veh

    2011-01-01

    Secondary recurrent miscarriage (RM) is defined as three or more consecutive pregnancy losses after delivery of a viable infant. Previous reports suggest that a firstborn male child is associated with less favourable subsequent reproductive potential, possibly due to maternal immunisation against male-specific minor histocompatibility antigens. In a retrospective cohort study of 85 cases of secondary RM we aimed to determine if secondary RM was associated with (i) gender of previous child, maternal age, or duration of miscarriage history, and (ii) increased risk of pregnancy complications. Fifty-three women (62.0%; 53\\/85) gave birth to a male child prior to RM compared to 32 (38.0%; 32\\/85) who gave birth to a female child (p=0.002). The majority (91.7%; 78\\/85) had uncomplicated, term deliveries and normal birth weight neonates, with one quarter of the women previously delivered by Caesarean section. All had routine RM investigations and 19.0% (16\\/85) had an abnormal result. Fifty-seven women conceived again and 33.3% (19\\/57) miscarried, but there was no significant difference in failure rates between those with a previous male or female child (13\\/32 vs. 6\\/25, p=0.2). When patients with abnormal results were excluded, or when women with only one previous child were considered, there was still no difference in these rates. A previous male birth may be associated with an increased risk of secondary RM but numbers preclude concluding whether this increases recurrence risk. The suggested association with previous male birth provides a basis for further investigations at a molecular level.

  3. Previous Experience a Model of Practice UNAE

    Directory of Open Access Journals (Sweden)

    Ormary Barberi Ruiz

    2017-02-01

    Full Text Available The statements presented in this article represents a preliminary version of the proposed model of pre-professional practices (PPP of the National University of Education (UNAE of Ecuador, an urgent institutional necessity is revealed in the descriptive analyzes conducted from technical support - administrative (reports, interviews, testimonials, pedagogical foundations of UNAE (curricular directionality, transverse axes in practice, career plan, approach and diagnostic examination as subject nature of the pre professional practice and the demand of socio educational contexts where the practices have been emerging to resize them. By relating these elements allowed conceiving the modeling of the processes of the pre-professional practices for the development of professional skills of future teachers through four components: contextual projective, implementation (tutoring, accompaniment (teaching couple and monitoring (meetings at the beginning, during and end of practice. The initial training of teachers is inherent to teaching (academic and professional training, research and links with the community, these are fundamental pillars of Ecuadorian higher education.

  4. The congenital "ant-egg" cataract phenotype is caused by a missense mutation in connexin46

    DEFF Research Database (Denmark)

    Hansen, Lars; Yao, Wenliang; Eiberg, Hans

    2006-01-01

    "Ant-egg" cataract is a rare, distinct variety of congenital/infantile cataract that was reported in a large Danish family in 1967. This cataract phenotype is characterized by ant-egg-like bodies embedded in the lens in a laminar configuration and is inherited as an autosomal dominant trait. We r...

  5. A missense mutation of HOXA13 underlies hand-foot-genital ...

    Indian Academy of Sciences (India)

    Lihua Cao

    2017-08-16

    Aug 16, 2017 ... These abnormalities in limb appears to be fully penetrant, bilateral, and ... gross deletions have also been reported (Frisén et al. 2003;. Utsch et al. 2007 .... known to be linked to human developmental disorders. Mutations in ...

  6. BRCA1 and BRCA2 missense variants of high and low clinical significance influence lymphoblastoid cell line post-irradiation gene expression.

    Directory of Open Access Journals (Sweden)

    Nic Waddell

    2008-05-01

    Full Text Available The functional consequences of missense variants in disease genes are difficult to predict. We assessed if gene expression profiles could distinguish between BRCA1 or BRCA2 pathogenic truncating and missense mutation carriers and familial breast cancer cases whose disease was not attributable to BRCA1 or BRCA2 mutations (BRCAX cases. 72 cell lines from affected women in high-risk breast ovarian families were assayed after exposure to ionising irradiation, including 23 BRCA1 carriers, 22 BRCA2 carriers, and 27 BRCAX individuals. A subset of 10 BRCAX individuals carried rare BRCA1/2 sequence variants considered to be of low clinical significance (LCS. BRCA1 and BRCA2 mutation carriers had similar expression profiles, with some subclustering of missense mutation carriers. The majority of BRCAX individuals formed a distinct cluster, but BRCAX individuals with LCS variants had expression profiles similar to BRCA1/2 mutation carriers. Gaussian Process Classifier predicted BRCA1, BRCA2 and BRCAX status, with a maximum of 62% accuracy, and prediction accuracy decreased with inclusion of BRCAX samples carrying an LCS variant, and inclusion of pathogenic missense carriers. Similarly, prediction of mutation status with gene lists derived using Support Vector Machines was good for BRCAX samples without an LCS variant (82-94%, poor for BRCAX with an LCS (40-50%, and improved for pathogenic BRCA1/2 mutation carriers when the gene list used for prediction was appropriate to mutation effect being tested (71-100%. This study indicates that mutation effect, and presence of rare variants possibly associated with a low risk of cancer, must be considered in the development of array-based assays of variant pathogenicity.

  7. A novel missense mutation in the gene EDARADD associated with an unusual phenotype of hypohidrotic ectodermal dysplasia.

    Science.gov (United States)

    Wohlfart, Sigrun; Söder, Stephan; Smahi, Asma; Schneider, Holm

    2016-01-01

    Hypohidrotic ectodermal dysplasia (HED) is a rare disorder characterized by deficient development of structures derived from the ectoderm including hair, nails, eccrine glands, and teeth. HED forms that are caused by mutations in the genes EDA, EDAR, or EDARADD may show almost identical phenotypes, explained by a common signaling pathway. Proper interaction of the proteins encoded by these three genes is important for the activation of the NF-κB signaling pathway and subsequent transcription of the target genes. Mutations in the gene EDARADD are most rarely implicated in HED. Here we describe a novel missense mutation, c.367G>A (p.Asp123Asn), in this gene which did not appear to influence the interaction between EDAR and EDARADD proteins, but led to an impaired ability to activate NF-κB signaling. Female members of the affected family showed either unilateral or bilateral amazia. In addition, an affected girl developed bilateral ovarian teratomas, possibly associated with her genetic condition. © 2015 Wiley Periodicals, Inc.

  8. A novel missense mutation in CCDC88C activates the JNK pathway and causes a dominant form of spinocerebellar ataxia.

    Science.gov (United States)

    Tsoi, Ho; Yu, Allen C S; Chen, Zhefan S; Ng, Nelson K N; Chan, Anne Y Y; Yuen, Liz Y P; Abrigo, Jill M; Tsang, Suk Ying; Tsui, Stephen K W; Tong, Tony M F; Lo, Ivan F M; Lam, Stephen T S; Mok, Vincent C T; Wong, Lawrence K S; Ngo, Jacky C K; Lau, Kwok-Fai; Chan, Ting-Fung; Chan, H Y Edwin

    2014-09-01

    Spinocerebellar ataxias (SCAs) are a group of clinically and genetically diverse and autosomal-dominant disorders characterised by neurological deficits in the cerebellum. At present, there is no cure for SCAs. Of the different distinct subtypes of autosomal-dominant SCAs identified to date, causative genes for only a fraction of them are currently known. In this study, we investigated the cause of an autosomal-dominant SCA phenotype in a family that exhibits cerebellar ataxia and pontocerebellar atrophy along with a global reduction in brain volume. Whole-exome analysis revealed a missense mutation c.G1391A (p.R464H) in the coding region of the coiled-coil domain containing 88C (CCDC88C) gene in all affected individuals. Functional studies showed that the mutant form of CCDC88C activates the c-Jun N-terminal kinase (JNK) pathway, induces caspase 3 cleavage and triggers apoptosis. This study expands our understanding of the cause of autosomal-dominant SCAs, a group of heterogeneous congenital neurological conditions in humans, and unveils a link between the JNK stress pathway and cerebellar atrophy. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  9. Identification of a missense mutation in the tyrosinase gene in a Chinese family with oculocutaneous albinism type 1.

    Science.gov (United States)

    Lu, Qian; Yuan, Lamei; Xu, Hongbo; Huang, Xiangjun; Yang, Zhijian; Yi, Junhui; Ni, Bin; Chen, Yong; Deng, Hao

    2017-03-01

    Oculocutaneous albinism (OCA) is a group of heterogeneous and autosomal recessive disorders characterized by a reduction or complete loss of melanin biosynthesis in melanocytes. OCA type 1 (OCA1) is the most severe and common form of OCA, and is caused by mutations in the tyrosinase gene (TYR). The present study aimed to identify the genetic cause of OCA1 in a four‑generation consanguineous Chinese Han family. Complete physical examinations were performed and blood samples were collected from five members of the family and 100 unrelated healthy controls. Exome sequencing was conducted in the proband, followed by verification in other family members, using Sanger sequencing. Patients in the family presented with typical OCA1 features, including hypopigmentation of the skin and hair, and distinctive ocular changes. A homozygous missense variant, c.896G>A (p.R299H), in the TYR gene was identified in two patients, which co‑segregated with disease in the family. This variant was not present in the 100 healthy controls. These results expand the number of mutations identified to be responsible for OCA1 in the Chinese Han population, and may have implications for genetic counseling and clinical management of the disease.

  10. [A young boy with elevated aminotransferases in physical examination--Two novel missense mutations associated with Wilson's disease were found].

    Science.gov (United States)

    Zhu, Yu; Deng, Si-Yan; Wan, Chao-Min

    2015-07-01

    A 3-year-old boy had abnormal liver function, which was found in physical examination, for 5 months before admission. He had no symptoms such as anorexia, poor appetite, and jaundice, had normal growth and development, and showed no hepatosplenomegaly. Laboratory examination revealed significantly reduced ceruloplasmin (35 mg/L), as well as negative hepatotropic virus, cytomegalovirus, and Epstein-Barr virus. There were normal muscle enzymes, blood glucose, and blood ammonia and negative liver-specific autoantibodies. The boy had negative K-F ring and normal 24-hour urine copper (0.56 μmol/L). The ATP7B gene testing for the boy, his sister, and their parents detected two novel missense mutations in the boy and his sister, i.e., compound heterozygous mutations in exon 7 (c.2075T>C, p.L692P) and exon 13 (c.3044T>C, p.L1015P), which were inherited from their father and mother, respectively. Wilson's disease was confirmed by genetic diagnosis in the boy and his sister. The boy and his sister were given a low-copper diet. The boy was administered with penicillamine for decoppering and zinc supplement against copper uptake. His sister received zinc supplement alone because no clinical symptoms were observed. The boy showed normal liver function in the reexamination after 3 months of treatment.

  11. A novel common large genomic deletion and two new missense mutations identified in the Romanian phenylketonuria population.

    Science.gov (United States)

    Gemperle-Britschgi, Corinne; Iorgulescu, Daniela; Mager, Monica Alina; Anton-Paduraru, Dana; Vulturar, Romana; Thöny, Beat

    2016-01-15

    The mutation spectrum for the phenylalanine hydroxylase (PAH) gene was investigated in a cohort of 84 hyperphenylalaninemia (HPA) patients from Romania identified through newborn screening or neurometabolic investigations. Differential diagnosis identified 81 patients with classic PAH deficiency while 3 had tetrahydropterin-cofactor deficiency and/or remained uncertain due to insufficient specimen. PAH-genetic analysis included a combination of Sanger sequencing of exons and exon–intron boundaries, MLPA and NGS with genomic DNA, and cDNA analysis from immortalized lymphoblasts. A diagnostic efficiency of 99.4% was achieved, as for one allele (out of a total of 162 alleles) no mutation could be identified. The most prevalent mutation was p.Arg408Trp which was found in ~ 38% of all PKU alleles. Three novel mutations were identified, including the two missense mutations p.Gln226Lys and p.Tyr268Cys that were both disease causing by prediction algorithms, and the large genomic deletion EX6del7831 (c.509 + 4140_706 + 510del7831) that resulted in skipping of exon 6 based on PAH-cDNA analysis in immortalized lymphocytes. The genomic deletion was present in a heterozygous state in 12 patients, i.e. in ~ 8% of all the analyzed PKU alleles, and might have originated from a Romanian founder.

  12. Severe hypertriglyceridemia in a patient heterozygous for a lipoprotein lipase gene allele with two novel missense variants.

    Science.gov (United States)

    Kassner, Ursula; Salewsky, Bastian; Wühle-Demuth, Marion; Szijarto, Istvan Andras; Grenkowitz, Thomas; Binner, Priska; März, Winfried; Steinhagen-Thiessen, Elisabeth; Demuth, Ilja

    2015-09-01

    Rare monogenic hyperchylomicronemia is caused by loss-of-function mutations in genes involved in the catabolism of triglyceride-rich lipoproteins, including the lipoprotein lipase gene, LPL. Clinical hallmarks of this condition are eruptive xanthomas, recurrent pancreatitis and abdominal pain. Patients with LPL deficiency and severe or recurrent pancreatitis are eligible for the first gene therapy treatment approved by the European Union. Therefore the precise molecular diagnosis of familial hyperchylomicronemia may affect treatment decisions. We present a 57-year-old male patient with excessive hypertriglyceridemia despite intensive lipid-lowering therapy. Abdominal sonography showed signs of chronic pancreatitis. Direct DNA sequencing and cloning revealed two novel missense variants, c.1302A>T and c.1306G>A, in exon 8 of the LPL gene coexisting on the same allele. The variants result in the amino-acid exchanges p.(Lys434Asn) and p.(Gly436Arg). They are located in the carboxy-terminal domain of lipoprotein lipase that interacts with the glycosylphosphatidylinositol-anchored HDL-binding protein (GPIHBP1) and are likely of functional relevance. No further relevant mutations were found by direct sequencing of the genes for APOA5, APOC2, LMF1 and GPIHBP1. We conclude that heterozygosity for damaging mutations of LPL may be sufficient to produce severe hypertriglyceridemia and that chylomicronemia may be transmitted in a dominant manner, at least in some families.

  13. Whole Genome Sequencing Identifies a Missense Mutation in HES7 Associated with Short Tails in Asian Domestic Cats.

    Science.gov (United States)

    Xu, Xiao; Sun, Xin; Hu, Xue-Song; Zhuang, Yan; Liu, Yue-Chen; Meng, Hao; Miao, Lin; Yu, He; Luo, Shu-Jin

    2016-08-25

    Domestic cats exhibit abundant variations in tail morphology and serve as an excellent model to study the development and evolution of vertebrate tails. Cats with shortened and kinked tails were first recorded in the Malayan archipelago by Charles Darwin in 1868 and remain quite common today in Southeast and East Asia. To elucidate the genetic basis of short tails in Asian cats, we built a pedigree of 13 cats segregating at the trait with a founder from southern China and performed linkage mapping based on whole genome sequencing data from the pedigree. The short-tailed trait was mapped to a 5.6 Mb region of Chr E1, within which the substitution c. 5T > C in the somite segmentation-related gene HES7 was identified as the causal mutation resulting in a missense change (p.V2A). Validation in 245 unrelated cats confirmed the correlation between HES7-c. 5T > C and Chinese short-tailed feral cats as well as the Japanese Bobtail breed, indicating a common genetic basis of the two. In addition, some of our sampled kinked-tailed cats could not be explained by either HES7 or the Manx-related T-box, suggesting at least three independent events in the evolution of domestic cats giving rise to short-tailed traits.

  14. Screening of Missense SNPs in Coding Regions of COX-2 as a Key Enzyme Involved in Cancer

    Directory of Open Access Journals (Sweden)

    Sodabeh Jahanbakhsh-Godehkahriz

    2013-09-01

    Full Text Available Background & Objectives: Non-synonymous single nucleotide polymorphism (nsSNPs which results in disruption of protein function are used as markers in linkage and association of human proteins that might be involved in diseases and cancers .   Methods: To study the functional effect of nsSNP in cyclooxygenase-2 (COX2 amino acids, the nucleotide sequences encoding COX-2 gene in cancers were extracted from the NCBI (gi|223941909 data bank (283 cases and analyzed by SIFT, I-Mutant 2.0, SNP and GO, PANTHER and FASTSNP servers. These servers involve programs that predict the effects of amino acid substitution on protein function, stability and missense .   Results: COX-2 is an essential enzyme for the production of pro-inflammatory prostaglandins which are relevant to cancer development and progression. The substitutions in some positions such as R228H and S428A of COX-2 in most of cancers linked to reformed protein function through disruption in enzyme active site.   Conclusion: Amino acid substitutions as a consequence of COX-2 nsSNPs have important role in human disease. Substitutions which are located in catalytic domain are important for the enzymatic function of COX-2 and associated with higher expression of COX-2.

  15. A homozygous founder missense variant in arylsulfatase G abolishes its enzymatic activity causing atypical Usher syndrome in humans.

    Science.gov (United States)

    Khateb, Samer; Kowalewski, Björn; Bedoni, Nicola; Damme, Markus; Pollack, Netta; Saada, Ann; Obolensky, Alexey; Ben-Yosef, Tamar; Gross, Menachem; Dierks, Thomas; Banin, Eyal; Rivolta, Carlo; Sharon, Dror

    2018-01-04

    PurposeWe aimed to identify the cause of disease in patients suffering from a distinctive, atypical form of Usher syndrome.MethodsWhole-exome and genome sequencing were performed in five patients from three families of Yemenite Jewish origin, suffering from distinctive retinal degeneration phenotype and sensorineural hearing loss. Functional analysis of the wild-type and mutant proteins was performed in human fibrosarcoma cells.ResultsWe identified a homozygous founder missense variant, c.133G>T (p.D45Y) in arylsulfatase G (ARSG). All patients shared a distinctive retinal phenotype with ring-shaped atrophy along the arcades engirdling the fovea, resulting in ring scotoma. In addition, patients developed moderate to severe sensorineural hearing loss. Both vision and hearing loss appeared around the age of 40 years. The identified variant affected a fully conserved amino acid that is part of the catalytic site of the enzyme. Functional analysis of the wild-type and mutant proteins showed no basal activity of p.D45Y.ConclusionHomozygosity for ARSG-p.D45Y in humans leads to protein dysfunction, causing an atypical combination of late-onset Usher syndrome. Although there is no evidence for generalized clinical manifestations of lysosomal storage diseases in this set of patients, we cannot rule out the possibility that mild and late-onset symptoms may appear.GENETICS in MEDICINE advance online publication, 4 January 2018; doi:10.1038/gim.2017.227.

  16. Missense variants in AIMP1 gene are implicated in autosomal recessive intellectual disability without neurodegeneration

    OpenAIRE

    Iqbal, Zafar; P?ttmann, Lucia; Musante, Luciana; Razzaq, Attia; Zahoor, Muhammad Yasir; Hu, Hao; Wienker, Thomas F; Garshasbi, Masoud; Fattahi, Zohreh; Gilissen, Christian; Vissers, Lisenka ELM; de Brouwer, Arjan PM; Veltman, Joris A; Pfundt, Rolph; Najmabadi, Hossein

    2015-01-01

    AIMP1/p43 is a multifunctional non-catalytic component of the multisynthetase complex. The complex consists of nine catalytic and three non-catalytic proteins, which catalyze the ligation of amino acids to their cognate tRNA isoacceptors for use in protein translation. To date, two allelic variants in the AIMP1 gene have been reported as the underlying cause of autosomal recessive primary neurodegenerative disorder. Here, we present two consanguineous families from Pakistan and Iran, presenti...

  17. Squamous cell carcinoma arising in previously burned or irradiated skin

    International Nuclear Information System (INIS)

    Edwards, M.J.; Hirsch, R.M.; Broadwater, J.R.; Netscher, D.T.; Ames, F.C.

    1989-01-01

    Squamous cell carcinoma (SCC) arising in previously burned or irradiated skin was reviewed in 66 patients treated between 1944 and 1986. Healing of the initial injury was complicated in 70% of patients. Mean interval from initial injury to diagnosis of SCC was 37 years. The overwhelming majority of patients presented with a chronic intractable ulcer in previously injured skin. The regional relapse rate after surgical excision was very high, 58% of all patients. Predominant patterns of recurrence were in local skin and regional lymph nodes (93% of recurrences). Survival rates at 5, 10, and 20 years were 52%, 34%, and 23%, respectively. Five-year survival rates in previously burned and irradiated patients were not significantly different (53% and 50%, respectively). This review, one of the largest reported series, better defines SCC arising in previously burned or irradiated skin as a locally aggressive disease that is distinct from SCC arising in sunlight-damaged skin. An increased awareness of the significance of chronic ulceration in scar tissue may allow earlier diagnosis. Regional disease control and survival depend on surgical resection of all known disease and may require radical lymph node dissection or amputation

  18. A missense mutation in Grm6 reduces but does not eliminate mGluR6 expression or rod depolarizing bipolar cell function.

    Science.gov (United States)

    Peachey, Neal S; Hasan, Nazarul; FitzMaurice, Bernard; Burrill, Samantha; Pangeni, Gobinda; Karst, Son Yong; Reinholdt, Laura; Berry, Melissa L; Strobel, Marge; Gregg, Ronald G; McCall, Maureen A; Chang, Bo

    2017-08-01

    GRM6 encodes the metabotropic glutamate receptor 6 (mGluR6) used by retinal depolarizing bipolar cells (DBCs). Mutations in GRM6 lead to DBC dysfunction and underlie the human condition autosomal recessive complete congenital stationary night blindness. Mouse mutants for Grm6 are important models for this condition. Here we report a new Grm6 mutant, identified in an electroretinogram (ERG) screen of mice maintained at The Jackson Laboratory. The Grm6 nob8 mouse has a reduced-amplitude b-wave component of the ERG, which reflects light-evoked DBC activity. Sequencing identified a missense mutation that converts a highly conserved methionine within the ligand binding domain to leucine (p.Met66Leu). Consistent with prior studies of Grm6 mutant mice, the laminar size and structure in the Grm6 nob8 retina were comparable to control. The Grm6 nob8 phenotype is distinguished from other Grm6 mutants that carry a null allele by a reduced but not absent ERG b-wave, decreased but present expression of mGluR6 at DBC dendritic tips, and mislocalization of mGluR6 to DBC somas. Consistent with a reduced but not absent b-wave, there were a subset of retinal ganglion cells whose responses to light onset have times to peak within the range of those in control retinas. These data indicate that the p.Met66Leu mutant mGluR6 is trafficked less than control. However, the mGluR6 that is localized to the DBC dendritic tips is able to initiate DBC signal transduction. The Grm6 nob8 mouse extends the Grm6 allelic series and will be useful for elucidating the role of mGluR6 in DBC signal transduction and in human disease. NEW & NOTEWORTHY This article describes a mouse model of the human disease complete congenital stationary night blindness in which the mutation reduces but does not eliminate GRM6 expression and bipolar cell function, a distinct phenotype from that seen in other Grm6 mouse models.

  19. Identification of Missense Mutation (I12T in the BSND Gene and Bioinformatics Analysis

    Directory of Open Access Journals (Sweden)

    Hina Iqbal

    2011-01-01

    Full Text Available Nonsyndromic hearing loss is a paradigm of genetic heterogeneity with 85 loci and 39 nuclear disease genes reported so far. Mutations of BSND have been shown to cause Bartter syndrome type IV, characterized by significant renal abnormalities and deafness and nonsyndromic nearing loss. We studied a Pakistani consanguineous family. Clinical examinations of affected individuals did not reveal the presence of any associated signs, which are hallmarks of the Bartter syndrome type IV. Linkage analysis identified an area of 18.36 Mb shared by all affected individuals between markers D1S2706 and D1S1596. A maximum two-point LOD score of 2.55 with markers D1S2700 and multipoint LOD score of 3.42 with marker D1S1661 were obtained. BSND mutation, that is, p.I12T, cosegregated in all extant members of our pedigree. BSND mutations can cause nonsyndromic hearing loss, and it is a second report for this mutation. The respected protein, that is, BSND, was first modeled, and then, the identified mutation was further analyzed by using different bioinformatics tools; finally, this protein and its mutant was docked with CLCNKB and REN, interactions of BSND, respectively.

  20. A novel lipoprotein lipase gene missense mutation in Chinese patients with severe hypertriglyceridemia and pancreatitis

    Science.gov (United States)

    2014-01-01

    Background Alterations or mutations in the lipoprotein lipase (LPL) gene contribute to severe hypertriglyceridemia (HTG). This study reported on two patients in a Chinese family with LPL gene mutations and severe HTG and acute pancreatitis. Methods Two patients with other five family members were included in this study for DNA-sequences of hyperlipidemia-related genes (such as LPL, APOC2, APOA5, LMF1, and GPIHBP1) and 43 healthy individuals and 70 HTG subjects were included for the screening of LPL gene mutations. Results Both patients were found to have a compound heterozygote for a novel LPL gene mutation (L279V) and a known mutation (A98T). Furthermore, one HTG subject out of 70 was found to carry this novel LPL L279V mutation. Conclusions The data from this study showed that compound heterozygote mutations of A98T and L279V inactivate lipoprotein lipase enzymatic activity and contribute to severe HTG and acute pancreatitis in two Chinese patients. Further study will investigate how these LPL gene mutations genetically inactivate the LPL enzyme. PMID:24646025

  1. Missense mutation in CAPN1 is associated with spinocerebellar ataxia in the Parson Russell Terrier dog breed.

    Directory of Open Access Journals (Sweden)

    Oliver P Forman

    Full Text Available Spinocerebellar ataxia (SCA in the Parson Russell Terrier (PRT dog breed is a disease of progressive incoordination of gait and loss of balance. Clinical signs usually become notable between 6 and 12 months of age with affected dogs presenting with symmetric spinocerebellar ataxia particularly evident in the pelvic limbs. The degree of truncal ataxia, pelvic limb hypermetria and impaired balance is progressive, particularly during the initial months of disease. A certain degree of stabilisation as well as intermittent worsening may occur. At the later stages of the disease ambulation often becomes difficult, with owners often electing to euthanise affected dogs on welfare grounds. Using a GWAS approach and target-enriched massively-parallel sequencing, a strongly associated non-synonymous SNP in the CAPN1 gene, encoding the calcium dependent cysteine protease calpain1 (mu-calpain, was identified. The SNP is a missense mutation causing a cysteine to tyrosine substitution at residue 115 of the CAPN1 protein. Cysteine 115 is a highly conserved residue and forms a key part of a catalytic triad of amino acids that are crucial to the enzymatic activity of cysteine proteases. The CAPN1 gene shows high levels of expression in the brain and nervous system and roles for the protein in both neuronal necrosis and maintenance have been suggested. Given the functional implications and high level of conservation observed across species, the CAPN1 variant represents a provocative candidate for the cause of SCA in the PRT and a novel potential cause of ataxia in humans.

  2. A Comprehensive Functional Analysis of NTRK1 Missense Mutations Causing Hereditary Sensory and Autonomic Neuropathy Type IV (HSAN IV).

    Science.gov (United States)

    Shaikh, Samiha S; Chen, Ya-Chun; Halsall, Sally-Anne; Nahorski, Michael S; Omoto, Kiyoyuki; Young, Gareth T; Phelan, Anne; Woods, Christopher Geoffrey

    2017-01-01

    Hereditary sensory and autonomic neuropathy type IV (HSAN IV) is an autosomal recessive disorder characterized by a complete lack of pain perception and anhidrosis. Here, we studied a cohort of seven patients with HSAN IV and describe a comprehensive functional analysis of seven novel NTRK1 missense mutations, c.1550G >A, c.1565G >A, c.1970T >C, c.2096T >C, c.2254T >A, c.2288G >C, and c.2311C >T, corresponding to p.G517E, p.G522E, p.L657P, p.I699T, p.C752S, p.C763S, and p.R771C, all of which were predicted pathogenic by in silico analysis. The results allowed us to assess the pathogenicity of each mutation and to gain novel insights into tropomyosin receptor kinase A (TRKA) downstream signaling. Each mutation was systematically analyzed for TRKA glycosylation states, intracellular and cell membrane expression patterns, nerve growth factor stimulated TRKA autophosphorylation, TRKA-Y496 phosphorylation, PLCγ activity, and neurite outgrowth. We showed a diverse range of functional effects: one mutation appeared fully functional, another had partial activity in all assays, one mutation affected only the PLCγ pathway and four mutations were proved null in all assays. Thus, we conclude that complete abolition of TRKA kinase activity is not the only pathogenic mechanism underlying HSAN IV. By corollary, the assessment of the clinical pathogenicity of HSAN IV mutations is more complex than initially predicted and requires a multifaceted approach. © 2016 WILEY PERIODICALS, INC.

  3. Identification of rare heterozygous missense mutations in FANCA in esophageal atresia patients using next-generation sequencing.

    Science.gov (United States)

    Feng, Yu; Chen, Runsen; Da, Min; Qian, Bo; Mo, Xuming

    2018-06-30

    Esophageal atresia and tracheoesophageal fistula (EA/TEF) are relatively common malformations in newborns, but the etiology of EA/TEF remains unknown. Fanconi anemia (FA) complementation group A (FANCA) is a key component of the FA core complex and is essential for the activation of the DNA repair pathway. The middle region (amino acids 674-1208) of FANCA is required for its interaction with FAAP20. We performed targeted sequencing of this binding region of FANCA (exons 23-36) in 40 EA/TEF patients. We also investigated the effect of the p.A958V mutation on the protein-protein interaction between FANCA and FAAP20 using an in vitro binding assay and co-immunoprecipitation. Immunolocalization analysis was performed to investigate the subcellular localization of FANCA, and tissue sections and immunohistochemistry were used to explore the expression of FANCA. We identified four rare missense variants in the FANCA binding region. FANCA mutations were significantly overrepresented in EA/TEF patients compared with 4300 control subjects from the NHLBI-ESP project (Fisher's exact p = 2.17 × 10 -5 , odds ratio = 31.75). p.A958V, a novel de novo mutation in the FANCA gene, was identified in one patient with EA/TEF. We provide further evidence that the p.A958V mutation reduces the binding affinity of FANCA for FAAP20. Interestingly, the p.A958V mutation impaired the nuclear localization of the FANCA protein expressed in HeLa cells. We found that FANCA was more highly expressed in stratified squamous epithelium than in smooth muscle. In conclusion, mutations in the FANCA gene are associated with EA/TEF in humans. Copyright © 2018. Published by Elsevier B.V.

  4. A Homozygous Missense Mutation in TGM5 Abolishes Epidermal Transglutaminase 5 Activity and Causes Acral Peeling Skin Syndrome

    Science.gov (United States)

    Cassidy, Andrew J.; van Steensel, Maurice A. M.; Steijlen, Peter M.; van Geel, Michel; Velden, Jaap van der; Morley, Susan M.; Terrinoni, Alessandro; Melino, Gerry; Candi, Eleonora; McLean, W. H. Irwin

    2005-01-01

    Peeling skin syndrome is an autosomal recessive genodermatosis characterized by the shedding of the outer epidermis. In the acral form, the dorsa of the hands and feet are predominantly affected. Ultrastructural analysis has revealed tissue separation at the junction between the granular cells and the stratum corneum in the outer epidermis. Genomewide linkage analysis in a consanguineous Dutch kindred mapped the gene to 15q15.2 in the interval between markers D15S1040 and D15S1016. Two homozygous missense mutations, T109M and G113C, were found in TGM5, which encodes transglutaminase 5 (TG5), in all affected persons in two unrelated families. The mutation was present on the same haplotype in both kindreds, indicating a probable ancestral mutation. TG5 is strongly expressed in the epidermal granular cells, where it cross-links a variety of structural proteins in the terminal differentiation of the epidermis to form the cornified cell envelope. An established, in vitro, biochemical cross-linking assay revealed that, although T109M is not pathogenic, G113C completely abolishes TG5 activity. Three-dimensional modeling of TG5 showed that G113C lies close to the catalytic domain, and, furthermore, that this glycine residue is conserved in all known transglutaminases, which is consistent with pathogenicity. Other families with more-widespread peeling skin phenotypes lacked TGM5 mutations. This study identifies the first causative gene in this heterogeneous group of skin disorders and demonstrates that the protein cross-linking function performed by TG5 is vital for maintaining cell-cell adhesion between the outermost layers of the epidermis. PMID:16380904

  5. A COLQ missense mutation in Labrador Retrievers having congenital myasthenic syndrome.

    Directory of Open Access Journals (Sweden)

    Caitlin J Rinz

    Full Text Available Congenital myasthenic syndromes (CMSs are heterogeneous neuromuscular disorders characterized by skeletal muscle weakness caused by disruption of signal transmission across the neuromuscular junction (NMJ. CMSs are rarely encountered in veterinary medicine, and causative mutations have only been identified in Old Danish Pointing Dogs and Brahman cattle to date. Herein, we characterize a novel CMS in 2 Labrador Retriever littermates with an early onset of marked generalized muscle weakness. Because the sire and dam share 2 recent common ancestors, CMS is likely the result of recessive alleles inherited identical by descent (IBD. Genome-wide SNP profiles generated from the Illumina HD array for 9 nuclear family members were used to determine genomic inheritance patterns in chromosomal regions encompassing 18 functional candidate genes. SNP haplotypes spanning 3 genes were consistent with autosomal recessive transmission, and microsatellite data showed that only the segment encompassing COLQ was inherited IBD. COLQ encodes the collagenous tail of acetylcholinesterase, the enzyme responsible for termination of signal transduction in the NMJ. Sequences from COLQ revealed a variant in exon 14 (c.1010T>C that results in the substitution of a conserved amino acid (I337T within the C-terminal domain. Both affected puppies were homozygous for this variant, and 16 relatives were heterozygous, while 288 unrelated Labrador Retrievers and 112 dogs of other breeds were wild-type. A recent study in which 2 human CMS patients were found to be homozygous for an identical COLQ mutation (c.1010T>C; I337T provides further evidence that this mutation is pathogenic. This report describes the first COLQ mutation in canine CMS and demonstrates the utility of SNP profiles from nuclear family members for the identification of private mutations.

  6. A missense mutation in MKRN3 in a Danish girl with central precocious puberty and her brother with early puberty

    DEFF Research Database (Denmark)

    Känsäkoski, Johanna; Raivio, Taneli; Juul, Anders

    2015-01-01

    BACKGROUND: Idiopathic central precocious puberty (ICPP) results from the premature reactivation of the hypothalamic-pituitary-gonadal axis leading to development of secondary sexual characteristics prior to 8 y in girls or 9 y in boys. Since the initial discovery of mutations in the maternally...... hypothalamic complementary DNA (cDNA) was investigated by PCR. RESULTS: One paternally inherited rare variant, c.1034G>A (p.Arg345His), was identified in one girl with ICPP and in her brother with early puberty. The variant is predicted to be deleterious by three different in silico prediction programs....... Expression of MKRN3 was confirmed in adult human hypothalamus. CONCLUSION: Our results are in line with previous studies in which paternally inherited MKRN3 mutations have been found both in males and in females with ICPP or early puberty. Our report further expands the set of MKRN3 mutations identified...

  7. A missense mutation in MKRN3 in a Danish girl with central precocious puberty and her brother with early puberty.

    Science.gov (United States)

    Känsäkoski, Johanna; Raivio, Taneli; Juul, Anders; Tommiska, Johanna

    2015-12-01

    Idiopathic central precocious puberty (ICPP) results from the premature reactivation of the hypothalamic-pituitary-gonadal axis leading to development of secondary sexual characteristics prior to 8 y in girls or 9 y in boys. Since the initial discovery of mutations in the maternally imprinted MKRN3 gene in 2013, several case reports have described mutations in this gene in ICPP patients from different populations, highlighting the importance of MKRN3 as a regulator of pubertal onset. We screened 29 Danish girls with ICPP for mutations in MKRN3. Expression of MKRN3 in human hypothalamic complementary DNA (cDNA) was investigated by PCR. One paternally inherited rare variant, c.1034G>A (p.Arg345His), was identified in one girl with ICPP and in her brother with early puberty. The variant is predicted to be deleterious by three different in silico prediction programs. Expression of MKRN3 was confirmed in adult human hypothalamus. Our results are in line with previous studies in which paternally inherited MKRN3 mutations have been found both in males and in females with ICPP or early puberty. Our report further expands the set of MKRN3 mutations identified in ICPP patients across diverse populations, thus supporting the major regulatory function of MKRN3 in pubertal onset.

  8. [beta]-hexosaminidase isozymes from cells cotransfected with [alpha] and [beta] cDNA constructs: Analysis of the [alpha]-subunit missense mutation associated with the adult form of Tay-Sachs disease

    Energy Technology Data Exchange (ETDEWEB)

    Brown, C.A.; Mahuran, D.J. (Univ. of Toronto (Canada))

    1993-08-01

    In vitro mutagenesis and transient expression in COS cells has been used to associate a missense mutation with a clinical or biochemical phenotype. Mutations affecting the [alpha]-subunit of [beta]-hexosaminidase A ([alpha][beta]) (E.C.3.2.1.52) result in Tay-Sachs disease. Because hexosaminidase A is heterodimeric, analysis of [alpha]-chain mutations is not straightforward. The authors examine three approaches utilizing previously identified mutations affecting [alpha]-chain folding. These involve transfection of (1) the [alpha] cDNA alone; (2) a [beta] cDNA construct encoding a [beta]-subunit substituted at a position homologous to that of the [alpha]-subunit, and (3) both [alpha] and [beta] cDNAs. The latter two procedures amplified residual activity levels over that of patient samples, an effect not previously found with mutations affecting an [open quotes]active[close quotes] [alpha]Arg residue. This effect may help to discriminate between protein-folding and active-site mutations. The authors conclude that, with proper controls, the latter method of cotransfection can be used to evaluate the effects and perhaps to predict the clinical course of some [alpha]-chain mutations. Using this technique, they demonstrate that the adult-onset Tay-Sachs mutation, [alpha]Gly[yields]Ser[sup 269], does not directly affect [alpha][beta] dimerization but exerts an indirect effect on the dimer through destabilizing the folded [alpha]-subunit at physiological temperatures. Two other [alpha] mutations linked to more severe phenotypes appear to inhibit the initial folding of the subunit. 36 refs., 2 figs., 5 tabs.

  9. High-Grade Leiomyosarcoma Arising in a Previously Replanted Limb

    Directory of Open Access Journals (Sweden)

    Tiffany J. Pan

    2015-01-01

    Full Text Available Sarcoma development has been associated with genetics, irradiation, viral infections, and immunodeficiency. Reports of sarcomas arising in the setting of prior trauma, as in burn scars or fracture sites, are rare. We report a case of a leiomyosarcoma arising in an arm that had previously been replanted at the level of the elbow joint following traumatic amputation when the patient was eight years old. He presented twenty-four years later with a 10.8 cm mass in the replanted arm located on the volar forearm. The tumor was completely resected and pathology examination showed a high-grade, subfascial spindle cell sarcoma diagnosed as a grade 3 leiomyosarcoma with stage pT2bNxMx. The patient underwent treatment with brachytherapy, reconstruction with a free flap, and subsequently chemotherapy. To the best of our knowledge, this is the first case report of leiomyosarcoma developing in a replanted extremity. Development of leiomyosarcoma in this case could be related to revascularization, scar formation, or chronic injury after replantation. The patient remains healthy without signs of recurrence at three-year follow-up.

  10. A novel missense mutation pattern of the GCH1 gene in dopa-responsive dystonia Novo padrão de mutação missense no gene GCH1 na distonia dopa-responsiva

    Directory of Open Access Journals (Sweden)

    Rosana H. Scola

    2007-12-01

    Full Text Available Dopa-responsive dystonia (DRD is an inherited metabolic disorder now classified as DYT5 with two different biochemical defects: autosomal dominant GTP cyclohydrolase 1 (GCH1 deficiency or autosomal recessive tyrosine hydroxylase deficiency. We report the case of a 10-years-old girl with progressive generalized dystonia and gait disorder who presented dramatic response to levodopa. The phenylalanine to tyrosine ratio was significantly higher after phenylalanine loading test. This condition had two different heterozygous mutations in the GCH1 gene: the previously reported P23L mutation and a new Q182E mutation. The characteristics of the DRD and the molecular genetic findings are discussed.Distonia dopa-responsiva (DRD, classificada como DYT5, é um erro inato do metabolismo que pode ser causado por dois diferentes tipos de defeito bioquímico: deficiência de GTP ciclo-hidrolase 1 (GCH1 (autossômica dominante ou de tirosina hidroxilase (autossômica recessiva. Descrevemos o caso de menina de 10 anos com distonia generalizada progressiva e alteração da marcha com importante melhora após uso de levodopa. A relação fenilalanina/tirosina estava aumentada após teste de sobrecarga com fenilalanina. O estudo molecular mostrou que o paciente apresenta uma combinação hererozigótica de mutação no gene GCH1: a já conhecida mutação P23L e uma nova mutação Q182E. Discutem-se as características da DRD e as alterações genéticas possíveis.

  11. GM2 gangliosidosis associated with a HEXA missense mutation in Japanese Chin dogs: a potential model for Tay Sachs disease.

    Science.gov (United States)

    Sanders, Douglas N; Zeng, Rong; Wenger, David A; Johnson, Gary S; Johnson, Gayle C; Decker, Jared E; Katz, Martin L; Platt, Simon R; O'Brien, Dennis P

    2013-01-01

    GM2 gangliosidosis is a fatal lysosomal storage disease caused by a deficiency of β-hexosaminidase (EC 3.2.1.52). There are two major isoforms of the enzyme: hexosaminidase A composed of an α and a β subunit (encoded by HEXA and HEXB genes, respectively); and, hexosaminidase B composed of two β subunits. Hexosaminidase A requires an activator protein encoded by GM2A to catabolize GM2 ganglioside, but even in the absence of the activator protein, it can hydrolyze the synthetic substrates commonly used to assess enzyme activity. GM2 gangliosidosis has been reported in Japanese Chin dogs, and we identified the disease in two related Japanese Chin dogs based on clinical signs, histopathology and elevated brain GM2 gangliosides. As in previous reports, we found normal or elevated hexosaminidase activity when measured with the synthetic substrates. This suggested that the canine disease is analogous to human AB variant of G(M2) gangliosidosis, which results from mutations in GM2A. However, only common neutral single nucleotide polymorphisms were found upon sequence analysis of the canine ortholog of GM2A from the affected Japanese Chins. When the same DNA samples were used to sequence HEXA, we identified a homozygous HEXA:c967G>A transition which predicts a p.E323K substitution. The glutamyl moiety at 323 is known to make an essential contribution to the active site of hexosaminidase A, and none of the 128 normal Japanese Chins and 92 normal dogs of other breeds that we tested was homozygous for HEXA:c967A. Thus it appears that the HEXA:c967G>A transition is responsible for the GM2 gangliosidosis in Japanese Chins. Copyright © 2012 Elsevier Inc. All rights reserved.

  12. A missense mutation in ALDH1A3 causes isolated microphthalmia/anophthalmia in nine individuals from an inbred Muslim kindred.

    Science.gov (United States)

    Mory, Adi; Ruiz, Francesc X; Dagan, Efrat; Yakovtseva, Evgenia A; Kurolap, Alina; Parés, Xavier; Farrés, Jaume; Gershoni-Baruch, Ruth

    2014-03-01

    Nine affected individuals with isolated anophthalmia/microphthalmia from a large Muslim-inbred kindred were investigated. Assuming autosomal-recessive mode of inheritance, whole-genome linkage analysis, on DNA samples from four affected individuals, was undertaken. Homozygosity mapping techniques were employed and a 1.5-Mbp region, homozygous in all affected individuals, was delineated. The region contained nine genes, one of which, aldehyde dehydrogenase 1 (ALDH1A3), was a clear candidate. This gene seems to encode a key enzyme in the formation of a retinoic-acid gradient along the dorsoventral axis during an early eye development and the development of the olfactory system. Sanger sequence analysis revealed a missense mutation, causing a substitution of valine (Val) to methionine (Met) at position 71. Analyzing the p.Val71Met missense mutation using standard open access software (MutationTaster online, PolyPhen, SIFT/PROVEAN) predicts this variant to be damaging. Enzymatic activity, studied in vitro, showed no changes between the mutated and the wild-type ALDH1A3 protein.

  13. Identification of a Novel Heterozygous Missense Mutation in the CACNA1F Gene in a Chinese Family with Retinitis Pigmentosa by Next Generation Sequencing

    Directory of Open Access Journals (Sweden)

    Qi Zhou

    2015-01-01

    Full Text Available Background. Retinitis pigmentosa (RP is an inherited retinal degenerative disease, which is clinically and genetically heterogeneous, and the inheritance pattern is complex. In this study, we have intended to study the possible association of certain genes with X-linked RP (XLRP in a Chinese family. Methods. A Chinese family with RP was recruited, and a total of seven individuals were enrolled in this genetic study. Genomic DNA was isolated from peripheral leukocytes, and used for the next generation sequencing (NGS. Results. The affected individual presented the clinical signs of XLRP. A heterozygous missense mutation (c.1555C>T, p.R519W was identified by NGS in exon 13 of the CACNA1F gene on X chromosome, and was confirmed by Sanger sequencing. It showed perfect cosegregation with the disease in the family. The mutation at this position in the CACNA1F gene of RP was found novel by database searching. Conclusion. By using NGS, we have found a novel heterozygous missense mutation (c.1555C>T, p.R519W in CACNA1F gene, which is probably associated with XLRP. The findings might provide new insights into the cause and diagnosis of RP, and have implications for genetic counseling and clinical management in this family.

  14. Clinical and genetic investigation of a Japanese family with cardiac fabry disease. Identification of a novel α-galactosidase A missense mutation (G195V).

    Science.gov (United States)

    Nakagawa, Naoki; Maruyama, Hiroki; Ishihara, Takayuki; Seino, Utako; Kawabe, Jun-ichi; Takahashi, Fumihiko; Kobayashi, Motoi; Yamauchi, Atsushi; Sasaki, Yukie; Sakamoto, Naka; Ota, Hisanobu; Tanabe, Yasuko; Takeuchi, Toshiharu; Takenaka, Toshihiro; Kikuchi, Kenjiro; Hasebe, Naoyuki

    2011-01-01

    Fabry disease is an X-linked lysosomal storage disorder caused by mutations of the α-galactosidase A gene (GLA), and the disease is a relatively prevalent cause of left ventricular hypertrophy mimicking idiopathic hypertrophic cardiomyopathy. We assessed clinically 5 patients of a three-generation family and also searched for GLA mutations in 10 family members. The proband had left ventricular hypertrophy with localized thinning in the basal posterior wall and late gadolinium enhancement (LGE) in the near-circumferential wall in cardiovascular magnetic resonance images and her sister had vasospastic angina pectoris without organic stenosis of the coronary arteries. LGE notably appeared in parallel with decreased α-galactosidase A activity and increased NT-pro BNP in our patients. We detected a new GLA missense mutation (G195V) in exon 4, resulting in a glycine-to-valine substitution. Of the 10 family members, 5 family members each were positive and negative for this mutation. These new data extend our clinical and molecular knowledge of GLA gene mutations and confirm that a novel missense mutation in the GLA gene is important not only for a precise diagnosis of heterozygous status, but also for confirming relatives who are negative for this mutation.

  15. Orphan missense mutations in the cystic fibrosis transmembrane conductance regulator: A three-step biological approach to establishing a correlation between genotype and phenotype.

    Science.gov (United States)

    Fresquet, Fleur; Clement, Romain; Norez, Caroline; Sterlin, Adélaïde; Melin, Patricia; Becq, Frédéric; Kitzis, Alain; Thoreau, Vincent; Bilan, Frédéric

    2011-09-01

    More than 1860 mutations have been found within the human cystic fibrosis transmembrane conductance regulator (CFTR) gene sequence. These mutations can be classified according to their degree of severity in CF disease. Although the most common mutations are well characterized, few data are available for rare mutations. Thus, genetic counseling is particularly difficult when fetuses or patients with CF present these orphan variations. We describe a three-step in vitro assay that can evaluate rare missense CFTR mutation consequences to establish a correlation between genotype and phenotype. By using a green fluorescent protein-tagged CFTR construct, we expressed mutated proteins in COS-7 cells. CFTR trafficking was visualized by confocal microscopy, and the cellular localization of CFTR was determined using intracellular markers. We studied the CFTR maturation process using Western blot analysis and evaluated CFTR channel activity by automated iodide efflux assays. Of six rare mutations that we studied, five have been isolated in our laboratory. The cellular and functional impact that we observed in each case was compared with the clinical data concerning the patients in whom we encountered these mutations. In conclusion, we propose that performing this type of analysis for orphan CFTR missense mutations can improve CF genetic counseling. Copyright © 2011 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

  16. Two Thai families with Norrie disease (ND): association of two novel missense mutations with severe ND phenotype, seizures, and a manifesting carrier.

    Science.gov (United States)

    Yamada, K; Limprasert, P; Ratanasukon, M; Tengtrisorn, S; Yingchareonpukdee, J; Vasiknanonte, P; Kitaoka, T; Ghadami, M; Niikawa, N; Kishino, T

    2001-04-15

    We describe two Thai families with Norrie disease (ND) in three generations, including 10 affected males and one manifesting female. All affected males in each family had severely defective eye development with complete loss of vision. In addition, three male patients (one from family 1 and two from family 2) suffered from epilepsy, and one female carrier from one family manifested blindness with phthisis bulbi in her right eye. Mutation analysis of the ND gene (NDP) revealed two different novel missense mutations (L16P and S75P) that co-segregated with ND in each family, suggesting that the newly appearing proline at codon 16 or codon 75 alters the conformation of the ND protein and contributes to the severe phenotype of ND in each family. Other studies suggest that epileptic seizures or growth retardation that is associated with ND is the consequence of loss of contiguous genes, because most such patients had deletions extending beyond the Norrie locus. Our finding that the three affected males in the two families with the missense mutations had epilepsy does not support a contiguous gene effect, but favors the pleiotropism of NDP, at least as far as the epileptic manifestation is concerned. The unilateral blindness in the female carrier may have been due to non-random X-inactivation. Copyright 2001 Wiley-Liss, Inc.

  17. Cerebral Metastasis from a Previously Undiagnosed Appendiceal Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Antonio Biroli

    2012-01-01

    Full Text Available Brain metastases arise in 10%–40% of all cancer patients. Up to one third of the patients do not have previous cancer history. We report a case of a 67-years-old male patient who presented with confusion, tremor, and apraxia. A brain MRI revealed an isolated right temporal lobe lesion. A thorax-abdomen-pelvis CT scan showed no primary lesion. The patient underwent a craniotomy with gross-total resection. Histopathology revealed an intestinal-type adenocarcinoma. A colonoscopy found no primary lesion, but a PET-CT scan showed elevated FDG uptake in the appendiceal nodule. A right hemicolectomy was performed, and the specimen showed a moderately differentiated mucinous appendiceal adenocarcinoma. Whole brain radiotherapy was administrated. A subsequent thorax-abdomen CT scan revealed multiple lung and hepatic metastasis. Seven months later, the patient died of disease progression. In cases of undiagnosed primary lesions, patients present in better general condition, but overall survival does not change. Eventual identification of the primary tumor does not affect survival. PET/CT might be a helpful tool in detecting lesions of the appendiceal region. To the best of our knowledge, such a case was never reported in the literature, and an appendiceal malignancy should be suspected in patients with brain metastasis from an undiagnosed primary tumor.

  18. Gastrointestinal tolerability with ibandronate after previous weekly bisphosphonate treatment.

    Science.gov (United States)

    Derman, Richard; Kohles, Joseph D; Babbitt, Ann

    2009-01-01

    Data from two open-label trials (PRIOR and CURRENT) of women with postmenopausal osteoporosis or osteopenia were evaluated to assess whether monthly oral and quarterly intravenous (IV) ibandronate dosing improved self-reported gastrointestinal (GI) tolerability for patients who had previously experienced GI irritation with bisphosphonate (BP) use. In PRIOR, women who had discontinued daily or weekly BP treatment due to GI intolerance received monthly oral or quarterly IV ibandronate for 12 months. The CURRENT subanalysis included women receiving weekly BP treatment who switched to monthly oral ibandronate for six months. GI symptom severity and frequency were assessed using the Osteoporosis Patient Satisfaction Questionnaire. In PRIOR, mean GI tolerability scores increased significantly at month 1 from screening for both treatment groups (oral: 79.3 versus 54.1; IV: 84.4 versus 51.0; p 90% at Month 10). In the CURRENT subanalysis >60% of patients reported improvements in heartburn or acid reflux and >70% indicated improvement in other stomach upset at month 6. Postmenopausal women with GI irritability with daily or weekly BPs experienced improvement in symptoms with extended dosing monthly or quarterly ibandronate compared with baseline.

  19. A novel KCNQ1 nonsense variant in the isoform-specific first exon causes both jervell and Lange-Nielsen syndrome 1 and long QT syndrome 1: a case report.

    Science.gov (United States)

    Nishimura, Motoi; Ueda, Marehiko; Ebata, Ryota; Utsuno, Emi; Ishii, Takuma; Matsushita, Kazuyuki; Ohara, Osamu; Shimojo, Naoki; Kobayashi, Yoshio; Nomura, Fumio

    2017-06-08

    According to previous KCNQ1 (potassium channel, voltage gated, KQT-like subfamily, member 1) gene screening studies, missense variants, but not nonsense or frame-shift variants, cause the majority of long QT syndrome (LQTS; Romano-Ward syndrome [RWS]) 1 cases. Several missense variants are reported to cause RWS by a dominant-negative mechanism, and some KCNQ1 variants can cause both Jervell and Lange-Nielsen Syndrome (JLNS; in an autosomal recessive manner) and LQTS1 (in an autosomal dominant manner), while other KCNQ1 variants cause only JLNS. The human KCNQ1 gene is known to have two transcript isoforms (kidney isoform and pancreas isoform), and both isoforms can form a functional cardiac potassium channel. Here, we report a novel nonsense KCNQ1 variant causing not only JLNS, but also significant QTc prolongation identical to RWS in an autosomal dominant manner. Our case study supports that haploinsufficiency in the KCNQ1 gene is causative of significant QTc prolongation identical to RWS. Interestingly, the nonsense variant (NM_000218.2:c.115G > T [p.Glu39X]) locates in exon 1a of KCNQ1, which is a kidney-isoform specific exon. The variant is located closer to the N-terminus than previously identified nonsense or frame-shift variants. To the best of our knowledge, this is the first report showing that a nonsense variant in exon 1a of KCNQ1, which is the kidney-isoform specific exon, causes JLNS. Our findings may be informative to the genetic pathogenesis of RWS and JLNS caused by KCNQ1 variants.

  20. Gastrointestinal tolerability with ibandronate after previous weekly bisphosphonate treatment

    Directory of Open Access Journals (Sweden)

    Richard Derman

    2009-09-01

    Full Text Available Richard Derman1, Joseph D Kohles2, Ann Babbitt31Department of Obstetrics and Gynecology, Christiana Hospital, Newark, DE, USA; 2Roche, Nutley, NJ, USA; 3Greater Portland Bone and Joint Specialists, Portland, ME, USAAbstract: Data from two open-label trials (PRIOR and CURRENT of women with postmenopausal osteoporosis or osteopenia were evaluated to assess whether monthly oral and quarterly intravenous (IV ibandronate dosing improved self-reported gastrointestinal (GI tolerability for patients who had previously experienced GI irritation with bisphosphonate (BP use. In PRIOR, women who had discontinued daily or weekly BP treatment due to GI intolerance received monthly oral or quarterly IV ibandronate for 12 months. The CURRENT subanalysis included women receiving weekly BP treatment who switched to monthly oral ibandronate for six months. GI symptom severity and frequency were assessed using the Osteoporosis Patient Satisfaction Questionnaire™. In PRIOR, mean GI tolerability scores increased significantly at month 1 from screening for both treatment groups (oral: 79.3 versus 54.1; IV: 84.4 versus 51.0; p < 0.001 for both. Most patients reported improvement in GI symptom severity and frequency from baseline at all post-screening assessments (>90% at Month 10. In the CURRENT subanalysis >60% of patients reported improvements in heartburn or acid reflux and >70% indicated improvement in other stomach upset at month 6. Postmenopausal women with GI irritability with daily or weekly BPs experienced improvement in symptoms with extended dosing monthly or quarterly ibandronate compared with baseline.Keywords: ibandronate, osteoporosis, bisphosphonate, gastrointestinal

  1. Bilateral orbital infarction and retinal detachment in a previously undiagnosed sickle cell hemoglobinopathy African child

    Science.gov (United States)

    Helen, Onakpoya Oluwatoyin; Ajite, K. O.; Oyelami, O. A.; Asaleye, C. M.; Adeoye, A. O.

    2013-01-01

    Bone infarction involving the orbit in sickle cell disease is not common. Bilateral orbital infarction in a previously undiagnosed sickle cell hemoglobinopathy has not been previously reported. In this report, we present a case of an 11-year-old previously undiagnosed sickle cell disease Nigerian girl with severe acute bilateral orbital infarction and retinal detachment to highlight that hemoglobinopathy induced orbital infarction should be considered in African children with acute onset proptosis with or without previous history of sickle cell hemoglobinopathy. PMID:23901183

  2. Impact of previously disadvantaged land-users on sustainable ...

    African Journals Online (AJOL)

    Impact of previously disadvantaged land-users on sustainable agricultural ... about previously disadvantaged land users involved in communal farming systems ... of input, capital, marketing, information and land use planning, with effect on ...

  3. Case report: a novel KERA mutation associated with cornea plana and its predicted effect on protein function

    DEFF Research Database (Denmark)

    Roos, Laura; Bertelsen, Birgitte; Harris, Pernille

    2015-01-01

    individuals, hypotrichosis was found. KERA was screened for mutations using Sanger sequencing. We detected a novel KERA variant, p.(Ile225Thr), that segregates with the disease in the homozygous form. The three-dimensional structure of keratocan protein was modelled, and we showed that this missense variation...... of the keratocan gene (KERA) on chromosome 12q22. To date, only nine different disease-associated KERA mutations, including four missense mutations, have been described. Case presentation: In this report, we present clinical data from a Turkish family with autosomal recessive cornea plana. In some of the affected...... are predicted to result in destabilization of the protein. Conclusion: We present the 10th pathogenic KERA mutation identified so far. Protein modelling is a useful tool in predicting the effect of missense mutations. This case underline the importance of the leucin rich repeat domain for the protein function...

  4. 22 CFR 40.91 - Certain aliens previously removed.

    Science.gov (United States)

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Certain aliens previously removed. 40.91... IMMIGRANTS UNDER THE IMMIGRATION AND NATIONALITY ACT, AS AMENDED Aliens Previously Removed § 40.91 Certain aliens previously removed. (a) 5-year bar. An alien who has been found inadmissible, whether as a result...

  5. Determining root correspondence between previously and newly detected objects

    Science.gov (United States)

    Paglieroni, David W.; Beer, N Reginald

    2014-06-17

    A system that applies attribute and topology based change detection to networks of objects that were detected on previous scans of a structure, roadway, or area of interest. The attributes capture properties or characteristics of the previously detected objects, such as location, time of detection, size, elongation, orientation, etc. The topology of the network of previously detected objects is maintained in a constellation database that stores attributes of previously detected objects and implicitly captures the geometrical structure of the network. A change detection system detects change by comparing the attributes and topology of new objects detected on the latest scan to the constellation database of previously detected objects.

  6. Radon anomalies prior to earthquakes (1). Review of previous studies

    International Nuclear Information System (INIS)

    Ishikawa, Tetsuo; Tokonami, Shinji; Yasuoka, Yumi; Shinogi, Masaki; Nagahama, Hiroyuki; Omori, Yasutaka; Kawada, Yusuke

    2008-01-01

    The relationship between radon anomalies and earthquakes has been studied for more than 30 years. However, most of the studies dealt with radon in soil gas or in groundwater. Before the 1995 Hyogoken-Nanbu earthquake, an anomalous increase of atmospheric radon was observed at Kobe Pharmaceutical University. The increase was well fitted with a mathematical model related to earthquake fault dynamics. This paper reports the significance of this observation, reviewing previous studies on radon anomaly before earthquakes. Groundwater/soil radon measurements for earthquake prediction began in 1970's in Japan as well as foreign countries. One of the most famous studies in Japan is groundwater radon anomaly before the 1978 Izu-Oshima-kinkai earthquake. We have recognized the significance of radon in earthquake prediction research, but recently its limitation was also pointed out. Some researchers are looking for a better indicator for precursors; simultaneous measurements of radon and other gases are new trials in recent studies. Contrary to soil/groundwater radon, we have not paid much attention to atmospheric radon before earthquakes. However, it might be possible to detect precursors in atmospheric radon before a large earthquake. In the next issues, we will discuss the details of the anomalous atmospheric radon data observed before the Hyogoken-Nanbu earthquake. (author)

  7. 77 FR 44113 - Airworthiness Directives; Gulfstream Aerospace LP (Type Certificate Previously Held by Israel...

    Science.gov (United States)

    2012-07-27

    ... Airworthiness Directives; Gulfstream Aerospace LP (Type Certificate Previously Held by Israel Aircraft... Aerospace LP (Type Certificate previously held by Israel Aircraft Industries, Ltd.) Model Gulfstream G150... to the manufacturer. This action was prompted by a report from the Civil Aviation Authority of Israel...

  8. The Chemical Chaperone, PBA, Reduces ER Stress and Autophagy and Increases Collagen IV α5 Expression in Cultured Fibroblasts From Men With X-Linked Alport Syndrome and Missense Mutations

    Directory of Open Access Journals (Sweden)

    Dongmao Wang

    2017-07-01

    Discussion: Sodium 4-phenylbutyrate increases collagen IV α5 mRNA levels, reduces ER stress and autophagy, and possibly facilitates collagen IV α5 extracellular transport. Whether these actions delay end-stage renal failure in men with X-linked Alport syndrome and missense mutations will only be determined with clinical trials.

  9. A novel missense NDP mutation [p.(Cys93Arg)] with a manifesting carrier in an austrian family with Norrie disease.

    Science.gov (United States)

    Parzefall, Thomas; Lucas, Trevor; Ritter, Markus; Ludwig, Martin; Ramsebner, Reinhard; Frohne, Alexandra; Schöfer, Christian; Hengstschläger, Markus; Frei, Klemens

    2014-01-01

    Norrie disease is a rare, X-linked genetic syndrome characterized by combined congenital blindness and progressive hearing impairment. Norrie disease is caused by alterations in the NDP gene encoding the growth factor norrin that plays a key role in vascular development and stabilization of the eye, inner ear and brain. We identified a family with 3 affected deafblind males and a single female carrier presenting with a serous retinal detachment but normal hearing. Genetic analysis revealed a novel c.277T>C missense mutation causing the substitution of a hydrophobic cysteine to a hydrophilic arginine [p.(Cys93Arg)] within the highly conserved cysteine knot domain of the norrin protein. These results should expand the scope for amniocentesis and genetic testing for Norrie disease which is gaining in importance due to novel postnatal therapeutic concepts to alleviate the devastating retinal symptoms of Norrie disease. © 2014 S. Karger AG, Basel.

  10. Massively Parallel Sequencing of a Chinese Family with DFNA9 Identified a Novel Missense Mutation in the LCCL Domain of COCH

    Directory of Open Access Journals (Sweden)

    Xiaodong Gu

    2016-01-01

    Full Text Available DFNA9 is a late-onset, progressive, autosomal dominantly inherited sensorineural hearing loss with vestibular dysfunction, which is caused by mutations in the COCH (coagulation factor C homology gene. In this study, we investigated a Chinese family segregating autosomal dominant nonsyndromic sensorineural hearing loss. We identified a missense mutation c.T275A p.V92D in the LCCL domain of COCH cosegregating with the disease and absent in 100 normal hearing controls. This mutation leads to substitution of the hydrophobic valine to an acidic amino acid aspartic acid. Our data enriched the mutation spectrum of DFNA9 and implied the importance for mutation screening of COCH in age related hearing loss with vestibular dysfunctions.

  11. Contribution of novel ATGL missense mutations to the clinical phenotype of NLSD-M: a strikingly low amount of lipase activity may preserve cardiac function.

    Science.gov (United States)

    Tavian, Daniela; Missaglia, Sara; Redaelli, Chiara; Pennisi, Elena M; Invernici, Gloria; Wessalowski, Ruediger; Maiwald, Robert; Arca, Marcello; Coleman, Rosalind A

    2012-12-15

    The lack of adipose triglyceride lipase (ATGL), a patatin-like phospholipase domain-containing enzyme that hydrolyzes fatty acids from triacylglycerol (TAG) stored in multiple tissues, causes the autosomal recessive disorder neutral lipid storage disease with myopathy (NLSD-M). In two families of Lebanese and Italian origin presenting with NLSD-M, we identified two new missense mutations in highly conserved regions of ATGL (p.Arg221Pro and p.Asn172Lys) and a novel nonsense mutation (p.Trp8X). The Lebanese patients harbor homozygous p.Arg221Pro, whereas the Italian patients are heterozygotes for p.Asn172Lys and the p.Trp8X mutation. The p.Trp8X mutation results in a complete absence of ATGL protein, while the p.Arg221Pro and p.Asn172Lys mutations result in proteins with minimal lipolytic activity. Although these mutations did not affect putative catalytic residues or the lipid droplet (LD)-binding domain of ATGL, cytosolic LDs accumulated in cultured skin fibroblasts from the patients. The missense mutations might destabilize a random coil (p.Asn172Lys) or a helix (p.Arg221Pro) structure within or proximal to the patatin domain of the lipase, thereby interfering with the enzyme activity, while leaving intact the residues required to localize the protein to LDs. Overexpressing wild-type ATGL in one patient's fibroblasts corrected the metabolic defect and effectively reduced the number and area of cellular LDs. Despite the poor lipase activity in vitro, the Lebanese siblings have a mild myopathy and not clinically evident myocardial dysfunction. The patients of Italian origin show a late-onset and slowly progressive skeletal myopathy. These findings suggest that a small amount of correctly localized lipase activity preserves cardiac function in NLSD-M.

  12. Over-Expression of Porcine Myostatin Missense Mutant Leads to A Gender Difference in Skeletal Muscle Growth between Transgenic Male and Female Mice.

    Science.gov (United States)

    Ma, Dezun; Gao, Pengfei; Qian, Lili; Wang, Qingqing; Cai, Chunbo; Jiang, Shengwang; Xiao, Gaojun; Cui, Wentao

    2015-08-24

    Myostatin, a transforming growth factor-β family member, is a negative regulator of skeletal muscle development and growth. Piedmontese cattle breeds have a missense mutation, which results in a cysteine to tyrosine substitution in the mature myostatin protein (C313Y). This loss-of-function mutation in myostatin results in a double-muscled phenotype in cattle. Myostatin propeptide is an inhibitor of myostatin activity and is considered a potential agent to stimulate muscle growth in livestock. In this study, we generated transgenic mice overexpressing porcine myostatin missense mutant (pmMS), C313Y, and wild-type porcine myostatin propeptide (ppMS), respectively, to examine their effects on muscle growth in mice. Enhanced muscle growth was observed in both pmMS and ppMS transgenic female mice and also in ppMS transgenic male mice. However, there was no enhanced muscle growth observed in pmMS transgenic male mice. To explore why there is such a big difference in muscle growth between pmMS and ppMS transgenic male mice, the expression level of androgen receptor (AR) mutant AR45 was measured by Western blot. Results indicated that AR45 expression significantly increased in pmMS transgenic male mice while it decreased dramatically in ppMS transgenic male mice. Our data demonstrate that both pmMS and ppMS act as myostatin inhibitors in the regulation of muscle growth, but the effect of pmMS in male mice is reversed by an increased AR45 expression. These results provide useful insight and basic theory to future studies on improving pork quality by genetically manipulating myostatin expression or by regulating myostatin activity.

  13. A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis.

    Science.gov (United States)

    Olson, Heather E; Jean-Marçais, Nolwenn; Yang, Edward; Heron, Delphine; Tatton-Brown, Katrina; van der Zwaag, Paul A; Bijlsma, Emilia K; Krock, Bryan L; Backer, E; Kamsteeg, Erik-Jan; Sinnema, Margje; Reijnders, Margot R F; Bearden, David; Begtrup, Amber; Telegrafi, Aida; Lunsing, Roelineke J; Burglen, Lydie; Lesca, Gaetan; Cho, Megan T; Smith, Lacey A; Sheidley, Beth R; Moufawad El Achkar, Christelle; Pearl, Phillip L; Poduri, Annapurna; Skraban, Cara M; Tarpinian, Jennifer; Nesbitt, Addie I; Fransen van de Putte, Dietje E; Ruivenkamp, Claudia A L; Rump, Patrick; Chatron, Nicolas; Sabatier, Isabelle; De Bellescize, Julitta; Guibaud, Laurent; Sweetser, David A; Waxler, Jessica L; Wierenga, Klaas J; Donadieu, Jean; Narayanan, Vinodh; Ramsey, Keri M; Nava, Caroline; Rivière, Jean-Baptiste; Vitobello, Antonio; Tran Mau-Them, Frédéric; Philippe, Christophe; Bruel, Ange-Line; Duffourd, Yannis; Thomas, Laurel; Lelieveld, Stefan H; Schuurs-Hoeijmakers, Janneke; Brunner, Han G; Keren, Boris; Thevenon, Julien; Faivre, Laurence; Thomas, Gary; Thauvin-Robinet, Christel

    2018-05-03

    Developmental and epileptic encephalopathies (DEEs) represent a large clinical and genetic heterogeneous group of neurodevelopmental diseases. The identification of pathogenic genetic variants in DEEs remains crucial for deciphering this complex group and for accurately caring for affected individuals (clinical diagnosis, genetic counseling, impacting medical, precision therapy, clinical trials, etc.). Whole-exome sequencing and intensive data sharing identified a recurrent de novo PACS2 heterozygous missense variant in 14 unrelated individuals. Their phenotype was characterized by epilepsy, global developmental delay with or without autism, common cerebellar dysgenesis, and facial dysmorphism. Mixed focal and generalized epilepsy occurred in the neonatal period, controlled with difficulty in the first year, but many improved in early childhood. PACS2 is an important PACS1 paralog and encodes a multifunctional sorting protein involved in nuclear gene expression and pathway traffic regulation. Both proteins harbor cargo(furin)-binding regions (FBRs) that bind cargo proteins, sorting adaptors, and cellular kinase. Compared to the defined PACS1 recurrent variant series, individuals with PACS2 variant have more consistently neonatal/early-infantile-onset epilepsy that can be challenging to control. Cerebellar abnormalities may be similar but PACS2 individuals exhibit a pattern of clear dysgenesis ranging from mild to severe. Functional studies demonstrated that the PACS2 recurrent variant reduces the ability of the predicted autoregulatory domain to modulate the interaction between the PACS2 FBR and client proteins, which may disturb cellular function. These findings support the causality of this recurrent de novo PACS2 heterozygous missense in DEEs with facial dysmorphim and cerebellar dysgenesis. Copyright © 2018 American Society of Human Genetics. All rights reserved.

  14. Case report: a novel KERA mutation associated with cornea plana and its predicted effect on protein function

    DEFF Research Database (Denmark)

    Roos, Laura; Bertelsen, Birgitte; Harris, Pernille

    2015-01-01

    of the keratocan gene (KERA) on chromosome 12q22. To date, only nine different disease-associated KERA mutations, including four missense mutations, have been described. Case presentation: In this report, we present clinical data from a Turkish family with autosomal recessive cornea plana. In some of the affected...

  15. 49 CFR 173.23 - Previously authorized packaging.

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 2 2010-10-01 2010-10-01 false Previously authorized packaging. 173.23 Section... REQUIREMENTS FOR SHIPMENTS AND PACKAGINGS Preparation of Hazardous Materials for Transportation § 173.23 Previously authorized packaging. (a) When the regulations specify a packaging with a specification marking...

  16. 28 CFR 10.5 - Incorporation of papers previously filed.

    Science.gov (United States)

    2010-07-01

    ... 28 Judicial Administration 1 2010-07-01 2010-07-01 false Incorporation of papers previously filed... CARRYING ON ACTIVITIES WITHIN THE UNITED STATES Registration Statement § 10.5 Incorporation of papers previously filed. Papers and documents already filed with the Attorney General pursuant to the said act and...

  17. 75 FR 76056 - FEDERAL REGISTER CITATION OF PREVIOUS ANNOUNCEMENT:

    Science.gov (United States)

    2010-12-07

    ... SECURITIES AND EXCHANGE COMMISSION Sunshine Act Meeting FEDERAL REGISTER CITATION OF PREVIOUS ANNOUNCEMENT: STATUS: Closed meeting. PLACE: 100 F Street, NE., Washington, DC. DATE AND TIME OF PREVIOUSLY ANNOUNCED MEETING: Thursday, December 9, 2010 at 2 p.m. CHANGE IN THE MEETING: Time change. The closed...

  18. No discrimination against previous mates in a sexually cannibalistic spider

    Science.gov (United States)

    Fromhage, Lutz; Schneider, Jutta M.

    2005-09-01

    In several animal species, females discriminate against previous mates in subsequent mating decisions, increasing the potential for multiple paternity. In spiders, female choice may take the form of selective sexual cannibalism, which has been shown to bias paternity in favor of particular males. If cannibalistic attacks function to restrict a male's paternity, females may have little interest to remate with males having survived such an attack. We therefore studied the possibility of female discrimination against previous mates in sexually cannibalistic Argiope bruennichi, where females almost always attack their mate at the onset of copulation. We compared mating latency and copulation duration of males having experienced a previous copulation either with the same or with a different female, but found no evidence for discrimination against previous mates. However, males copulated significantly shorter when inserting into a used, compared to a previously unused, genital pore of the female.

  19. Implant breast reconstruction after salvage mastectomy in previously irradiated patients.

    Science.gov (United States)

    Persichetti, Paolo; Cagli, Barbara; Simone, Pierfranco; Cogliandro, Annalisa; Fortunato, Lucio; Altomare, Vittorio; Trodella, Lucio

    2009-04-01

    The most common surgical approach in case of local tumor recurrence after quadrantectomy and radiotherapy is salvage mastectomy. Breast reconstruction is the subsequent phase of the treatment and the plastic surgeon has to operate on previously irradiated and manipulated tissues. The medical literature highlights that breast reconstruction with tissue expanders is not a pursuable option, considering previous radiotherapy a contraindication. The purpose of this retrospective study is to evaluate the influence of previous radiotherapy on 2-stage breast reconstruction (tissue expander/implant). Only patients with analogous timing of radiation therapy and the same demolitive and reconstructive procedures were recruited. The results of this study prove that, after salvage mastectomy in previously irradiated patients, implant reconstruction is still possible. Further comparative studies are, of course, advisable to draw any conclusion on the possibility to perform implant reconstruction in previously irradiated patients.

  20. 75 FR 54215 - Agency Request for Approval of a Previously Approved Information Collection(s): Uniform...

    Science.gov (United States)

    2010-09-03

    ... about our intention to request Office of Management and Budget (OMB) approval to renew a previously... because of management and oversight responsibilities of the agency imposed by OMB Circular 2 CFR 215 (A... Department has terminated Financial Status Report (SF-269 and SF-269A) and Federal Cash Transactions Report...

  1. Report to the CCT on COOMET comparison COOMET.T-K3.1 (previously COOMET.T-S1): Key regional comparison of the national standards of temperature in the range from the triple point of water to the freezing point of zinc

    Science.gov (United States)

    Pokhodun, A. I.

    2010-01-01

    In the framework of the CIPM MRA, a first COOMET comparison "Comparison of the ITS-90 realizations in the range from 0.01 °C to 429.7485 °C (from the triple point of water to the freezing point of zinc)", registered in the KCDB under the identifier "COOMET.T-K3", was carried out in 2005-2007. Four national metrology institutes took part in this comparison: VNIIM (Russian Federation), SMU (Slovakia), BelGIM (Republic of Belarus) and NSC IM (Ukraine), and two of them (VNIIM and SMU) ensured the linkage with key comparisons CCT-K3 and CCT-K4, in order to disseminate the metrological equivalence to the measurement standards of NSC IM and BelGIM. NSC IM, however, had to withdraw its results, and at the meeting of Technical Committee T-10 of COOMET it was decided to carry out a supplementary bilateral comparison between VNIIM and the NSC IM for realization of the ITS-90 in the same range of temperature. This was registered in the KCDB under the identifier COOMET.T-S1 and measurements were performed in 2008-2009. From the results presented in this report, it is possible to draw the conclusion that the COOMET supplementary comparison COOMET.T-S1 demonstrates the CMC uncertainties claimed by the NSC IM for the melting point of gallium 0.236 mK (k = 2), and the freezing points of indium 1.040 mK (k = 2), tin 0.858 mK (k = 2) and zinc 0.944 mK (k = 2). In September 2012 the Working Group on key Comparisons (WG 7) of the CCT upgraded this comparison to a COOMET key comparison of the 'CCT-K3' type. It is now identified as COOMET.T-K3.1. In April 2013 this report was superseded by item 03006 in the Technical Supplement of 2013. Main text. To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/. The final report has been peer-reviewed and approved for publication by the CCT, according to the provisions of the CIPM Mutual Recognition Arrangement (MRA).

  2. Personality disorders in previously detained adolescent females: a prospective study

    NARCIS (Netherlands)

    Krabbendam, A.; Colins, O.F.; Doreleijers, T.A.H.; van der Molen, E.; Beekman, A.T.F.; Vermeiren, R.R.J.M.

    2015-01-01

    This longitudinal study investigated the predictive value of trauma and mental health problems for the development of antisocial personality disorder (ASPD) and borderline personality disorder (BPD) in previously detained women. The participants were 229 detained adolescent females who were assessed

  3. Payload specialist Reinhard Furrer show evidence of previous blood sampling

    Science.gov (United States)

    1985-01-01

    Payload specialist Reinhard Furrer shows evidence of previous blood sampling while Wubbo J. Ockels, Dutch payload specialist (only partially visible), extends his right arm after a sample has been taken. Both men show bruises on their arms.

  4. Choice of contraception after previous operative delivery at a family ...

    African Journals Online (AJOL)

    Choice of contraception after previous operative delivery at a family planning clinic in Northern Nigeria. Amina Mohammed‑Durosinlorun, Joel Adze, Stephen Bature, Caleb Mohammed, Matthew Taingson, Amina Abubakar, Austin Ojabo, Lydia Airede ...

  5. Previous utilization of service does not improve timely booking in ...

    African Journals Online (AJOL)

    Previous utilization of service does not improve timely booking in antenatal care: Cross sectional study ... Journal Home > Vol 24, No 3 (2010) > ... Results: Past experience on antenatal care service utilization did not come out as a predictor for ...

  6. A previous hamstring injury affects kicking mechanics in soccer players.

    Science.gov (United States)

    Navandar, Archit; Veiga, Santiago; Torres, Gonzalo; Chorro, David; Navarro, Enrique

    2018-01-10

    Although the kicking skill is influenced by limb dominance and sex, how a previous hamstring injury affects kicking has not been studied in detail. Thus, the objective of this study was to evaluate the effect of sex and limb dominance on kicking in limbs with and without a previous hamstring injury. 45 professional players (males: n=19, previously injured players=4, age=21.16 ± 2.00 years; females: n=19, previously injured players=10, age=22.15 ± 4.50 years) performed 5 kicks each with their preferred and non-preferred limb at a target 7m away, which were recorded with a three-dimensional motion capture system. Kinematic and kinetic variables were extracted for the backswing, leg cocking, leg acceleration and follow through phases. A shorter backswing (20.20 ± 3.49% vs 25.64 ± 4.57%), and differences in knee flexion angle (58 ± 10o vs 72 ± 14o) and hip flexion velocity (8 ± 0rad/s vs 10 ± 2rad/s) were observed in previously injured, non-preferred limb kicks for females. A lower peak hip linear velocity (3.50 ± 0.84m/s vs 4.10 ± 0.45m/s) was observed in previously injured, preferred limb kicks of females. These differences occurred in the backswing and leg-cocking phases where the hamstring muscles were the most active. A variation in the functioning of the hamstring muscles and that of the gluteus maximus and iliopsoas in the case of a previous injury could account for the differences observed in the kicking pattern. Therefore, the effects of a previous hamstring injury must be considered while designing rehabilitation programs to re-educate kicking movement.

  7. Carrier frequency of guanidinoacetate methyltransferase deficiency in the general population by functional characterization of missense variants in the GAMT gene

    NARCIS (Netherlands)

    Desroches, C.L.; Patel, J.; Wang, P.X.; Minassian, B.; Marshall, C.R.; Salomons, G.; Mercimek-Mahmutoglu, S.

    2015-01-01

    Guanidinoacetate methyltransferase (GAMT) deficiency is a neurodegenerative disease. Although no symptomatic patients on treatment achieved normal neurodevelopment, three asymptomatic newborns were reported with normal neurodevelopmental outcome on neonatal treatment. GAMT deficiency is therefore a

  8. Erlotinib-induced rash spares previously irradiated skin

    International Nuclear Information System (INIS)

    Lips, Irene M.; Vonk, Ernest J.A.; Koster, Mariska E.Y.; Houwing, Ronald H.

    2011-01-01

    Erlotinib is an epidermal growth factor receptor inhibitor prescribed to patients with locally advanced or metastasized non-small cell lung carcinoma after failure of at least one earlier chemotherapy treatment. Approximately 75% of the patients treated with erlotinib develop acneiform skin rashes. A patient treated with erlotinib 3 months after finishing concomitant treatment with chemotherapy and radiotherapy for non-small cell lung cancer is presented. Unexpectedly, the part of the skin that had been included in his previously radiotherapy field was completely spared from the erlotinib-induced acneiform skin rash. The exact mechanism of erlotinib-induced rash sparing in previously irradiated skin is unclear. The underlying mechanism of this phenomenon needs to be explored further, because the number of patients being treated with a combination of both therapeutic modalities is increasing. The therapeutic effect of erlotinib in the area of the previously irradiated lesion should be assessed. (orig.)

  9. Reasoning with Previous Decisions: Beyond the Doctrine of Precedent

    DEFF Research Database (Denmark)

    Komárek, Jan

    2013-01-01

    in different jurisdictions use previous judicial decisions in their argument, we need to move beyond the concept of precedent to a wider notion, which would embrace practices and theories in legal systems outside the Common law tradition. This article presents the concept of ‘reasoning with previous decisions...... law method’, but they are no less rational and intellectually sophisticated. The reason for the rather conceited attitude of some comparatists is in the dominance of the common law paradigm of precedent and the accompanying ‘case law method’. If we want to understand how courts and lawyers......’ as such an alternative and develops its basic models. The article first points out several shortcomings inherent in limiting the inquiry into reasoning with previous decisions by the common law paradigm (1). On the basis of numerous examples provided in section (1), I will present two basic models of reasoning...

  10. [Prevalence of previously diagnosed diabetes mellitus in Mexico.

    Science.gov (United States)

    Rojas-Martínez, Rosalba; Basto-Abreu, Ana; Aguilar-Salinas, Carlos A; Zárate-Rojas, Emiliano; Villalpando, Salvador; Barrientos-Gutiérrez, Tonatiuh

    2018-01-01

    To compare the prevalence of previously diagnosed diabetes in 2016 with previous national surveys and to describe treatment and its complications. Mexico's national surveys Ensa 2000, Ensanut 2006, 2012 and 2016 were used. For 2016, logistic regression models and measures of central tendency and dispersion were obtained. The prevalence of previously diagnosed diabetes in 2016 was 9.4%. The increase of 2.2% relative to 2012 was not significant and only observed in patients older than 60 years. While preventive measures have increased, the access to medical treatment and lifestyle has not changed. The treatment has been modified, with an increase in insulin and decrease in hypoglycaemic agents. Population aging, lack of screening actions and the increase in diabetes complications will lead to an increase on the burden of disease. Policy measures targeting primary and secondary prevention of diabetes are crucial.

  11. A Tandem Duplicate of Anti-Müllerian Hormone with a Missense SNP on the Y Chromosome Is Essential for Male Sex Determination in Nile Tilapia, Oreochromis niloticus

    Science.gov (United States)

    Li, Minghui; Sun, Yunlv; Zhao, Jiue; Shi, Hongjuan; Zeng, Sheng; Ye, Kai; Jiang, Dongneng; Zhou, Linyan; Sun, Lina; Tao, Wenjing; Nagahama, Yoshitaka; Kocher, Thomas D.; Wang, Deshou

    2015-01-01

    Variation in the TGF-β signaling pathway is emerging as an important mechanism by which gonadal sex determination is controlled in teleosts. Here we show that amhy, a Y-specific duplicate of the anti-Müllerian hormone (amh) gene, induces male sex determination in Nile tilapia. amhy is a tandem duplicate located immediately downstream of amhΔ-y on the Y chromosome. The coding sequence of amhy was identical to the X-linked amh (amh) except a missense SNP (C/T) which changes an amino acid (Ser/Leu92) in the N-terminal region. amhy lacks 5608 bp of promoter sequence that is found in the X-linked amh homolog. The amhΔ-y contains several insertions and deletions in the promoter region, and even a 5 bp insertion in exonVI that results in a premature stop codon and thus a truncated protein product lacking the TGF-β binding domain. Both amhy and amhΔ-y expression is restricted to XY gonads from 5 days after hatching (dah) onwards. CRISPR/Cas9 knockout of amhy in XY fish resulted in male to female sex reversal, while mutation of amhΔ-y alone could not. In contrast, overexpression of Amhy in XX fish, using a fosmid transgene that carries the amhy/amhΔ-y haplotype or a vector containing amhy ORF under the control of CMV promoter, resulted in female to male sex reversal, while overexpression of AmhΔ-y alone in XX fish could not. Knockout of the anti-Müllerian hormone receptor type II (amhrII) in XY fish also resulted in 100% complete male to female sex reversal. Taken together, these results strongly suggest that the duplicated amhy with a missense SNP is the candidate sex determining gene and amhy/amhrII signal is essential for male sex determination in Nile tilapia. These findings highlight the conserved roles of TGF-β signaling pathway in fish sex determination. PMID:26588702

  12. Cardiovascular magnetic resonance in adults with previous cardiovascular surgery.

    Science.gov (United States)

    von Knobelsdorff-Brenkenhoff, Florian; Trauzeddel, Ralf Felix; Schulz-Menger, Jeanette

    2014-03-01

    Cardiovascular magnetic resonance (CMR) is a versatile non-invasive imaging modality that serves a broad spectrum of indications in clinical cardiology and has proven evidence. Most of the numerous applications are appropriate in patients with previous cardiovascular surgery in the same manner as in non-surgical subjects. However, some specifics have to be considered. This review article is intended to provide information about the application of CMR in adults with previous cardiovascular surgery. In particular, the two main scenarios, i.e. following coronary artery bypass surgery and following heart valve surgery, are highlighted. Furthermore, several pictorial descriptions of other potential indications for CMR after cardiovascular surgery are given.

  13. Biochemical characterization of MLH3 missense mutations does not reveal an apparent role of MLH3 in Lynch syndrome

    DEFF Research Database (Denmark)

    Ou, Jianghua; Rasmussen, Merete; Westers, Helga

    2009-01-01

    for eight of these MLH3 UVs identified in suspected Lynch syndrome patients, we performed several biochemical tests. We determined the protein expression and stability, protein localization and interaction of the mutant MLH3 proteins with wildtype MLH1. All eight MLH3 UVs gave protein expression levels...... comparable with wildtype MLH3. Furthermore, the UV-containing proteins, in contrast to previous studies, were all localized normally in the nucleus and they interacted normally with wildtype MLH1. Our different biochemical assays yielded no evidence that the eight MLH3 UVs tested are the cause of hereditary...

  14. Outcome Of Pregnancy Following A Previous Lower Segment ...

    African Journals Online (AJOL)

    Background: A previous ceasarean section is an important variable that influences patient management in subsequent pregnancies. A trial of vaginal delivery in such patients is a feasible alternative to a secondary section, thus aiding to reduce the ceasarean section rate and its associated co-morbidities. Objective: To ...

  15. 24 CFR 1710.552 - Previously accepted state filings.

    Science.gov (United States)

    2010-04-01

    ... of Substantially Equivalent State Law § 1710.552 Previously accepted state filings. (a) Materials... and contracts or agreements contain notice of purchaser's revocation rights. In addition see § 1715.15..., unless the developer is obligated to do so in the contract. (b) If any such filing becomes inactive or...

  16. The job satisfaction of principals of previously disadvantaged schools

    African Journals Online (AJOL)

    The aim of this study was to identify influences on the job satisfaction of previously disadvantaged ..... I am still riding the cloud … I hope it lasts. .... as a way of creating a climate and culture in schools where individuals are willing to explore.

  17. Research Note Effects of previous cultivation on regeneration of ...

    African Journals Online (AJOL)

    We investigated the effects of previous cultivation on regeneration potential under miombo woodlands in a resettlement area, a spatial product of Zimbabwe's land reforms. We predicted that cultivation would affect population structure, regeneration, recruitment and potential grazing capacity of rangelands. Plant attributes ...

  18. Cryptococcal meningitis in a previously healthy child | Chimowa ...

    African Journals Online (AJOL)

    An 8-year-old previously healthy female presented with a 3 weeks history of headache, neck stiffness, deafness, fever and vomiting and was diagnosed with cryptococcal meningitis. She had documented hearing loss and was referred to tertiary-level care after treatment with fluconazole did not improve her neurological ...

  19. Investigation of previously derived Hyades, Coma, and M67 reddenings

    International Nuclear Information System (INIS)

    Taylor, B.J.

    1980-01-01

    New Hyades polarimetry and field star photometry have been obtained to check the Hyades reddening, which was found to be nonzero in a previous paper. The new Hyades polarimetry implies essentially zero reddening; this is also true of polarimetry published by Behr (which was incorrectly interpreted in the previous paper). Four photometric techniques which are presumed to be insensitive to blanketing are used to compare the Hyades to nearby field stars; these four techniques also yield essentially zero reddening. When all of these results are combined with others which the author has previously published and a simultaneous solution for the Hyades, Coma, and M67 reddenings is made, the results are E (B-V) =3 +- 2 (sigma) mmag, -1 +- 3 (sigma) mmag, and 46 +- 6 (sigma) mmag, respectively. No support for a nonzero Hyades reddening is offered by the new results. When the newly obtained reddenings for the Hyades, Coma, and M67 are compared with results from techniques given by Crawford and by users of the David Dunlap Observatory photometric system, no differences between the new and other reddenings are found which are larger than about 2 sigma. The author had previously found that the M67 main-sequence stars have about the same blanketing as that of Coma and less blanketing than the Hyades; this conclusion is essentially unchanged by the revised reddenings

  20. Rapid fish stock depletion in previously unexploited seamounts: the ...

    African Journals Online (AJOL)

    Rapid fish stock depletion in previously unexploited seamounts: the case of Beryx splendens from the Sierra Leone Rise (Gulf of Guinea) ... A spectral analysis and red-noise spectra procedure (REDFIT) algorithm was used to identify the red-noise spectrum from the gaps in the observed time-series of catch per unit effort by ...

  1. 18 CFR 154.302 - Previously submitted material.

    Science.gov (United States)

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Previously submitted material. 154.302 Section 154.302 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY... concurrently with the rate change filing. There must be furnished to the Director, Office of Energy Market...

  2. The job satisfaction of principals of previously disadvantaged schools

    African Journals Online (AJOL)

    The aim of this study was to identify influences on the job satisfaction of previously disadvantaged school principals in North-West Province. Evans's theory of job satisfaction, morale and motivation was useful as a conceptual framework. A mixedmethods explanatory research design was important in discovering issues with ...

  3. Obstructive pulmonary disease in patients with previous tuberculosis ...

    African Journals Online (AJOL)

    Obstructive pulmonary disease in patients with previous tuberculosis: Pathophysiology of a community-based cohort. B.W. Allwood, R Gillespie, M Galperin-Aizenberg, M Bateman, H Olckers, L Taborda-Barata, G.L. Calligaro, Q Said-Hartley, R van Zyl-Smit, C.B. Cooper, E van Rikxoort, J Goldin, N Beyers, E.D. Bateman ...

  4. Abiraterone in metastatic prostate cancer without previous chemotherapy

    NARCIS (Netherlands)

    Ryan, Charles J.; Smith, Matthew R.; de Bono, Johann S.; Molina, Arturo; Logothetis, Christopher J.; de Souza, Paul; Fizazi, Karim; Mainwaring, Paul; Piulats, Josep M.; Ng, Siobhan; Carles, Joan; Mulders, Peter F. A.; Basch, Ethan; Small, Eric J.; Saad, Fred; Schrijvers, Dirk; van Poppel, Hendrik; Mukherjee, Som D.; Suttmann, Henrik; Gerritsen, Winald R.; Flaig, Thomas W.; George, Daniel J.; Yu, Evan Y.; Efstathiou, Eleni; Pantuck, Allan; Winquist, Eric; Higano, Celestia S.; Taplin, Mary-Ellen; Park, Youn; Kheoh, Thian; Griffin, Thomas; Scher, Howard I.; Rathkopf, Dana E.; Boyce, A.; Costello, A.; Davis, I.; Ganju, V.; Horvath, L.; Lynch, R.; Marx, G.; Parnis, F.; Shapiro, J.; Singhal, N.; Slancar, M.; van Hazel, G.; Wong, S.; Yip, D.; Carpentier, P.; Luyten, D.; de Reijke, T.

    2013-01-01

    Abiraterone acetate, an androgen biosynthesis inhibitor, improves overall survival in patients with metastatic castration-resistant prostate cancer after chemotherapy. We evaluated this agent in patients who had not received previous chemotherapy. In this double-blind study, we randomly assigned

  5. Response to health insurance by previously uninsured rural children.

    Science.gov (United States)

    Tilford, J M; Robbins, J M; Shema, S J; Farmer, F L

    1999-08-01

    To examine the healthcare utilization and costs of previously uninsured rural children. Four years of claims data from a school-based health insurance program located in the Mississippi Delta. All children who were not Medicaid-eligible or were uninsured, were eligible for limited benefits under the program. The 1987 National Medical Expenditure Survey (NMES) was used to compare utilization of services. The study represents a natural experiment in the provision of insurance benefits to a previously uninsured population. Premiums for the claims cost were set with little or no information on expected use of services. Claims from the insurer were used to form a panel data set. Mixed model logistic and linear regressions were estimated to determine the response to insurance for several categories of health services. The use of services increased over time and approached the level of utilization in the NMES. Conditional medical expenditures also increased over time. Actuarial estimates of claims cost greatly exceeded actual claims cost. The provision of a limited medical, dental, and optical benefit package cost approximately $20-$24 per member per month in claims paid. An important uncertainty in providing health insurance to previously uninsured populations is whether a pent-up demand exists for health services. Evidence of a pent-up demand for medical services was not supported in this study of rural school-age children. States considering partnerships with private insurers to implement the State Children's Health Insurance Program could lower premium costs by assembling basic data on previously uninsured children.

  6. Reoperative sentinel lymph node biopsy after previous mastectomy.

    Science.gov (United States)

    Karam, Amer; Stempel, Michelle; Cody, Hiram S; Port, Elisa R

    2008-10-01

    Sentinel lymph node (SLN) biopsy is the standard of care for axillary staging in breast cancer, but many clinical scenarios questioning the validity of SLN biopsy remain. Here we describe our experience with reoperative-SLN (re-SLN) biopsy after previous mastectomy. Review of the SLN database from September 1996 to December 2007 yielded 20 procedures done in the setting of previous mastectomy. SLN biopsy was performed using radioisotope with or without blue dye injection superior to the mastectomy incision, in the skin flap in all patients. In 17 of 20 patients (85%), re-SLN biopsy was performed for local or regional recurrence after mastectomy. Re-SLN biopsy was successful in 13 of 20 patients (65%) after previous mastectomy. Of the 13 patients, 2 had positive re-SLN, and completion axillary dissection was performed, with 1 having additional positive nodes. In the 11 patients with negative re-SLN, 2 patients underwent completion axillary dissection demonstrating additional negative nodes. One patient with a negative re-SLN experienced chest wall recurrence combined with axillary recurrence 11 months after re-SLN biopsy. All others remained free of local or axillary recurrence. Re-SLN biopsy was unsuccessful in 7 of 20 patients (35%). In three of seven patients, axillary dissection was performed, yielding positive nodes in two of the three. The remaining four of seven patients all had previous modified radical mastectomy, so underwent no additional axillary surgery. In this small series, re-SLN was successful after previous mastectomy, and this procedure may play some role when axillary staging is warranted after mastectomy.

  7. Upon Further Review: V. An Examination of Previous Lightcurve Analysis from the Palmer Divide Observatory

    Science.gov (United States)

    Warner, Brian D.

    2011-01-01

    Updated results are given for nine asteroids previously reported from the Palmer Divide Observatory (PDO). The original images were re-measured to obtain new data sets using the latest version of MPO Canopus photometry software, analysis tools, and revised techniques for linking multiple observing runs covering several days to several weeks. Results that were previously not reported or were moderately different were found for 1659 Punkajarju, 1719 Jens, 1987 Kaplan, 2105 Gudy, 2961 Katsurahama, 3285 Ruth Wolfe, 3447 Burckhalter, 7816 Hanoi, and (34817) 2000 SE116. This is one in a series of papers that will examine results obtained during the initial years of the asteroid lightcurve program at PDO.

  8. Severe G6PD Deficiency Due to a New Missense Mutation in an Infant of Northern European Descent

    DEFF Research Database (Denmark)

    Warny, Marie; Lausen, Birgitte; Birgens, Henrik

    2015-01-01

    We report a term male infant born to parents of Danish descent, who on the second day of life developed jaundice peaking at 67 hours and decreasing on applied double-sided phototherapy. In the weeks following, the infant showed signs of ongoing hemolysis. Laboratory tests showed very low glucose-6...

  9. Matched cohort study of external cephalic version in women with previous cesarean delivery.

    Science.gov (United States)

    Keepanasseril, Anish; Anand, Keerthana; Soundara Raghavan, Subrahmanian

    2017-07-01

    To evaluate the efficacy and safety of external cephalic version (ECV) among women with previous cesarean delivery. A retrospective study was conducted using data for women with previous cesarean delivery and breech presentation who underwent ECV at or after 36 weeks of pregnancy during 2011-2016. For every case, two multiparous women without previous cesarean delivery who underwent ECV and were matched for age and pregnancy duration were included. Characteristics and outcomes were compared between groups. ECV was successful for 32 (84.2%) of 38 women with previous cesarean delivery and 62 (81.6%) in the control group (P=0.728). Multivariate regression analysis confirmed that previous cesarean was not associated with ECV success (odds ratio 1.89, 95% confidence interval 0.19-18.47; P=0.244). Successful vaginal delivery after successful ECV was reported for 19 (59.4%) women in the previous cesarean delivery group and 52 (83.9%) in the control group (P<0.001). No ECV-associated complications occurred in women with previous cesarean delivery. To avoid a repeat cesarean delivery, ECV can be offered to women with breech presentation and previous cesarean delivery who are otherwise eligible for a trial of labor. © 2017 International Federation of Gynecology and Obstetrics.

  10. Targeted Resequencing and Functional Testing Identifies Low-Frequency Missense Variants in the Gene Encoding GARP as Significant Contributors to Atopic Dermatitis Risk.

    Science.gov (United States)

    Manz, Judith; Rodríguez, Elke; ElSharawy, Abdou; Oesau, Eva-Maria; Petersen, Britt-Sabina; Baurecht, Hansjörg; Mayr, Gabriele; Weber, Susanne; Harder, Jürgen; Reischl, Eva; Schwarz, Agatha; Novak, Natalija; Franke, Andre; Weidinger, Stephan

    2016-12-01

    Gene-mapping studies have consistently identified a susceptibility locus for atopic dermatitis and other inflammatory diseases on chromosome band 11q13.5, with the strongest association observed for a common variant located in an intergenic region between the two annotated genes C11orf30 and LRRC32. Using a targeted resequencing approach we identified low-frequency and rare missense mutations within the LRRC32 gene encoding the protein GARP, a receptor on activated regulatory T cells that binds latent transforming growth factor-β. Subsequent association testing in more than 2,000 atopic dermatitis patients and 2,000 control subjects showed a significant excess of these LRRC32 variants in individuals with atopic dermatitis. Structural protein modeling and bioinformatic analysis predicted a disruption of protein transport upon these variants, and overexpression assays in CD4 + CD25 - T cells showed a significant reduction in surface expression of the mutated protein. Consistently, flow cytometric (FACS) analyses of different T-cell subtypes obtained from atopic dermatitis patients showed a significantly reduced surface expression of GARP and a reduced conversion of CD4 + CD25 - T cells into regulatory T cells, along with lower expression of latency-associated protein upon stimulation in carriers of the LRRC32 A407T variant. These results link inherited disturbances of transforming growth factor-β signaling with atopic dermatitis risk. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  11. SNP2Structure: A Public and Versatile Resource for Mapping and Three-Dimensional Modeling of Missense SNPs on Human Protein Structures

    Directory of Open Access Journals (Sweden)

    Difei Wang

    2015-01-01

    Full Text Available One of the long-standing challenges in biology is to understand how non-synonymous single nucleotide polymorphisms (nsSNPs change protein structure and further affect their function. While it is impractical to solve all the mutated protein structures experimentally, it is quite feasible to model the mutated structures in silico. Toward this goal, we built a publicly available structure database resource (SNP2Structure, https://apps.icbi.georgetown.edu/snp2structure focusing on missense mutations, msSNP. Compared with web portals with similar aims, SNP2Structure has the following major advantages. First, our portal offers direct comparison of two related 3D structures. Second, the protein models include all interacting molecules in the original PDB structures, so users are able to determine regions of potential interaction changes when a protein mutation occurs. Third, the mutated structures are available to download locally for further structural and functional analysis. Fourth, we used Jsmol package to display the protein structure that has no system compatibility issue. SNP2Structure provides reliable, high quality mapping of nsSNPs to 3D protein structures enabling researchers to explore the likely functional impact of human disease-causing mutations.

  12. Missense mutations located in structural p53 DNA-binding motifs are associated with extremely poor survival in chronic lymphocytic leukemia.

    Science.gov (United States)

    Trbusek, Martin; Smardova, Jana; Malcikova, Jitka; Sebejova, Ludmila; Dobes, Petr; Svitakova, Miluse; Vranova, Vladimira; Mraz, Marek; Francova, Hana Skuhrova; Doubek, Michael; Brychtova, Yvona; Kuglik, Petr; Pospisilova, Sarka; Mayer, Jiri

    2011-07-01

    There is a distinct connection between TP53 defects and poor prognosis in chronic lymphocytic leukemia (CLL). It remains unclear whether patients harboring TP53 mutations represent a homogenous prognostic group. We evaluated the survival of patients with CLL and p53 defects identified at our institution by p53 yeast functional assay and complementary interphase fluorescence in situ hybridization analysis detecting del(17p) from 2003 to 2010. A defect of the TP53 gene was identified in 100 of 550 patients. p53 mutations were strongly associated with the deletion of 17p and the unmutated IgVH locus (both P DBMs), structurally well-defined parts of the DNA-binding domain, manifested a clearly shorter median survival (12 months) compared with patients having missense mutations outside DBMs (41 months; P = .002) or nonmissense alterations (36 months; P = .005). The difference in survival was similar in the analysis limited to patients harboring mutation accompanied by del(17p) and was also confirmed in a subgroup harboring TP53 defect at diagnosis. The patients with p53 DBMs mutation (at diagnosis) also manifested a short median time to first therapy (TTFT; 1 month). The substantially worse survival and the short TTFT suggest a strong mutated p53 gain-of-function phenotype in patients with CLL with DBMs mutations. The impact of p53 DBMs mutations on prognosis and response to therapy should be analyzed in investigative clinical trials.

  13. Intrafamilial variability of the ocular phenotype in a Polish family with a missense mutation (A63D) in the Norrie disease gene.

    Science.gov (United States)

    Zaremba, J; Feil, S; Juszko, J; Myga, W; van Duijnhoven, G; Berger, W

    1998-09-01

    To describe the phenotypic variability in a Polish Norrie disease (ND) family associated with the missense mutation A63D. A patient with spared vision from a Polish ND family underwent detailed ophthalmological examinations including slit-lamp biomicroscopy, ultrasound (USG), angiography, Goldmann kinetic visual field, and electroretinography (ERG). Mutation screening was carried out using the single-strand conformation polymorphism (SSCP) technique and subsequent DNA sequencing of the coding part of the ND gene. A mutation was detected (exon 3, A63D) in a large Polish family with 12 affected males, all but one presenting with classical ND symptoms. In one male, partially preserved vision was observed up to 40 years of age (distance acuity of the right eye 1/50 and left eye 2/50). Slit-lamp examination revealed remnants of a persistent primary vitreous and hyaloid artery. Upon angiography, the retina was vascularized within the posterior pole but not in the periphery. The ERG revealed pathological changes characteristic for chorioretinal degenerations. Within one family, individuals with identical sequence alterations in the ND gene can show remarkable phenotypic variability of the ocular symptoms. These findings indicate the involvement of additional factors (epigenetic or genetic) in ocular pathogenesis of ND.

  14. Exome Sequencing Identifies a Missense Variant in EFEMP1 Co-Segregating in a Family with Autosomal Dominant Primary Open-Angle Glaucoma.

    Directory of Open Access Journals (Sweden)

    Donna S Mackay

    Full Text Available Primary open-angle glaucoma (POAG is a clinically important and genetically heterogeneous cause of progressive vision loss as a result of retinal ganglion cell death. Here we have utilized trio-based, whole-exome sequencing to identify the genetic defect underlying an autosomal dominant form of adult-onset POAG segregating in an African-American family. Exome sequencing identified a novel missense variant (c.418C>T, p.Arg140Trp in exon-5 of the gene coding for epidermal growth factor (EGF containing fibulin-like extracellular matrix protein 1 (EFEMP1 that co-segregated with disease in the family. Linkage and haplotype analyses with microsatellite markers indicated that the disease interval overlapped a known POAG locus (GLC1H on chromosome 2p. The p.Arg140Trp substitution was predicted in silico to have damaging effects on protein function and transient expression studies in cultured cells revealed that the Trp140-mutant protein exhibited increased intracellular accumulation compared with wild-type EFEMP1. In situ hybridization of the mouse eye with oligonucleotide probes detected the highest levels of EFEMP1 transcripts in the ciliary body, cornea, inner nuclear layer of the retina, and the optic nerve head. The recent finding that a common variant near EFEMP1 was associated with optic nerve-head morphology supports the possibility that the EFEMP1 variant identified in this POAG family may be pathogenic.

  15. The effect of the pathological V72I, D109N and T190M missense mutations on the molecular structure of α-dystroglycan.

    Directory of Open Access Journals (Sweden)

    Sonia Covaceuszach

    Full Text Available Dystroglycan (DG is a highly glycosylated protein complex that links the cytoskeleton with the extracellular matrix, mediating fundamental physiological functions such as mechanical stability of tissues, matrix organization and cell polarity. A crucial role in the glycosylation of the DG α subunit is played by its own N-terminal region that is required by the glycosyltransferase LARGE. Alteration in this O-glycosylation deeply impairs the high affinity binding to other extracellular matrix proteins such as laminins. Recently, three missense mutations in the gene encoding DG, mapped in the α-DG N-terminal region, were found to be responsible for hypoglycosylated states, causing congenital diseases of different severity referred as primary dystroglycanopaties.To gain insight on the molecular basis of these disorders, we investigated the crystallographic and solution structures of these pathological point mutants, namely V72I, D109N and T190M. Small Angle X-ray Scattering analysis reveals that these mutations affect the structures in solution, altering the distribution between compact and more elongated conformations. These results, supported by biochemical and biophysical assays, point to an altered structural flexibility of the mutant α-DG N-terminal region that may have repercussions on its interaction with LARGE and/or other DG-modifying enzymes, eventually reducing their catalytic efficiency.

  16. [Fatal amnioinfusion with previous choriocarcinoma in a parturient woman].

    Science.gov (United States)

    Hrgović, Z; Bukovic, D; Mrcela, M; Hrgović, I; Siebzehnrübl, E; Karelovic, D

    2004-04-01

    The case of 36-year-old tercipare is described who developed choriocharcinoma in a previous pregnancy. During the first term labour the patient developed cardiac arrest, so reanimation and sectio cesarea was performed. A male new-born was delivered in good condition, but even after intensive therapy and reanimation occurred death of parturient woman with picture of disseminate intravascular coagulopathia (DIK). On autopsy and on histology there was no sign of malignant disease, so it was not possible to connect previous choricarcinoma with amniotic fluid embolism. Maybe was place of choriocarcinoma "locus minoris resistentiae" which later resulted with failure in placentation what was hard to prove. On autopsy we found embolia of lung with a microthrombosis of terminal circulation with punctiformis bleeding in mucous, what stands for DIK.

  17. Challenging previous conceptions of vegetarianism and eating disorders.

    Science.gov (United States)

    Fisak, B; Peterson, R D; Tantleff-Dunn, S; Molnar, J M

    2006-12-01

    The purpose of this study was to replicate and expand upon previous research that has examined the potential association between vegetarianism and disordered eating. Limitations of previous research studies are addressed, including possible low reliability of measures of eating pathology within vegetarian samples, use of only a few dietary restraint measures, and a paucity of research examining potential differences in body image and food choice motives of vegetarians versus nonvegetarians. Two hundred and fifty-six college students completed a number of measures of eating pathology and body image, and a food choice motives questionnaire. Interestingly, no significant differences were found between vegetarians and nonvegetarians in measures of eating pathology or body image. However, significant differences in food choice motives were found. Implications for both researchers and clinicians are discussed.

  18. Previous climatic alterations are caused by the sun

    International Nuclear Information System (INIS)

    Groenaas, Sigbjoern

    2003-01-01

    The article surveys the scientific results of previous research into the contribution of the sun to climatic alterations. The author concludes that there is evidence of eight cold periods after the last ice age and that the alterations largely were due to climate effects from the sun. However, these effects are only causing a fraction of the registered global warming. It is assumed that the human activities are contributing to the rest of the greenhouse effect

  19. Influence of previous knowledge in Torrance tests of creative thinking

    OpenAIRE

    Aranguren, María; Consejo Nacional de Investigaciones Científicas y Técnicas CONICET

    2015-01-01

    The aim of this work is to analyze the influence of study field, expertise and recreational activities participation in Torrance Tests of Creative Thinking (TTCT, 1974) performance. Several hypotheses were postulated to explore the possible effects of previous knowledge in TTCT verbal and TTCT figural university students’ outcomes. Participants in this study included 418 students from five study fields: Psychology;Philosophy and Literature, Music; Engineering; and Journalism and Advertisin...

  20. Analysis of previous screening examinations for patients with breast cancer

    International Nuclear Information System (INIS)

    Lee, Eun Hye; Cha, Joo Hee; Han, Dae Hee; Choi, Young Ho; Hwang, Ki Tae; Ryu, Dae Sik; Kwak, Jin Ho; Moon, Woo Kyung

    2007-01-01

    We wanted to improve the quality of subsequent screening by reviewing the previous screening of breast cancer patients. Twenty-four breast cancer patients who underwent previous screening were enrolled. All 24 took mammograms and 15 patients also took sonograms. We reviewed the screening retrospectively according to the BI-RADS criteria and we categorized the results into false negative, true negative, true positive and occult cancers. We also categorized the causes of false negative cancers into misperception, misinterpretation and technical factors and then we analyzed the attributing factors. Review of the previous screening revealed 66.7% (16/24) false negative, 25.0% (6/24) true negative, and 8.3% (2/24) true positive cancers. False negative cancers were caused by the mammogram in 56.3% (9/16) and by the sonogram in 43.7% (7/16). For the false negative cases, all of misperception were related with mammograms and this was attributed to dense breast, a lesion located at the edge of glandular tissue or the image, and findings seen on one view only. Almost all misinterpretations were related with sonograms and attributed to loose application of the final assessment. To improve the quality of breast screening, it is essential to overcome the main causes of false negative examinations, including misperception and misinterpretation. We need systematic education and strict application of final assessment categories of BI-RADS. For effective communication among physicians, it is also necessary to properly educate them about BI-RADS

  1. Docking-based modeling of protein-protein interfaces for extensive structural and functional characterization of missense mutations.

    Science.gov (United States)

    Barradas-Bautista, Didier; Fernández-Recio, Juan

    2017-01-01

    Next-generation sequencing (NGS) technologies are providing genomic information for an increasing number of healthy individuals and patient populations. In the context of the large amount of generated genomic data that is being generated, understanding the effect of disease-related mutations at molecular level can contribute to close the gap between genotype and phenotype and thus improve prevention, diagnosis or treatment of a pathological condition. In order to fully characterize the effect of a pathological mutation and have useful information for prediction purposes, it is important first to identify whether the mutation is located at a protein-binding interface, and second to understand the effect on the binding affinity of the affected interaction/s. Computational methods, such as protein docking are currently used to complement experimental efforts and could help to build the human structural interactome. Here we have extended the original pyDockNIP method to predict the location of disease-associated nsSNPs at protein-protein interfaces, when there is no available structure for the protein-protein complex. We have applied this approach to the pathological interaction networks of six diseases with low structural data on PPIs. This approach can almost double the number of nsSNPs that can be characterized and identify edgetic effects in many nsSNPs that were previously unknown. This can help to annotate and interpret genomic data from large-scale population studies, and to achieve a better understanding of disease at molecular level.

  2. Docking-based modeling of protein-protein interfaces for extensive structural and functional characterization of missense mutations.

    Directory of Open Access Journals (Sweden)

    Didier Barradas-Bautista

    Full Text Available Next-generation sequencing (NGS technologies are providing genomic information for an increasing number of healthy individuals and patient populations. In the context of the large amount of generated genomic data that is being generated, understanding the effect of disease-related mutations at molecular level can contribute to close the gap between genotype and phenotype and thus improve prevention, diagnosis or treatment of a pathological condition. In order to fully characterize the effect of a pathological mutation and have useful information for prediction purposes, it is important first to identify whether the mutation is located at a protein-binding interface, and second to understand the effect on the binding affinity of the affected interaction/s. Computational methods, such as protein docking are currently used to complement experimental efforts and could help to build the human structural interactome. Here we have extended the original pyDockNIP method to predict the location of disease-associated nsSNPs at protein-protein interfaces, when there is no available structure for the protein-protein complex. We have applied this approach to the pathological interaction networks of six diseases with low structural data on PPIs. This approach can almost double the number of nsSNPs that can be characterized and identify edgetic effects in many nsSNPs that were previously unknown. This can help to annotate and interpret genomic data from large-scale population studies, and to achieve a better understanding of disease at molecular level.

  3. The pathogenicity of genetic variants previously associated with left ventricular non-compaction

    DEFF Research Database (Denmark)

    Abbasi, Yeganeh; Jabbari, Javad; Jabbari, Reza

    2016-01-01

    BACKGROUND: Left ventricular non-compaction (LVNC) is a rare cardiomyopathy. Many genetic variants have been associated with LVNC. However, the number of the previous LVNC-associated variants that are common in the background population remains unknown. The aim of this study was to provide...... an updated list of previously reported LVNC-associated variants with biologic description and investigate the prevalence of LVNC variants in healthy general population to find false-positive LVNC-associated variants. METHODS AND RESULTS: The Human Gene Mutation Database and PubMed were systematically...... searched to identify all previously reported LVNC-associated variants. Thereafter, the Exome Sequencing Project (ESP) and the Exome Aggregation Consortium (ExAC), that both represent the background population, was searched for all variants. Four in silico prediction tools were assessed to determine...

  4. Study of some physical aspects previous to design of an exponential experiment

    International Nuclear Information System (INIS)

    Caro, R.; Francisco, J. L. de

    1961-01-01

    This report presents the theoretical study of some physical aspects previous to the design of an exponential facility. The are: Fast and slow flux distribution in the multiplicative medium and in the thermal column, slowing down in the thermal column, geometrical distribution and minimum needed intensity of sources access channels and perturbations produced by possible variations in its position and intensity. (Author) 4 refs

  5. Possible pulmonary Rhizopus oryzae infection in a previously healthy child after a near-drowning incident.

    Science.gov (United States)

    Gerlach, Magdalena M; Lippmann, Norman; Kobelt, Louise; Petzold-Quinque, Stefanie; Ritter, Lutz; Kiess, Wieland; Siekmeyer, Manuela

    2016-06-01

    This article reports on a previously healthy 17-month-old boy who developed pulmonary mucormycosis after a near-drowning incident in a goose pond. The patient survived without neurological sequelae and recovered, under treatment with amphotericin B, from the rare and often invasive fungal infection with Rhizopus spp., usually occurring in immunodeficient patients.

  6. Reading Aloud: Does Previous Trial History Modulate the Joint Effects of Stimulus Quality and Word Frequency?

    Science.gov (United States)

    O'Malley, Shannon; Besner, Derek

    2013-01-01

    No one would argue with the proposition that how we process events in the world is strongly affected by our experience. Nonetheless, recent experience (e.g., from the previous trial) is typically not considered in the analysis of timed cognitive performance in the laboratory. Masson and Kliegl (2013) reported that, in the context of the lexical…

  7. Wolff-Parkinson-White syndrome with cleft lip and palate: A rare, previously unreported association

    Directory of Open Access Journals (Sweden)

    K Kannan

    2008-01-01

    Full Text Available Wolff-Parkinson-White syndrome, also called Pre Excitation Syndrome, is characterized by an extra pathway that conducts the electrical impulses from the atria to the ventricles without the normal delay. We are reporting a case of WPW syndrome with a cleft lip and palate, which is a rare association and previously unreported in literature.

  8. Previous Mental Disorders and Subsequent Onset of Chronic Back or Neck Pain : Findings From 19 Countries

    NARCIS (Netherlands)

    Viana, Maria Carmen; Lim, Carmen C W; Garcia Pereira, Flavia; Aguilar-Gaxiola, Sergio; Alonso, Jordi; Bruffaerts, Ronny; de Jonge, Peter; Caldas-de-Almeida, Jose Miguel; O'Neill, Siobhan; Stein, Dan J; Al-Hamzawi, Ali; Benjet, Corina; Cardoso, Graça; Florescu, Silvia; de Girolamo, Giovanni; Haro, Josep Maria; Hu, Chiyi; Kovess-Masfety, Viviane; Levinson, Daphna; Piazza, Marina; Posada-Villa, José; Rabczenko, Daniel; Kessler, Ronald C; Scott, Kate M

    Associations between depression/anxiety and pain are well established, but its directionality is not clear. We examined the associations between temporally previous mental disorders and subsequent self-reported chronic back/neck pain onset, and investigated the variation in the strength of

  9. Effects of previous growth hormone excess and current medical treatment for acromegaly on cognition

    NARCIS (Netherlands)

    Brummelman, Pauline; Koerts, Janneke; Dullaart, Robin P. F.; van den Berg, Gerrit; Tucha, Oliver; Wolffenbuttel, Bruce H. R.; van Beek, Andre P.

    2012-01-01

    Background In untreated acromegaly patients, decreased cognitive functioning is reported to be associated with the degree of growth hormone (GH) and IGF-1 excess. Whether previous GH excess or current medical treatment for acromegaly specifically affects cognition remains unclear. The aim of this

  10. Iodine-131 induced hepatotoxicity in previously healthy patients with Grave's disease.

    Science.gov (United States)

    Jhummon, Navina Priya; Tohooloo, Bhavna; Qu, Shen

    2013-01-01

    To describe the association of the rare and serious complication of liver toxicity in previously healthy Grave's disease (GD) patients after the treatment with radioactive iodine (131)I (RAI). We report the clinical, laboratory and pathologic findings of 2 cases of severe liver toxicity associated with the treatment with RAI in previously healthy patients with GD. Clinical examination and laboratory investigations excluded viral hepatitis, autoimmune hepatitis, granulomatous disease, primary biliary disease, extrahepatic biliary obstruction, and heart failure. Case 1: A previously healthy 52-years old man reportedly having a typical GD but following RAI treatment, concomitantly developed severe liver toxicity that required 1 week of treatment in hospital. Case 2: A previously healthy 34-years old woman is reported as having a typical GD but developed jaundice following RAI treatment that required several weeks of in hospital treatment in the hepato-biliary department. In both cases, the liver dysfunction resolved after intensive treatment with hepato-protective agents. In this report the therapeutic considerations as well as the pathogenetic possibilities are reviewed. To the best of our knowledge, this is the first description of the association observed, which is rare but may be severe and should be considered in any case of thyrotoxicosis where a liver dysfunction develops after the treatment with radioactive iodine (131)I.

  11. Iodine-131 induced hepatotoxicity in previously healthy patients with Grave’s disease

    Science.gov (United States)

    2013-01-01

    Objective To describe the association of the rare and serious complication of liver toxicity in previously healthy Grave’s disease (GD) patients after the treatment with radioactive iodine 131I (RAI). Case presentation We report the clinical, laboratory and pathologic findings of 2 cases of severe liver toxicity associated with the treatment with RAI in previously healthy patients with GD. Clinical examination and laboratory investigations excluded viral hepatitis, autoimmune hepatitis, granulomatous disease, primary biliary disease, extrahepatic biliary obstruction, and heart failure. Case 1: A previously healthy 52-years old man reportedly having a typical GD but following RAI treatment, concomitantly developed severe liver toxicity that required 1 week of treatment in hospital. Case 2: A previously healthy 34-years old woman is reported as having a typical GD but developed jaundice following RAI treatment that required several weeks of in hospital treatment in the hepato-biliary department. In both cases, the liver dysfunction resolved after intensive treatment with hepato-protective agents. In this report the therapeutic considerations as well as the pathogenetic possibilities are reviewed. Conclusion To the best of our knowledge, this is the first description of the association observed, which is rare but may be severe and should be considered in any case of thyrotoxicosis where a liver dysfunction develops after the treatment with radioactive iodine 131I. PMID:23497434

  12. Long-term effects of previous oxandrolone treatment in adult women with Turner syndrome

    NARCIS (Netherlands)

    Freriks, K.; Sas, T.C.J.; Traas, M.A.F.; Netea-Maier, R.T.; Heijer, M. den; Hermus, A.R.M.M.; Wit, J.M.; Alfen-van der Velden, J. van; Otten, B.J.; Muinck Keizer-Schrama, S.M.P.F. de; Gotthardt, M.; Dejonckere, P.H.; Zandwijken, G.R.; Menke, L.A.; Timmers, H.J.L.M.

    2013-01-01

    OBJECTIVE: Short stature is a prominent feature of Turner syndrome (TS), which is partially overcome by GH treatment. We have previously reported the results of a trial on the effect of oxandrolone (Ox) in girls with TS. Ox in a dose of 0.03 mg/kg per day (Ox 0.03) significantly increased adult

  13. Long-term effects of previous oxandrolone treatment in adult women with Turner syndrome

    NARCIS (Netherlands)

    K. Freriks (Kim); T.C.J. Sas (Theo); T. Traas (Theo); R.T. Netea-Maier (Romana ); M. den Heijer (Martin); A.R.M.M. Hermus (Ad); J.M. Wit (Jan); J.A.E.M. Van Alfen-van Der Velden (Janiëlle A. E.); B.J. Otten (Barto); S.M.P.F. de Muinck Keizer-Schrama (Sabine); M. Gotthardt (Martin); P.H. Dejonckere (Philippe); G.R.J. Zandwijken (Gladys); L.A. Menke (Leonie); H.J.L.M. Timmers

    2013-01-01

    textabstractObjective: Short stature is a prominent feature of Turner syndrome (TS), which is partially overcome by GH treatment. We have previously reported the results of a trial on the effect of oxandrolone (Ox) in girls with TS. Ox in a dose of 0.03 mg/kg per day (Ox 0.03) significantly

  14. Pulmonary carcinosarcoma initially presenting as invasive aspergillosis: a case report of previously unreported combination

    Directory of Open Access Journals (Sweden)

    Van Thien

    2010-01-01

    Full Text Available Abstract Carcinosarcoma of the lung is a malignant tumor composed of a mixture of carcinoma and sarcoma elements. The carcinomatous component is most commonly squamous followed by adenocarcinoma. The sarcomatous component commonly comprises the bulk of the tumor and shows poorly differentiated spindle cell features. Foci of differentiated sarcomatous elements such as chondrosarcoma and osteosarcoma may be seen. Aspergillus pneumonia is the most common form of invasive aspergillosis and occurs mainly in patients with malignancy, immunocompromizing or debilitating diseases. Patients with Aspergillus pneumonia present with fever, cough, chest pain and occasionally hemoptysis. Tissue examination is the most reliable method for diagnosis, and mortality rate is high. We describe a case of primary carcinosarcoma of the lung concurrently occurring with invasive pulmonary aspergillosis in a 66-year old patient.

  15. Non-detection of Previously Reported Transits of HD 97658b with MOST Photometry

    DEFF Research Database (Denmark)

    Dragomir, Diana; Matthews, Jaymie M.; Howard, Andrew W.

    2012-01-01

    The radial velocity-discovered exoplanet HD 97658b was recently announced to transit, with a derived planetary radius of 2.93 ± 0.28 R ⊕. As a transiting super-Earth orbiting a bright star, this planet would make an attractive candidate for additional observations, including studies of its atmosp...

  16. Moyamoya disease in a child with previous acute necrotizing encephalopathy

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Taik-Kun; Cha, Sang Hoon; Chung, Kyoo Byung; Kim, Jung Hyuck; Kim, Baek Hyun; Chung, Hwan Hoon [Department of Diagnostic Radiology, Korea University College of Medicine, Ansan Hospital, 516 Kojan-Dong, Ansan City, Kyungki-Do 425-020 (Korea); Eun, Baik-Lin [Department of Pediatrics, Korea University College of Medicine, Seoul (Korea)

    2003-09-01

    A previously healthy 24-day-old boy presented with a 2-day history of fever and had a convulsion on the day of admission. MRI showed abnormal signal in the thalami, caudate nuclei and central white matter. Acute necrotising encephalopathy was diagnosed, other causes having been excluded after biochemical and haematological analysis of blood, urine and CSF. He recovered, but with spastic quadriparesis. At the age of 28 months, he suffered sudden deterioration of consciousness and motor weakness of his right limbs. MRI was consistent with an acute cerebrovascular accident. Angiography showed bilateral middle cerebral artery stenosis or frank occlusion with numerous lenticulostriate collateral vessels consistent with moyamoya disease. (orig.)

  17. MCNP HPGe detector benchmark with previously validated Cyltran model.

    Science.gov (United States)

    Hau, I D; Russ, W R; Bronson, F

    2009-05-01

    An exact copy of the detector model generated for Cyltran was reproduced as an MCNP input file and the detection efficiency was calculated similarly with the methodology used in previous experimental measurements and simulation of a 280 cm(3) HPGe detector. Below 1000 keV the MCNP data correlated to the Cyltran results within 0.5% while above this energy the difference between MCNP and Cyltran increased to about 6% at 4800 keV, depending on the electron cut-off energy.

  18. HEART TRANSPLANTATION IN PATIENTS WITH PREVIOUS OPEN HEART SURGERY

    Directory of Open Access Journals (Sweden)

    R. Sh. Saitgareev

    2016-01-01

    Full Text Available Heart Transplantation (HTx to date remains the most effective and radical method of treatment of patients with end-stage heart failure. The defi cit of donor hearts is forcing to resort increasingly to the use of different longterm mechanical circulatory support systems, including as a «bridge» to the follow-up HTx. According to the ISHLT Registry the number of recipients underwent cardiopulmonary bypass surgery increased from 40% in the period from 2004 to 2008 to 49.6% for the period from 2009 to 2015. HTx performed in repeated patients, on the one hand, involves considerable technical diffi culties and high risks; on the other hand, there is often no alternative medical intervention to HTx, and if not dictated by absolute contradictions the denial of the surgery is equivalent to 100% mortality. This review summarizes the results of a number of published studies aimed at understanding the immediate and late results of HTx in patients, previously underwent open heart surgery. The effect of resternotomy during HTx and that of the specifi c features associated with its implementation in recipients previously operated on open heart, and its effects on the immediate and long-term survival were considered in this review. Results of studies analyzing the risk factors for perioperative complications in repeated recipients were also demonstrated. Separately, HTx risks after implantation of prolonged mechanical circulatory support systems were examined. The literature does not allow to clearly defi ning the impact factor of earlier performed open heart surgery on the course of perioperative period and on the prognosis of survival in recipients who underwent HTx. On the other hand, subject to the regular fl ow of HTx and the perioperative period the risks in this clinical situation are justifi ed as a long-term prognosis of recipients previously conducted open heart surgery and are comparable to those of patients who underwent primary HTx. Studies

  19. Proteomics Analysis Reveals Previously Uncharacterized Virulence Factors in Vibrio proteolyticus

    Directory of Open Access Journals (Sweden)

    Ann Ray

    2016-07-01

    Full Text Available Members of the genus Vibrio include many pathogens of humans and marine animals that share genetic information via horizontal gene transfer. Hence, the Vibrio pan-genome carries the potential to establish new pathogenic strains by sharing virulence determinants, many of which have yet to be characterized. Here, we investigated the virulence properties of Vibrio proteolyticus, a Gram-negative marine bacterium previously identified as part of the Vibrio consortium isolated from diseased corals. We found that V. proteolyticus causes actin cytoskeleton rearrangements followed by cell lysis in HeLa cells in a contact-independent manner. In search of the responsible virulence factor involved, we determined the V. proteolyticus secretome. This proteomics approach revealed various putative virulence factors, including active type VI secretion systems and effectors with virulence toxin domains; however, these type VI secretion systems were not responsible for the observed cytotoxic effects. Further examination of the V. proteolyticus secretome led us to hypothesize and subsequently demonstrate that a secreted hemolysin, belonging to a previously uncharacterized clan of the leukocidin superfamily, was the toxin responsible for the V. proteolyticus-mediated cytotoxicity in both HeLa cells and macrophages. Clearly, there remains an armory of yet-to-be-discovered virulence factors in the Vibrio pan-genome that will undoubtedly provide a wealth of knowledge on how a pathogen can manipulate host cells.

  20. Incidence of Acneform Lesions in Previously Chemically Damaged Persons-2004

    Directory of Open Access Journals (Sweden)

    N Dabiri

    2008-04-01

    Full Text Available ABSTRACT: Introduction & Objective: Chemical gas weapons especially nitrogen mustard which was used in Iraq-Iran war against Iranian troops have several harmful effects on skin. Some other chemical agents also can cause acne form lesions on skin. The purpose of this study was to compare the incidence of acneform in previously chemically damaged soldiers and non chemically damaged persons. Materials & Methods: In this descriptive and analytical study, 180 chemically damaged soldiers, who have been referred to dermatology clinic between 2000 – 2004, and forty non-chemically damaged people, were chosen randomly and examined for acneform lesions. SPSS software was used for statistic analysis of the data. Results: The mean age of the experimental group was 37.5 ± 5.2 and that of the control group was 38.7 ± 5.9 years. The mean percentage of chemical damage in cases was 31 percent and the time after the chemical damage was 15.2 ± 1.1 years. Ninety seven cases (53.9 percent of the subjects and 19 people (47.5 percent of the control group had some degree of acne. No significant correlation was found in incidence, degree of lesions, site of lesions and age of subjects between two groups. No significant correlation was noted between percentage of chemical damage and incidence and degree of lesions in case group. Conclusion: Incidence of acneform lesions among previously chemically injured peoples was not higher than the normal cases.

  1. Relationship of deer and moose populations to previous winters' snow

    Science.gov (United States)

    Mech, L.D.; McRoberts, R.E.; Peterson, R.O.; Page, R.E.

    1987-01-01

    (1) Linear regression was used to relate snow accumulation during single and consecutive winters with white-tailed deer (Odocoileus virginianus) fawn:doe ratios, mosse (Alces alces) twinning rates and calf:cow ratios, and annual changes in deer and moose populations. Significant relationships were found between snow accumulation during individual winters and these dependent variables during the following year. However, the strongest relationships were between the dependent variables and the sums of the snow accumulations over the previous three winters. The percentage of the variability explained was 36 to 51. (2) Significant relationships were also found between winter vulnerability of moose calves and the sum of the snow accumulations in the current, and up to seven previous, winters, with about 49% of the variability explained. (3) No relationship was found between wolf numbers and the above dependent variables. (4) These relationships imply that winter influences on maternal nutrition can accumulate for several years and that this cumulative effect strongly determines fecundity and/or calf and fawn survivability. Although wolf (Canis lupus L.) predation is the main direct mortality agent on fawns and calves, wolf density itself appears to be secondary to winter weather in influencing the deer and moose populations.

  2. Kidnapping Detection and Recognition in Previous Unknown Environment

    Directory of Open Access Journals (Sweden)

    Yang Tian

    2017-01-01

    Full Text Available An unaware event referred to as kidnapping makes the estimation result of localization incorrect. In a previous unknown environment, incorrect localization result causes incorrect mapping result in Simultaneous Localization and Mapping (SLAM by kidnapping. In this situation, the explored area and unexplored area are divided to make the kidnapping recovery difficult. To provide sufficient information on kidnapping, a framework to judge whether kidnapping has occurred and to identify the type of kidnapping with filter-based SLAM is proposed. The framework is called double kidnapping detection and recognition (DKDR by performing two checks before and after the “update” process with different metrics in real time. To explain one of the principles of DKDR, we describe a property of filter-based SLAM that corrects the mapping result of the environment using the current observations after the “update” process. Two classical filter-based SLAM algorithms, Extend Kalman Filter (EKF SLAM and Particle Filter (PF SLAM, are modified to show that DKDR can be simply and widely applied in existing filter-based SLAM algorithms. Furthermore, a technique to determine the adapted thresholds of metrics in real time without previous data is presented. Both simulated and experimental results demonstrate the validity and accuracy of the proposed method.

  3. [ANTITHROMBOTIC MEDICATION IN PREGNANT WOMEN WITH PREVIOUS INTRAUTERINE GROWTH RESTRICTION].

    Science.gov (United States)

    Neykova, K; Dimitrova, V; Dimitrov, R; Vakrilova, L

    2016-01-01

    To analyze pregnancy outcome in patients who were on antithrombotic medication (AM) because of previous pregnancy with fetal intrauterine growth restriction (IUGR). The studied group (SG) included 21 pregnancies in 15 women with history of previous IUGR. The patients were on low dose aspirin (LDA) and/or low molecular weight heparin (LMWH). Pregnancy outcome was compared to the one in two more groups: 1) primary group (PG) including the previous 15 pregnancies with IUGR of the same women; 2) control group (CG) including 45 pregnancies of women matched for parity with the ones in the SG, with no history of IUGR and without medication. The SG, PG and CG were compared for the following: mean gestational age (g.a.) at birth, mean birth weight (BW), proportion of cases with early preeclampsia (PE), IUGR (total, moderate, and severe), intrauterine fetal death (IUFD), neonatal death (NND), admission to NICU, cesarean section (CS) because of chronic or acute fetal distress (FD) related to IUGR, PE or placental abruption. Student's t-test was applied to assess differences between the groups. P values < 0.05 were considered statistically significant. The differences between the SG and the PG regarding mean g. a. at delivery (33.7 and 29.8 w.g. respectively) and the proportion of babies admitted to NICU (66.7% vs. 71.4%) were not statistically significant. The mean BW in the SG (2114,7 g.) was significantly higher than in the PG (1090.8 g.). In the SG compared with the PG there were significantly less cases of IUFD (14.3% and 53.3% respectively), early PE (9.5% vs. 46.7%) moderate and severe IUGR (10.5% and 36.8% vs. 41.7% and 58.3%). Neonatal mortality in the SG (5.6%) was significantly lower than in the PG (57.1%), The proportion of CS for FD was not significantly different--53.3% in the SG and 57.1% in the PG. On the other hand, comparison between the SG and the CG demonstrated significantly lower g.a. at delivery in the SG (33.7 vs. 38 w.g.) an lower BW (2114 vs. 3094 g

  4. Case reports of juvenile GM1 gangliosidosisis type II caused by mutation in GLB1 gene.

    Science.gov (United States)

    Karimzadeh, Parvaneh; Naderi, Samaneh; Modarresi, Farzaneh; Dastsooz, Hassan; Nemati, Hamid; Farokhashtiani, Tayebeh; Shamsian, Bibi Shahin; Inaloo, Soroor; Faghihi, Mohammad Ali

    2017-07-17

    Type II or juvenile GM1-gangliosidosis is an autosomal recessive lysosomal storage disorder, which is clinically distinct from infantile form of the disease by the lack of characteristic cherry-red spot and hepatosplenomegaly. The disease is characterized by slowly progressive neurodegeneration and mild skeletal changes. Due to the later age of onset and uncharacteristic presentation, diagnosis is frequently puzzled with other ataxic and purely neurological disorders. Up to now, 3-4 types of GM1-gangliosidosis have been reported and among them type I is the most common phenotype with the age of onset around 6 months. Various forms of GM1-gangliosidosis are caused by GLB1 gene mutations but severity of the disease and age of onset are directly related to the position and the nature of deleterious mutations. However, due to its unique genetic cause and overlapping clinical features, some researchers believe that GM1 gangliosidosis represents an overlapped disease spectrum instead of four distinct types. Here, we report a less frequent type of autosomal recessive GM1 gangliosidosis with perplexing clinical presentation in three families in the southwest part of Iran, who are unrelated but all from "Lurs" ethnic background. To identify disease-causing mutations, Whole Exome Sequencing (WES) utilizing next generation sequencing was performed. Four patients from three families were investigated with the age of onset around 3 years old. Clinical presentations were ataxia, gate disturbances and dystonia leading to wheelchair-dependent disability, regression of intellectual abilities, and general developmental regression. They all were born in consanguineous families with no previous documented similar disease in their parents. A homozygote missense mutation in GLB1 gene (c. 601 G > A, p.R201C) was found in all patients. Using Sanger sequencing this identified mutation was confirmed in the proband, their parents, grandparents, and extended family members, confirming

  5. The Kavirondo Escarpment: a previously unrecognized site of high ...

    African Journals Online (AJOL)

    Despite only a limited effort there, we report several new atlas square occurrences, presence of the local and poorly known Rock Cisticola Cisticola emini and a significant range extension for the Stone Partridge Ptilopachus petrosus. Our short visits indicate high avian species richness is associated with the escarpment and ...

  6. Metastatic papillary carcinoma of the thyroid in a patient previously ...

    African Journals Online (AJOL)

    Incidental papillary carcinoma of the thyroid in patients treated surgically for benign thyroid diseases including Graves' disease is a known phenomenon. However, the management of these patients remains an issue of concern and controversy for those who care for them. We report a case of metastatic paillary carcinoma of ...

  7. Elucidating the clinical significance of two PMS2 missense variants coexisting in a family fulfilling hereditary cancer criteria.

    Science.gov (United States)

    González-Acosta, Maribel; Del Valle, Jesús; Navarro, Matilde; Thompson, Bryony A; Iglesias, Sílvia; Sanjuan, Xavier; Paúles, María José; Padilla, Natàlia; Fernández, Anna; Cuesta, Raquel; Teulé, Àlex; Plotz, Guido; Cadiñanos, Juan; de la Cruz, Xavier; Balaguer, Francesc; Lázaro, Conxi; Pineda, Marta; Capellá, Gabriel

    2017-10-01

    The clinical spectrum of germline mismatch repair (MMR) gene variants continues increasing, encompassing Lynch syndrome, Constitutional MMR Deficiency (CMMRD), and the recently reported MSH3-associated polyposis. Genetic diagnosis of these hereditary cancer syndromes is often hampered by the presence of variants of unknown significance (VUS) and overlapping phenotypes. Two PMS2 VUS, c.2149G>A (p.V717M) and c.2444C>T (p.S815L), were identified in trans in one individual diagnosed with early-onset colorectal cancer (CRC) who belonged to a family fulfilling clinical criteria for hereditary cancer. Clinico-pathological data, multifactorial likelihood calculations and functional analyses were used to refine their clinical significance. Likelihood analysis based on cosegregation and tumor data classified the c.2444C>T variant as pathogenic, which was supported by impaired MMR activity associated with diminished protein expression in functional assays. Conversely, the c.2149G>A variant displayed MMR proficiency and protein stability. These results, in addition to the conserved PMS2 expression in normal tissues and the absence of germline microsatellite instability (gMSI) in the biallelic carrier ruled out a CMMRD diagnosis. The use of comprehensive strategies, including functional and clinico-pathological information, is mandatory to improve the clinical interpretation of naturally occurring MMR variants. This is critical for appropriate clinical management of cancer syndromes associated to MMR gene mutations.

  8. Deepwater Gulf of Mexico more profitable than previously thought

    International Nuclear Information System (INIS)

    Craig, M.J.K.; Hyde, S.T.

    1997-01-01

    Economic evaluations and recent experience show that the deepwater Gulf of Mexico (GOM) is much more profitable than previously thought. Four factors contributing to the changed viewpoint are: First, deepwater reservoirs have proved to have excellent productive capacity, distribution, and continuity when compared to correlative-age shelf deltaic sands. Second, improved technologies and lower perceived risks have lowered the cost of floating production systems (FPSs). Third, projects now get on-line quicker. Fourth, a collection of other important factors are: Reduced geologic risk and associated high success rates for deepwater GOM wells due primarily to improved seismic imaging and processing tools (3D, AVO, etc.); absence of any political risk in the deepwater GOM (common overseas, and very significant in some international areas); and positive impact of deepwater federal royalty relief. This article uses hypothetical reserve distributions and price forecasts to illustrate indicative economics of deepwater prospects. Economics of Shell Oil Co.'s three deepwater projects are also discussed

  9. Corneal perforation after conductive keratoplasty with previous refractive surgery.

    Science.gov (United States)

    Kymionis, George D; Titze, Patrik; Markomanolakis, Marinos M; Aslanides, Ioannis M; Pallikaris, Ioannis G

    2003-12-01

    A 56-year-old woman had conductive keratoplasty (CK) for residual hyperopia and astigmatism. Three years before the procedure, the patient had arcuate keratotomy, followed by laser in situ keratomileusis 2 years later for high astigmatism correction in both eyes. During CK, a corneal perforation occurred in the right eye; during the postoperative examination, an iris perforation and anterior subcapsule opacification were seen beneath the perforation site. The perforation was managed with a bandage contact lens and an antibiotic-steroid ointment; it had a negative Seidel sign by the third day. The surgery in the left eye was uneventful. Three months after the procedure, the uncorrected visual acuity was 20/32 and the best corrected visual acuity 20/20 in both eyes with a significant improvement in corneal topography. Care must be taken to prevent CK-treated spots from coinciding with areas in the corneal stroma that might have been altered by previous refractive procedures.

  10. Interference from previous distraction disrupts older adults' memory.

    Science.gov (United States)

    Biss, Renée K; Campbell, Karen L; Hasher, Lynn

    2013-07-01

    Previously relevant information can disrupt the ability of older adults to remember new information. Here, the researchers examined whether prior irrelevant information, or distraction, can also interfere with older adults' memory for new information. Younger and older adults first completed a 1-back task on pictures that were superimposed with distracting words. After a delay, participants learned picture-word paired associates and memory was tested using picture-cued recall. In 1 condition (high interference), some pairs included pictures from the 1-back task now paired with new words. In a low-interference condition, the transfer list used all new items. Older adults had substantially lower cued-recall performance in the high- compared with the low-interference condition. In contrast, younger adults' performance did not vary across conditions. These findings suggest that even never-relevant information from the past can disrupt older adults' memory for new associations.

  11. The long-term consequences of previous hyperthyroidism

    DEFF Research Database (Denmark)

    Hjelm Brandt Kristensen, Frans

    2015-01-01

    Thyroid hormones affect every cell in the human body, and the cardiovascular changes associated with increased levels of thyroid hormones are especially well described. As an example, short-term hyperthyroidism has positive chronotropic and inotropic effects on the heart, leading to a hyperdynamic...... with CVD, LD and DM both before and after the diagnosis of hyperthyroidism. Although the design used does not allow a stringent distinction between cause and effect, the findings indicate a possible direct association between hyperthyroidism and these morbidities, or vice versa....... vascular state. While it is biologically plausible that these changes may induce long-term consequences, the insight into morbidity as well as mortality in patients with previous hyperthyroidism is limited. The reasons for this are a combination of inadequately powered studies, varying definitions...

  12. Is Previous Respiratory Disease a Risk Factor for Lung Cancer?

    Science.gov (United States)

    Denholm, Rachel; Schüz, Joachim; Straif, Kurt; Stücker, Isabelle; Jöckel, Karl-Heinz; Brenner, Darren R.; De Matteis, Sara; Boffetta, Paolo; Guida, Florence; Brüske, Irene; Wichmann, Heinz-Erich; Landi, Maria Teresa; Caporaso, Neil; Siemiatycki, Jack; Ahrens, Wolfgang; Pohlabeln, Hermann; Zaridze, David; Field, John K.; McLaughlin, John; Demers, Paul; Szeszenia-Dabrowska, Neonila; Lissowska, Jolanta; Rudnai, Peter; Fabianova, Eleonora; Dumitru, Rodica Stanescu; Bencko, Vladimir; Foretova, Lenka; Janout, Vladimir; Kendzia, Benjamin; Peters, Susan; Behrens, Thomas; Vermeulen, Roel; Brüning, Thomas; Kromhout, Hans

    2014-01-01

    Rationale: Previous respiratory diseases have been associated with increased risk of lung cancer. Respiratory conditions often co-occur and few studies have investigated multiple conditions simultaneously. Objectives: Investigate lung cancer risk associated with chronic bronchitis, emphysema, tuberculosis, pneumonia, and asthma. Methods: The SYNERGY project pooled information on previous respiratory diseases from 12,739 case subjects and 14,945 control subjects from 7 case–control studies conducted in Europe and Canada. Multivariate logistic regression models were used to investigate the relationship between individual diseases adjusting for co-occurring conditions, and patterns of respiratory disease diagnoses and lung cancer. Analyses were stratified by sex, and adjusted for age, center, ever-employed in a high-risk occupation, education, smoking status, cigarette pack-years, and time since quitting smoking. Measurements and Main Results: Chronic bronchitis and emphysema were positively associated with lung cancer, after accounting for other respiratory diseases and smoking (e.g., in men: odds ratio [OR], 1.33; 95% confidence interval [CI], 1.20–1.48 and OR, 1.50; 95% CI, 1.21–1.87, respectively). A positive relationship was observed between lung cancer and pneumonia diagnosed 2 years or less before lung cancer (OR, 3.31; 95% CI, 2.33–4.70 for men), but not longer. Co-occurrence of chronic bronchitis and emphysema and/or pneumonia had a stronger positive association with lung cancer than chronic bronchitis “only.” Asthma had an inverse association with lung cancer, the association being stronger with an asthma diagnosis 5 years or more before lung cancer compared with shorter. Conclusions: Findings from this large international case–control consortium indicate that after accounting for co-occurring respiratory diseases, chronic bronchitis and emphysema continue to have a positive association with lung cancer. PMID:25054566

  13. Twelve previously unknown phage genera are ubiquitous in global oceans.

    Science.gov (United States)

    Holmfeldt, Karin; Solonenko, Natalie; Shah, Manesh; Corrier, Kristen; Riemann, Lasse; Verberkmoes, Nathan C; Sullivan, Matthew B

    2013-07-30

    Viruses are fundamental to ecosystems ranging from oceans to humans, yet our ability to study them is bottlenecked by the lack of ecologically relevant isolates, resulting in "unknowns" dominating culture-independent surveys. Here we present genomes from 31 phages infecting multiple strains of the aquatic bacterium Cellulophaga baltica (Bacteroidetes) to provide data for an underrepresented and environmentally abundant bacterial lineage. Comparative genomics delineated 12 phage groups that (i) each represent a new genus, and (ii) represent one novel and four well-known viral families. This diversity contrasts the few well-studied marine phage systems, but parallels the diversity of phages infecting human-associated bacteria. Although all 12 Cellulophaga phages represent new genera, the podoviruses and icosahedral, nontailed ssDNA phages were exceptional, with genomes up to twice as large as those previously observed for each phage type. Structural novelty was also substantial, requiring experimental phage proteomics to identify 83% of the structural proteins. The presence of uncommon nucleotide metabolism genes in four genera likely underscores the importance of scavenging nutrient-rich molecules as previously seen for phages in marine environments. Metagenomic recruitment analyses suggest that these particular Cellulophaga phages are rare and may represent a first glimpse into the phage side of the rare biosphere. However, these analyses also revealed that these phage genera are widespread, occurring in 94% of 137 investigated metagenomes. Together, this diverse and novel collection of phages identifies a small but ubiquitous fraction of unknown marine viral diversity and provides numerous environmentally relevant phage-host systems for experimental hypothesis testing.

  14. Typing DNA profiles from previously enhanced fingerprints using direct PCR.

    Science.gov (United States)

    Templeton, Jennifer E L; Taylor, Duncan; Handt, Oliva; Linacre, Adrian

    2017-07-01

    Fingermarks are a source of human identification both through the ridge patterns and DNA profiling. Typing nuclear STR DNA markers from previously enhanced fingermarks provides an alternative method of utilising the limited fingermark deposit that can be left behind during a criminal act. Dusting with fingerprint powders is a standard method used in classical fingermark enhancement and can affect DNA data. The ability to generate informative DNA profiles from powdered fingerprints using direct PCR swabs was investigated. Direct PCR was used as the opportunity to generate usable DNA profiles after performing any of the standard DNA extraction processes is minimal. Omitting the extraction step will, for many samples, be the key to success if there is limited sample DNA. DNA profiles were generated by direct PCR from 160 fingermarks after treatment with one of the following dactyloscopic fingerprint powders: white hadonite; silver aluminium; HiFi Volcano silk black; or black magnetic fingerprint powder. This was achieved by a combination of an optimised double-swabbing technique and swab media, omission of the extraction step to minimise loss of critical low-template DNA, and additional AmpliTaq Gold ® DNA polymerase to boost the PCR. Ninety eight out of 160 samples (61%) were considered 'up-loadable' to the Australian National Criminal Investigation DNA Database (NCIDD). The method described required a minimum of working steps, equipment and reagents, and was completed within 4h. Direct PCR allows the generation of DNA profiles from enhanced prints without the need to increase PCR cycle numbers beyond manufacturer's recommendations. Particular emphasis was placed on preventing contamination by applying strict protocols and avoiding the use of previously used fingerprint brushes. Based on this extensive survey, the data provided indicate minimal effects of any of these four powders on the chance of obtaining DNA profiles from enhanced fingermarks. Copyright © 2017

  15. Compared effects of missense mutations in Very-Long-Chain Acyl-CoA Dehydrogenase deficiency: Combined analysis by structural, functional and pharmacological approaches.

    Science.gov (United States)

    Gobin-Limballe, Stéphanie; McAndrew, Ryan P; Djouadi, Fatima; Kim, Jung-Ja; Bastin, Jean

    2010-05-01

    Very-Long-Chain Acyl-CoA Dehydrogenase deficiency (VLCADD) is an autosomal recessive disorder considered as one of the more common ss-oxidation defects, possibly associated with neonatal cardiomyopathy, infantile hepatic coma, or adult-onset myopathy. Numerous gene missense mutations have been described in these VLCADD phenotypes, but only few of them have been structurally and functionally analyzed, and the molecular basis of disease variability is still poorly understood. To address this question, we first analyzed fourteen disease-causing amino acid changes using the recently described crystal structure of VLCAD. The predicted effects varied from the replacement of amino acid residues lining the substrate binding cavity, involved in holoenzyme-FAD interactions or in enzyme dimerisation, predicted to have severe functional consequences, up to amino acid substitutions outside key enzyme domains or lying on near enzyme surface, with predicted milder consequences. These data were combined with functional analysis of residual fatty acid oxidation (FAO) and VLCAD protein levels in patient cells harboring these mutations, before and after pharmacological stimulation by bezafibrate. Mutations identified as detrimental to the protein structure in the 3-D model were generally associated to profound FAO and VLCAD protein deficiencies in the patient cells, however, some mutations affecting FAD binding or monomer-monomer interactions allowed a partial response to bezafibrate. On the other hand, bezafibrate restored near-normal FAO rates in some mutations predicted to have milder consequences on enzyme structure. Overall, combination of structural, biochemical, and pharmacological analysis allowed assessment of the relative severity of individual mutations, with possible applications for disease management and therapeutic approach. Copyright 2010 Elsevier B.V. All rights reserved.

  16. Hereditary 1,25-dihydroxyvitamin D-resistant rickets with alopecia resulting from a novel missense mutation in the DNA-binding domain of the vitamin D receptor

    Science.gov (United States)

    Malloy, Peter J.; Wang, Jining; Srivastava, Tarak; Feldman, David

    2009-01-01

    The rare genetic recessive disease, hereditary vitamin D resistant rickets (HVDRR), is caused by mutations in the vitamin D receptor (VDR) that result in resistance to the active hormone 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3 or calcitriol). In this study, we examined the VDR from a young boy with clinical features of HVDRR including severe rickets, hypocalcemia, hypophosphatemia and partial alopecia. The pattern of alopecia was very unusual with areas of total baldness, adjacent to normal hair and regions of scant hair. The child failed to improve on oral calcium and vitamin D therapy but his abnormal chemistries and his bone x-rays normalized with intravenous calcium therapy. We found that the child was homozygous for a unique missense mutation in the VDR gene that converted valine to methionine at amino acid 26 (V26M) in the VDR DNA-binding domain (DBD). The mutant VDR was studied in the patient’s cultured skin fibroblasts and found to exhibit normal [3H]1,25-(OH)2D3 binding and protein expression. However, the fibroblasts were unresponsive to treatment with high concentrations of 1,25(OH)2D3 as demonstrated by their failure to induce CYP24A1 gene expression, a marker of 1,25(OH)2D3 responsiveness. We recreated the V26M mutation in the WT VDR and showed that in transfected COS-7 cells the mutation abolished 1,25(OH)2D3-mediated transactivation. The mutant VDR exhibited normal ligand-induced binding to RXRα and to the coactivator DRIP205. However, the V26M mutation inhibited VDR binding to a consensus vitamin D response element (VDRE). In summary, we have identified a novel V26M mutation in the VDR DBD as the molecular defect in a patient with HVDRR and an unusual pattern of alopecia. PMID:19815438

  17. Rats with a missense mutation in Atm display neuroinflammation and neurodegeneration subsequent to accumulation of cytosolic DNA following unrepaired DNA damage.

    Science.gov (United States)

    Quek, Hazel; Luff, John; Cheung, KaGeen; Kozlov, Sergei; Gatei, Magtouf; Lee, C Soon; Bellingham, Mark C; Noakes, Peter G; Lim, Yi Chieh; Barnett, Nigel L; Dingwall, Steven; Wolvetang, Ernst; Mashimo, Tomoji; Roberts, Tara L; Lavin, Martin F

    2017-04-01

    Mutations in the ataxia-telangiectasia (A-T)-mutated ( ATM ) gene give rise to the human genetic disorder A-T, characterized by immunodeficiency, cancer predisposition, and neurodegeneration. Whereas a series of animal models recapitulate much of the A-T phenotype, they fail to present with ataxia or neurodegeneration. We describe here the generation of an Atm missense mutant [amino acid change of leucine (L) to proline (P) at position 2262 (L2262P)] rat by intracytoplasmic injection (ICSI) of mutant sperm into oocytes. Atm -mutant rats ( Atm L2262P/L2262P ) expressed low levels of ATM protein, suggesting a destabilizing effect of the mutation, and had a significantly reduced lifespan compared with Atm +/+ Whereas these rats did not show cerebellar atrophy, they succumbed to hind-limb paralysis (45%), and the remainder developed tumors. Closer examination revealed the presence of both dsDNA and ssDNA in the cytoplasm of cells in the hippocampus, cerebellum, and spinal cord of Atm L2262P/L2262P rats. Significantly increased levels of IFN-β and IL-1β in all 3 tissues were indicative of DNA damage induction of the type 1 IFN response. This was further supported by NF-κB activation, as evidenced by p65 phosphorylation (P65) and translocation to the nucleus in the spinal cord and parahippocampus. Other evidence of neuroinflammation in the brain and spinal cord was the loss of motor neurons and the presence of increased activation of microglia. These data provide support for a proinflammatory phenotype that is manifested in the Atm mutant rat as hind-limb paralysis. This mutant represents a useful model to investigate the importance of neuroinflammation in A-T. © Society for Leukocyte Biology.

  18. The albinism of the feral Asinara white donkeys (Equus asinus) is determined by a missense mutation in a highly conserved position of the tyrosinase (TYR) gene deduced protein.

    Science.gov (United States)

    Utzeri, V J; Bertolini, F; Ribani, A; Schiavo, G; Dall'Olio, S; Fontanesi, L

    2016-02-01

    A feral donkey population (Equus asinus), living in the Asinara National Park (an island north-west of Sardinia, Italy), includes a unique white albino donkey subpopulation or colour morph that is a major attraction of this park. Disrupting mutations in the tyrosinase (TYR) gene are known to cause recessive albinisms in humans (oculocutaneous albinism Type 1; OCA1) and other species. In this study, we analysed the donkey TYR gene as a strong candidate to identify the causative mutation of the albinism of these donkeys. The TYR gene was sequenced from 13 donkeys (seven Asinara white albino and six coloured animals). Seven single nucleotide polymorphisms were identified. A missense mutation (c.604C>G; p.His202Asp) in a highly conserved amino acid position (even across kingdoms), which disrupts the first copper-binding site (CuA) of functional protein, was identified in the homozygous condition (G/G or D/D) in all Asinara white albino donkeys and in the albino son of a trio (the grey parents had genotype C/G or H/D), supporting the recessive mode of inheritance of this mutation. Genotyping 82 donkeys confirmed that Asinara albino donkeys had genotype G/G whereas all other coloured donkeys had genotype C/C or C/G. Across-population association between the c.604C>G genotypes and the albino coat colour was highly significant (P = 6.17E-18). The identification of the causative mutation of the albinism in the Asinara white donkeys might open new perspectives to study the dynamics of this putative deleterious allele in a feral population and to manage this interesting animal genetic resource. © 2015 Stichting International Foundation for Animal Genetics.

  19. [Bentall operation after previous repair of tetralogy of Fallot].

    Science.gov (United States)

    Ballore, Luca; Tramontin, Corrado; Manca, Paolo; Tocco, Stefania; Lixi, Giovanni; Matta, Gildo; Cirio, Emiliano Maria; Martelli, Valentino

    2007-04-01

    Pathologies that involve the ascending aorta are described in case reports of patients after complete repair of tetralogy of Fallot. Here, we present a case report. Preoperative tests showed an aortic ratio of > 1.5. The patient was operated on replacement of the ascending aorta according to the Bentall technique. At present, the guidelines for replacement of the ascending aorta recommend an aortic ratio of > 1.5 and in case of Marfan syndrome of > 1.3. In these patient subsets, cystic medial necrosis and an increased risk of aortic dissection have been described. Therefore, as for Marfan syndrome, why an aortic ratio of >1.3 should not be considered a proper surgical indication also for these patients?

  20. Lithopaedon Presenting as Intestinal Obstruction with a Previous Co ...

    African Journals Online (AJOL)

    This is a case report of a 25 year old lady Para 4 + 0 gravida 5, who was referred to Kisii level 5 hospital from a district hospital with a diagnosis of intestinal obstruction and a four year history of an intra-abdominal mass. A year prior to the admission she conceived and delivered vaginally at home but the baby died a few ...

  1. [Parathyroid cancer in a patient with previous history of hypernephroma: a clinical case].

    Science.gov (United States)

    Martín Navarro, J; Mendoza, E; Mateos, P; Cereceda, A; Coca, S

    2007-01-01

    We report the clinical case of a 55 year-old male patient, with a previous history of nephrectomy by hypernephroma sixteen years ago, first presenting hypercalcemia and rising of intact parathyroid hormone (iPTH) levels. A localization study revealed an intrathyroid nodule with cystic appearance. After undergoing a hemi-thyroidectomy, the patient is diagnosed with parathyroid carcinoma. This article analyzes previously published cases presenting parathyroidal pathologies associated with hypernephroma. A broader differential diagnosis--including the screening of parathyroidal pathologies should be considered in patients with hypercalcemia and hypernephroma.

  2. The Relationship of Lumbar Multifidus Muscle Morphology to Previous, Current, and Future Low Back Pain

    DEFF Research Database (Denmark)

    Hebert, Jeffrey J; Kjær, Per; Fritz, Julie M

    2014-01-01

    of LBP after five and nine years.Summary of Background Data. Although low back pain (LBP) is a major source of disease burden, the biologic determinants of LBP are poorly understood.Methods. Participants were 40-year-old adults randomly sampled from a Danish population and followed-up at ages 45 and 49....... At each time point, participants underwent magnetic resonance imaging and reported ever having had LBP, LBP in the previous year, non-trivial LBP in the previous year, or a history of pain radiating into the legs. Pixel intensity and frequencies from T1-weighted magnetic resonance images identified...

  3. The prevalence of CHD7 missense versus truncating mutations is higher in patients with Kallmann syndrome than in typical CHARGE patients

    DEFF Research Database (Denmark)

    Marcos, Séverine; Sarfati, Julie; Leroy, Chrystel

    2014-01-01

    CONTEXT: Mutations in CHD7, a gene previously implicated in CHARGE (coloboma, heart defect, choanal atresia, retardation of growth and/or development, genital hypoplasia, ear anomalies) syndrome, have been reported in patients presenting with Kallmann syndrome (KS) or congenital hypogonadotropic...... hypogonadism (CHH). Most mutations causing CHARGE syndrome result in premature stop codons and occur de novo, but the proportion of truncating vs nontruncating mutations in KS and CHH patients is still unknown. OBJECTIVE: The objective of the study was to determine the nature, prevalence, mode of transmission......, and clinical spectrum of CHD7 mutations in a large series of patients. DESIGN: We studied 209 KS and 94 CHH patients. These patients had not been diagnosed with CHARGE syndrome according to the current criteria. We searched for mutations in 16 KS and CHH genes including CHD7. RESULTS: We found presumably...

  4. Mediastinal involvement in lymphangiomatosis: a previously unreported MRI sign

    Energy Technology Data Exchange (ETDEWEB)

    Shah, Vikas; Shah, Sachit; Barnacle, Alex; McHugh, Kieran [Great Ormond Street Hospital for Children, Department of Radiology, London (United Kingdom); Sebire, Neil J. [Great Ormond Street Hospital for Children, Department of Histopathology, London (United Kingdom); Brock, Penelope [Great Ormond Street Hospital for Children, Department of Oncology, London (United Kingdom); Harper, John I. [Great Ormond Street Hospital for Children, Department of Dermatology, London (United Kingdom)

    2011-08-15

    Multifocal lymphangiomatosis is a rare systemic disorder affecting children. Due to its rarity and wide spectrum of clinical, histological and imaging features, establishing the diagnosis of multifocal lymphangiomatosis can be challenging. The purpose of this study was to describe a new imaging sign in this disorder: paraspinal soft tissue and signal abnormality at MRI. We retrospectively reviewed the imaging, clinical and histopathological findings in a cohort of eight children with thoracic involvement from this condition. Evidence of paraspinal chest disease was identified at MRI and CT in all eight of these children. The changes comprise heterogeneous intermediate-to-high signal parallel to the thoracic vertebrae on T2-weighted sequences at MRI, with abnormal paraspinal soft tissue at CT and plain radiography. Multifocal lymphangiomatosis is a rare disorder with a broad range of clinicopathological and imaging features. MRI allows complete evaluation of disease extent without the use of ionising radiation and has allowed us to describe a previously unreported imaging sign in this disorder, namely, heterogeneous hyperintense signal in abnormal paraspinal tissue on T2-weighted images. (orig.)

  5. Coronary collateral vessels in patients with previous myocardial infarction

    International Nuclear Information System (INIS)

    Nakatsuka, M.; Matsuda, Y.; Ozaki, M.

    1987-01-01

    To assess the degree of collateral vessels after myocardial infarction, coronary angiograms, left ventriculograms, and exercise thallium-201 myocardial scintigrams of 36 patients with previous myocardial infarction were reviewed. All 36 patients had total occlusion of infarct-related coronary artery and no more than 70% stenosis in other coronary arteries. In 19 of 36 patients with transient reduction of thallium-201 uptake in the infarcted area during exercise (Group A), good collaterals were observed in 10 patients, intermediate collaterals in 7 patients, and poor collaterals in 2 patients. In 17 of 36 patients without transient reduction of thallium-201 uptake in the infarcted area during exercise (Group B), good collaterals were seen in 2 patients, intermediate collaterals in 7 patients, and poor collaterals in 8 patients (p less than 0.025). Left ventricular contractions in the infarcted area were normal or hypokinetic in 10 patients and akinetic or dyskinetic in 9 patients in Group A. In Group B, 1 patient had hypokinetic contraction and 16 patients had akinetic or dyskinetic contraction (p less than 0.005). Thus, patients with transient reduction of thallium-201 uptake in the infarcted area during exercise had well developed collaterals and preserved left ventricular contraction, compared to those in patients without transient reduction of thallium-201 uptake in the infarcted area during exercise. These results suggest that the presence of viable myocardium in the infarcted area might be related to the degree of collateral vessels

  6. Global functional atlas of Escherichia coli encompassing previously uncharacterized proteins.

    Directory of Open Access Journals (Sweden)

    Pingzhao Hu

    2009-04-01

    Full Text Available One-third of the 4,225 protein-coding genes of Escherichia coli K-12 remain functionally unannotated (orphans. Many map to distant clades such as Archaea, suggesting involvement in basic prokaryotic traits, whereas others appear restricted to E. coli, including pathogenic strains. To elucidate the orphans' biological roles, we performed an extensive proteomic survey using affinity-tagged E. coli strains and generated comprehensive genomic context inferences to derive a high-confidence compendium for virtually the entire proteome consisting of 5,993 putative physical interactions and 74,776 putative functional associations, most of which are novel. Clustering of the respective probabilistic networks revealed putative orphan membership in discrete multiprotein complexes and functional modules together with annotated gene products, whereas a machine-learning strategy based on network integration implicated the orphans in specific biological processes. We provide additional experimental evidence supporting orphan participation in protein synthesis, amino acid metabolism, biofilm formation, motility, and assembly of the bacterial cell envelope. This resource provides a "systems-wide" functional blueprint of a model microbe, with insights into the biological and evolutionary significance of previously uncharacterized proteins.

  7. Global functional atlas of Escherichia coli encompassing previously uncharacterized proteins.

    Science.gov (United States)

    Hu, Pingzhao; Janga, Sarath Chandra; Babu, Mohan; Díaz-Mejía, J Javier; Butland, Gareth; Yang, Wenhong; Pogoutse, Oxana; Guo, Xinghua; Phanse, Sadhna; Wong, Peter; Chandran, Shamanta; Christopoulos, Constantine; Nazarians-Armavil, Anaies; Nasseri, Negin Karimi; Musso, Gabriel; Ali, Mehrab; Nazemof, Nazila; Eroukova, Veronika; Golshani, Ashkan; Paccanaro, Alberto; Greenblatt, Jack F; Moreno-Hagelsieb, Gabriel; Emili, Andrew

    2009-04-28

    One-third of the 4,225 protein-coding genes of Escherichia coli K-12 remain functionally unannotated (orphans). Many map to distant clades such as Archaea, suggesting involvement in basic prokaryotic traits, whereas others appear restricted to E. coli, including pathogenic strains. To elucidate the orphans' biological roles, we performed an extensive proteomic survey using affinity-tagged E. coli strains and generated comprehensive genomic context inferences to derive a high-confidence compendium for virtually the entire proteome consisting of 5,993 putative physical interactions and 74,776 putative functional associations, most of which are novel. Clustering of the respective probabilistic networks revealed putative orphan membership in discrete multiprotein complexes and functional modules together with annotated gene products, whereas a machine-learning strategy based on network integration implicated the orphans in specific biological processes. We provide additional experimental evidence supporting orphan participation in protein synthesis, amino acid metabolism, biofilm formation, motility, and assembly of the bacterial cell envelope. This resource provides a "systems-wide" functional blueprint of a model microbe, with insights into the biological and evolutionary significance of previously uncharacterized proteins.

  8. Influence of Previous Knowledge in Torrance Tests of Creative Thinking

    Directory of Open Access Journals (Sweden)

    María Aranguren

    2015-07-01

    Full Text Available The aim of this work is to analyze the influence of study field, expertise and recreational activities participation in Torrance Tests of Creative Thinking (TTCT, 1974 performance. Several hypotheses were postulated to explore the possible effects of previous knowledge in TTCT verbal and TTCT figural university students’ outcomes. Participants in this study included 418 students from five study fields: Psychology;Philosophy and Literature, Music; Engineering; and Journalism and Advertising (Communication Sciences. Results found in this research seem to indicate that there in none influence of the study field, expertise and recreational activities participation in neither of the TTCT tests. Instead, the findings seem to suggest some kind of interaction between certain skills needed to succeed in specific studies fields and performance on creativity tests, such as the TTCT. These results imply that TTCT is a useful and valid instrument to measure creativity and that some cognitive process involved in innovative thinking can be promoted using different intervention programs in schools and universities regardless the students study field.

  9. Pertussis-associated persistent cough in previously vaccinated children.

    Science.gov (United States)

    Principi, Nicola; Litt, David; Terranova, Leonardo; Picca, Marina; Malvaso, Concetta; Vitale, Cettina; Fry, Norman K; Esposito, Susanna

    2017-11-01

    To evaluate the role of Bordetella pertussis infection, 96 otherwise healthy 7- to 17-year-old subjects who were suffering from a cough lasting from 2 to 8 weeks were prospectively recruited. At enrolment, a nasopharyngeal swab and an oral fluid sample were obtained to search for pertussis infection by the detection of B. pertussis DNA and/or an elevated titre of anti-pertussis toxin IgG. Evidence of pertussis infection was found in 18 (18.7 %; 95 % confidence interval, 11.5-28.0) cases. In 15 cases, the disease occurred despite booster administration. In two cases, pertussis was diagnosed less than 2 years after the booster injection, whereas in the other cases it was diagnosed between 2 and 9 years after the booster dose. This study used non-invasive testing to show that pertussis is one of the most important causes of long-lasting cough in school-age subjects. Moreover, the protection offered by acellular pertussis vaccines currently wanes more rapidly than previously thought.

  10. Multispecies Coevolution Particle Swarm Optimization Based on Previous Search History

    Directory of Open Access Journals (Sweden)

    Danping Wang

    2017-01-01

    Full Text Available A hybrid coevolution particle swarm optimization algorithm with dynamic multispecies strategy based on K-means clustering and nonrevisit strategy based on Binary Space Partitioning fitness tree (called MCPSO-PSH is proposed. Previous search history memorized into the Binary Space Partitioning fitness tree can effectively restrain the individuals’ revisit phenomenon. The whole population is partitioned into several subspecies and cooperative coevolution is realized by an information communication mechanism between subspecies, which can enhance the global search ability of particles and avoid premature convergence to local optimum. To demonstrate the power of the method, comparisons between the proposed algorithm and state-of-the-art algorithms are grouped into two categories: 10 basic benchmark functions (10-dimensional and 30-dimensional, 10 CEC2005 benchmark functions (30-dimensional, and a real-world problem (multilevel image segmentation problems. Experimental results show that MCPSO-PSH displays a competitive performance compared to the other swarm-based or evolutionary algorithms in terms of solution accuracy and statistical tests.

  11. Erlotinib in previously treated non-small-cell lung cancer

    International Nuclear Information System (INIS)

    Smrdel, U.; Kovac, V.

    2006-01-01

    Background. Erlotinib is a novel biological anti-tumour agent in the treatment of advanced non small cell lung cancer. It represents the molecularly-targeted therapy which has been studied extensively. Case report. We present a case of a patient who suffered from advanced non-small-cell lung cancer. After the progress of disease following a prior chemotherapy he was treated with erlotinib with remarkable effect which was shown at chest x ray and symptoms were quite reduced. Conclusions. In selected patients with advanced non-small-cell lung cancer Erlotinib improves survival and symptom control as it results in presented case. (author)

  12. Lung cancer in Hodgkin's disease: association with previous radiotherapy

    International Nuclear Information System (INIS)

    List, A.F.; Doll, D.C.; Greco, F.A.

    1985-01-01

    Seven cases of lung cancer were observed in patients with Hodgkin's disease (HD) since 1970. The risk ratio for the development of lung cancer among HD patients was 5.6 times that expected in the general population. The pertinent clinical data from these patients are described and compared to 28 additional patients reported from other institutions. Small-cell lung cancer represented the predominant histologic type of lung cancer encountered in both smoking and nonsmoking patients with HD, accounting for 42% of cases overall and greater than 55% of cases reported in reviews of second malignancies. Tobacco use was noted in only 53% of patients. Twenty-eight (94%) of 30 patients developing metachronous lung cancer received supradiaphragmatic irradiation as primary therapy for HD. Nineteen (68%) of these patients received subsequent chemotherapy salvage. The median age at diagnosis of HD and lung cancer was 39 and 45 years, respectively. The interval between diagnosis of HD and metachronous lung cancer averaged seven years but appeared to vary inversely with age. HD patients treated with supradiaphragmatic irradiation or combined modality therapy may be at increased risk for developing lung cancer. The high frequency of in-field malignancies that the authors observed and the prevalence of small-cell lung cancer in both smoking and nonsmoking patients suggests that chest irradiation may influence the development of metachronous lung cancer in these patients. The finding of a mean latent interval in excess of seven years emphasizes the need for close long-term observation

  13. Sacrococcygeal pilonidal disease: analysis of previously proposed risk factors

    Directory of Open Access Journals (Sweden)

    Ali Harlak

    2010-01-01

    Full Text Available PURPOSE: Sacrococcygeal pilonidal disease is a source of one of the most common surgical problems among young adults. While male gender, obesity, occupations requiring sitting, deep natal clefts, excessive body hair, poor body hygiene and excessive sweating are described as the main risk factors for this disease, most of these need to be verified with a clinical trial. The present study aimed to evaluate the value and effect of these factors on pilonidal disease. METHOD: Previously proposed main risk factors were evaluated in a prospective case control study that included 587 patients with pilonidal disease and 2,780 healthy control patients. RESULTS: Stiffness of body hair, number of baths and time spent seated per day were the three most predictive risk factors. Adjusted odds ratios were 9.23, 6.33 and 4.03, respectively (p<0.001. With an adjusted odds ratio of 1.3 (p<.001, body mass index was another risk factor. Family history was not statistically different between the groups and there was no specific occupation associated with the disease. CONCLUSIONS: Hairy people who sit down for more than six hours a day and those who take a bath two or less times per week are at a 219-fold increased risk for sacrococcygeal pilonidal disease than those without these risk factors. For people with a great deal of hair, there is a greater need for them to clean their intergluteal sulcus. People who engage in work that requires sitting in a seat for long periods of time should choose more comfortable seats and should also try to stand whenever possible.

  14. Impact of Students’ Class Attendance on Recalling Previously Acquired Information

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    Camellia Hemyari

    2018-03-01

    Full Text Available Background: In recent years, availability of class material including typed lectures, the professor’s Power Point slides, sound recordings, and even videos made a group of students feel that it is unnecessary to attend the classes. These students usually read and memorize typed lectures within two or three days prior to the exams and usually pass the tests even with low attendance rate. Thus, the question is how effective is this learning system and how long the one-night memorized lessons may last.Methods: A group of medical students (62 out of 106 students, with their class attendance and educational achievements in the Medical Mycology and Parasitology course being recorded since two years ago, was selected and their knowledge about this course was tested by multiple choice questions (MCQ designed based on the previous lectures.Results: Although the mean re-exam score of the students at the end of the externship was lower than the corresponding final score, a significant association was found between the scores of the students in these two exams (r=0.48, P=0.01. Moreover, a significant negative association was predicted between the number of absences and re-exam scores (r=-0.26, P=0.037.Conclusion: As our findings show, the phenomenon of recalling the acquired lessons is preserved for a long period of time and it is associated with the students’ attendance. Many factors including generation effect (by taking notes and cued-recall (via slide picture might play a significant role in the better recalling of the learned information in students with good class attendance.Keywords: STUDENT, MEMORY, LONG-TERM, RECALL, ABSENTEEISM, LEARNING

  15. Repeat immigration: A previously unobserved source of heterogeneity?

    Science.gov (United States)

    Aradhya, Siddartha; Scott, Kirk; Smith, Christopher D

    2017-07-01

    Register data allow for nuanced analyses of heterogeneities between sub-groups which are not observable in other data sources. One heterogeneity for which register data is particularly useful is in identifying unique migration histories of immigrant populations, a group of interest across disciplines. Years since migration is a commonly used measure of integration in studies seeking to understand the outcomes of immigrants. This study constructs detailed migration histories to test whether misclassified migrations may mask important heterogeneities. In doing so, we identify a previously understudied group of migrants called repeat immigrants, and show that they differ systematically from permanent immigrants. In addition, we quantify the degree to which migration information is misreported in the registers. The analysis is carried out in two steps. First, we estimate income trajectories for repeat immigrants and permanent immigrants to understand the degree to which they differ. Second, we test data validity by cross-referencing migration information with changes in income to determine whether there are inconsistencies indicating misreporting. From the first part of the analysis, the results indicate that repeat immigrants systematically differ from permanent immigrants in terms of income trajectories. Furthermore, income trajectories differ based on the way in which years since migration is calculated. The second part of the analysis suggests that misreported migration events, while present, are negligible. Repeat immigrants differ in terms of income trajectories, and may differ in terms of other outcomes as well. Furthermore, this study underlines that Swedish registers provide a reliable data source to analyze groups which are unidentifiable in other data sources.

  16. No. 155-Guidelines for Vaginal Birth After Previous Caesarean Birth.

    Science.gov (United States)

    Martel, Marie-Jocelyne; MacKinnon, Catherine Jane

    2018-03-01

    To provide evidence-based guidelines for the provision of a trial of labour (TOL) after Caesarean section. Fetal and maternal morbidity and mortality associated with vaginal birth after Caesarean (VBAC) and repeat Caesarean section. MEDLINE database was searched for articles published from January 1, 1995, to February 28, 2004, using the key words "vaginal birth after Caesarean (Cesarean) section." The quality of evidence is described using the Evaluation of Evidence criteria outlined in the Report of the Canadian Task Force on the Periodic Health Exam. VALIDATION: These guidelines were approved by the Clinical Practice Obstetrics and Executive Committees of the Society of Obstetricians and Gynaecologists of Canada. Copyright © 2018. Published by Elsevier Inc.

  17. Total knee arthroplasty in patients with a previous patellectomy.

    Science.gov (United States)

    Maslow, Jed; Zuckerman, Joseph D; Immerman, Igor

    2013-01-01

    Post-patellectomy patients represent a specific subgroup of patients that may develop arthritis and persistent knee pain and potentially require treatment with total knee arthroplasty. This article reviews the treatment and functional outcomes following total knee arthroplasty in patients with prior patellectomy. A case report is presented as an example of the clinical management of a post-patellectomy patient with significant knee pain and disability treated with total knee arthroplasty. Emphasis will be placed in decision- making, specifically with the use of a posterior stabilized implant. In addition, postoperative strengthening of the quadriceps is essential to compensate for the lack of the patella and increase the success of total knee arthroplasty in this subgroup of patients.

  18. Recurrent severe invasive pneumococcal disease in an adult with previously unknown hyposplenia

    DEFF Research Database (Denmark)

    Ballegaard, Vibe C; Schejbel, Lone; Hoffmann, Steen

    2015-01-01

    was found. Despite immunization against S. pneumoniae and measurement of what was interpreted as protective levels of serotype-specific IgG antibodies after vaccination, the patient suffered from a third episode of IPD. CONCLUSIONS: Individuals with predisposing medical conditions or a history of severe......BACKGROUND: The risk of life-threatening and invasive infections with encapsulated bacteria is increased in patients with hyposplenia or asplenia. We report a case of recurrent invasive pneumococcal meningitis in a woman with previous unknown hyposplenia. She was vaccinated after the first episode...... of meningitis and developed sufficient levels of pneumococcal antibodies. The pneumococcal strains isolated were serotype 7 F and 17 F. To our knowledge, there has been no previously reported case of recurrent invasive pneumococcal disease in a pneumococcal vaccinated adult with hyposplenia and apparently...

  19. Pulmonary Aspergillosis in a Previously Healthy 13-Year-Old Boy

    Directory of Open Access Journals (Sweden)

    Jonathan H. Rayment

    2016-01-01

    Full Text Available Chronic granulomatous disease (CGD is a rare, polygenic primary immunodeficiency. In this case report, we describe a previously healthy 13-year-old boy who presented with multifocal pulmonary aspergillosis and was subsequently diagnosed with an autosomal recessive form of chronic granulomatous disease. CGD has a variable natural history and age of presentation and should be considered when investigating a patient with recurrent or severe infections with catalase-positive organisms.

  20. The prevalence of previous self-harm amongst self-poisoning patients in Sri Lanka

    DEFF Research Database (Denmark)

    Mohamed, Fahim; Perera, Aravinda; Wijayaweera, Kusal

    2011-01-01

    BACKGROUND: One of the most important components of suicide prevention strategies is to target people who repeat self-harm as they are a high risk group. However, there is some evidence that the incidence of repeat self-harm is lower in Asia than in the West. The objective of this study...... was to investigate the prevalence of previous self-harm among a consecutive series of self-harm patients presenting to hospitals in rural Sri Lanka. METHOD: Six hundred and ninety-eight self-poisoning patients presenting to medical wards at two hospitals in Sri Lanka were interviewed about their previous episodes...... of self-harm. RESULTS: Sixty-one (8.7%, 95% CI 6.7-11%) patients reported at least one previous episode of self-harm [37 (10.7%) male, 24 (6.8%) female]; only 19 (2.7%, 95% CI 1.6-4.2%) patients had made more than one previous attempt. CONCLUSION: The low prevalence of previous self-harm is consistent...

  1. Anaesthetic management for caesarean section in a case of previously operated with residual pituitary tumour

    Directory of Open Access Journals (Sweden)

    Prerana N Shah

    2011-01-01

    Full Text Available Successful anaesthetic management for caesarean section in a case with previous pituitary tumour resection, with residual tumour, is reported. The pituitary gland undergoes global hyperplasia during pregnancy. Functional pituitary tumours may exhibit symptomatic enlargement during pregnancy. Growth hormone secreting tumour is associated with acromegaly which has associated anaesthetic implications of difficult airway, systemic hypertension, and diabetes and electrolyte imbalance. Intracranial space occupying lesions can increase intra cranial pressure and compromise cerebral perfusion or cause herniation. We report management of this case.

  2. Do emotional intelligence and previous caring experience influence student nurse performance? A comparative analysis.

    Science.gov (United States)

    Stenhouse, Rosie; Snowden, Austyn; Young, Jenny; Carver, Fiona; Carver, Hannah; Brown, Norrie

    2016-08-01

    Reports of poor nursing care have focused attention on values based selection of candidates onto nursing programmes. Values based selection lacks clarity and valid measures. Previous caring experience might lead to better care. Emotional intelligence (EI) might be associated with performance, is conceptualised and measurable. To examine the impact of 1) previous caring experience, 2) emotional intelligence 3) social connection scores on performance and retention in a cohort of first year nursing and midwifery students in Scotland. A longitudinal, quasi experimental design. Adult and mental health nursing, and midwifery programmes in a Scottish University. Adult, mental health and midwifery students (n=598) completed the Trait Emotional Intelligence Questionnaire-short form and Schutte's Emotional Intelligence Scale on entry to their programmes at a Scottish University, alongside demographic and previous caring experience data. Social connection was calculated from a subset of questions identified within the TEIQue-SF in a prior factor and Rasch analysis. Student performance was calculated as the mean mark across the year. Withdrawal data were gathered. 598 students completed baseline measures. 315 students declared previous caring experience, 277 not. An independent-samples t-test identified that those without previous caring experience scored higher on performance (57.33±11.38) than those with previous caring experience (54.87±11.19), a statistically significant difference of 2.47 (95% CI, 0.54 to 4.38), t(533)=2.52, p=.012. Emotional intelligence scores were not associated with performance. Social connection scores for those withdrawing (mean rank=249) and those remaining (mean rank=304.75) were statistically significantly different, U=15,300, z=-2.61, p$_amp_$lt;0.009. Previous caring experience led to worse performance in this cohort. Emotional intelligence was not a useful indicator of performance. Lower scores on the social connection factor were associated

  3. Naturally Occurring Missense MRGPRX2 Variants Display Loss of Function Phenotype for Mast Cell Degranulation in Response to Substance P, Hemokinin-1, Human β-Defensin-3, and Icatibant.

    Science.gov (United States)

    Alkanfari, Ibrahim; Gupta, Kshitij; Jahan, Tahsin; Ali, Hydar

    2018-05-23

    Human mast cells (MCs) express a novel G protein-coupled receptor (GPCR) known as Mas-related GPCR X2 (MRGPRX2). Activation of this receptor by a diverse group of cationic ligands such as neuropeptides, host defense peptides, and Food and Drug Administration-approved drugs contributes to chronic inflammatory diseases and pseudoallergic drug reactions. For most GPCRs, the extracellular (ECL) domains and their associated transmembrane (TM) domains display the greatest structural diversity and are responsible for binding different ligands. The goal of the current study was to determine if naturally occurring missense variants within MRGPRX2's ECL/TM domains contribute to gain or loss of function phenotype for MC degranulation in response to neuropeptides (substance P and hemokinin-1), a host defense peptide (human β-defensin-3) and a Food and Drug Administration-approved cationic drug (bradykinin B2 receptor antagonist, icatibant). We have identified eight missense variants within MRGPRX2's ECL/TM domains from publicly available exome-sequencing databases. We investigated the ability of MRGPRX2 ligands to induce degranulation in rat basophilic leukemia-2H3 cells individually expressing these naturally occurring MRGPRX2 missense variants. Using stable and transient transfections, we found that all variants express in rat basophilic leukemia cells. However, four natural MRGPRX2 variants, G165E (rs141744602), D184H (rs372988289), W243R (rs150365137), and H259Y (rs140862085) failed to respond to any of the ligands tested. Thus, diverse MRGPRX2 ligands use common sites on the receptor to induce MC degranulation. These findings have important clinical implications for MRGPRX2 and MC-mediated pseudoallergy and chronic inflammatory diseases. Copyright © 2018 by The American Association of Immunologists, Inc.

  4. Parental anxiety associated with Kawasaki disease in previously healthy children.

    Science.gov (United States)

    Chahal, Nita; Clarizia, Nadia A; McCrindle, Brian W; Boydell, Katherine M; Obadia, Maya; Manlhiot, Cedric; Dillenburg, Rejane; Yeung, Rae S M

    2010-01-01

    The objective of this study was to explore the lived experience of parents of children diagnosed with Kawasaki disease (KD) and to identify factors associated with increased levels of parental anxiety. Three focus groups were conducted including 25 parents of 17 patients with KD, seven (41%) of whom had coronary artery complications. A conceptual model was developed to depict parental experiences and illustrate the key issues related to heightened anxiety. Themes identified included anxiety related to the child's sudden illness and delay in obtaining a correct diagnosis because of the lack of health care providers' awareness and knowledge regarding KD. Parents were frustrated by the lack of information available in lay language and the limited scientific knowledge regarding the long-term consequences of the disease. Parents also reported positive transformations and different perspective toward challenges in life. However, the parents of children with coronary artery complications expressed persistent anxiety even years after the acute phase of the illness due to the uncertainty of the long-term prognosis. There remains a critical need for richly textured research data on the perspective and experience of families of children with KD. Copyright 2010 National Association of Pediatric Nurse Practitioners. Published by Mosby, Inc. All rights reserved.

  5. Social communication difficulties and autism in previously institutionalized children.

    Science.gov (United States)

    Levin, April R; Fox, Nathan A; Zeanah, Charles H; Nelson, Charles A

    2015-02-01

    To determine the risk of difficulties with social communication and restricted/repetitive behaviors as well as the rate of autism in children institutionalized in early infancy and to assess the impact of a foster care intervention on ameliorating this risk. Children abandoned at birth and raised in institutions in Bucharest, Romania were randomly assigned to a care-as-usual group (institutional care, CAUG), or placed in family-centered foster care (FCG) as part of the Bucharest Early Intervention Project (BEIP). At approximately 10 years of age, the Social Communication Questionnaire (SCQ) was administered to caregivers of children in both groups as well as to parents of a typically developing community sample (Never-Institutionalized group [NIG]) residing in Bucharest, Romania. Children scoring ≥12 on the SCQ underwent clinical evaluation for autism spectrum disorder (ASD). Caregivers of children with a history of institutionalization reported that these children had significantly more deviant behavior than never-institutionalized children on all subdomains of the SCQ (all p communication. Three of 60 CAUG children, 2 of 57 FCG children, and none of the NIG children received a formal ASD diagnosis. Early institutional rearing was associated with an increased risk of social communication difficulties and ASD. A family-centered foster care intervention improved social communication skills. Copyright © 2015 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

  6. Hepatotoxicity induced by methimazole in a previously healthy patient.

    Science.gov (United States)

    Gallelli, Luca; Staltari, Orietta; Palleria, Caterina; De Sarro, Giovambattista; Ferraro, Maria

    2009-09-01

    We report a case of hepatotoxicity induced by methimazole treatment in a patient affected by hyperthyroidism. A 54-year-old man, presented to our observation for palpitations, excessive sweating, weakness, heat intolerance and weight loss. On physical examination, his blood pressure was 140/90 mmHg and heart beat was 100/min regular. He had mild tremors and left exophthalmos. Laboratory test revealed a significant increase in serum thyroid hormone levels with a decrease in thyroid stimulating hormone levels. A diagnosis of hyperthyroidism was made and he began treatment with methimazole (30 mg/day). Fourteen days later, he returned for the development of scleral icterus, followed by dark urine, and abdominal pain in the right upper quadrant. Laboratory examinations and liver biopsy performed a diagnosis of cholestatic hepatitis, secondary to methimazole usage. Methimazole was promptly withdrawn and cholestyramine, ursodeoxycholic acid, and chlorpheniramine were given. After five days, abdominal pain resolved and laboratory parameters returned to normal. Naranjo probability scale indicated a probable relationship between hepatotoxicity and methimazole therapy. In conclusion physicians should be aware the risk of hepatotoxicity related with methimazole.

  7. Novel de novo variant in EBF3 is likely to impact DNA binding in a patient with a neurodevelopmental disorder and expanded phenotypes: patient report, in silico functional assessment, and review of published cases.

    Science.gov (United States)

    Blackburn, Patrick R; Barnett, Sarah S; Zimmermann, Michael T; Cousin, Margot A; Kaiwar, Charu; Pinto E Vairo, Filippo; Niu, Zhiyv; Ferber, Matthew J; Urrutia, Raul A; Selcen, Duygu; Klee, Eric W; Pichurin, Pavel N

    2017-05-01

    Pathogenic variants in EBF3 were recently described in three back-to-back publications in association with a novel neurodevelopmental disorder characterized by intellectual disability, speech delay, ataxia, and facial dysmorphisms. In this report, we describe an additional patient carrying a de novo missense variant in EBF3 (c.487C>T, p.(Arg163Trp)) that falls within a conserved residue in the zinc knuckle motif of the DNA binding domain. Without a solved structure of the DNA binding domain, we generated a homology-based atomic model and performed molecular dynamics simulations for EBF3, which predicted decreased DNA affinity for p.(Arg163Trp) compared with wild-type protein and control variants. These data are in agreement with previous experimental studies of EBF1 showing the paralogous residue is essential for DNA binding. The conservation and experimental evidence existing for EBF1 and in silico modeling and dynamics simulations to validate comparable behavior of multiple variants in EBF3 demonstrates strong support for the pathogenicity of p.(Arg163Trp). We show that our patient presents with phenotypes consistent with previously reported patients harboring EBF3 variants and expands the phenotypic spectrum of this newly identified disorder with the additional feature of a bicornuate uterus.

  8. Missense and nonsense mutations in melanocortin 1 receptor (MC1R gene of different goat breeds: association with red and black coat colour phenotypes but with unexpected evidences

    Directory of Open Access Journals (Sweden)

    Davoli Roberta

    2009-08-01

    Full Text Available Abstract Background Agouti and Extension loci control the relative amount of eumelanin and pheomelanin production in melanocytes that, in turn, affects pigmentation of skin and hair. The Extension locus encodes the melanocortin 1 receptor (MC1R whose permanent activation, caused by functional mutations, results in black coat colour, whereas other inactivating mutations cause red coat colour in different mammals. Results The whole coding region of the MC1R gene was sequenced in goats of six different breeds showing different coat colours (Girgentana, white cream with usually small red spots in the face; Maltese, white with black cheeks and ears; Derivata di Siria, solid red; Murciano-Granadina, solid black or solid brown; Camosciata delle Alpi, brown with black stripes; Saanen, white; F1 goats and the parental animals. Five single nucleotide polymorphisms (SNPs were identified: one nonsense mutation (p.Q225X, three missense mutations (p.A81V, p.F250V, and p.C267W, and one silent mutation. The stop codon at position 225 should cause the production of a shorter MC1R protein whose functionality may be altered. These SNPs were investigated in a larger sample of animals belonging to the six breeds. The Girgentana breed was almost fixed for the p.225X allele. However, there was not complete association between the presence of red spots in the face and the presence of this allele in homozygous condition. The same allele was identified in the Derivata di Siria breed. However, its frequency was only 33%, despite the fact that these animals are completely red. The p.267W allele was present in all Murciano-Granadina black goats, whereas it was never identified in the brown ones. Moreover, the same substitution was present in almost all Maltese goats providing evidence of association between this mutation and black coat colour. Conclusion According to the results obtained in the investigated goat breeds, MC1R mutations may determine eumelanic and pheomelanic

  9. Missense Mutation of Brain Derived Neurotrophic Factor (BDNF Alters Neurocognitive Performance in Patients with Mild Traumatic Brain Injury: A Longitudinal Study.

    Directory of Open Access Journals (Sweden)

    Vairavan Narayanan

    Full Text Available The predictability of neurocognitive outcomes in patients with traumatic brain injury is not straightforward. The extent and nature of recovery in patients with mild traumatic brain injury (mTBI are usually heterogeneous and not substantially explained by the commonly known demographic and injury-related prognostic factors despite having sustained similar injuries or injury severity. Hence, this study evaluated the effects and association of the Brain Derived Neurotrophic Factor (BDNF missense mutations in relation to neurocognitive performance among patients with mTBI. 48 patients with mTBI were prospectively recruited and MRI scans of the brain were performed within an average 10.1 (SD 4.2 hours post trauma with assessment of their neuropsychological performance post full Glasgow Coma Scale (GCS recovery. Neurocognitive assessments were repeated again at 6 months follow-up. The paired t-test, Cohen's d effect size and repeated measure ANOVA were performed to delineate statistically significant differences between the groups [wildtype G allele (Val homozygotes vs. minor A allele (Met carriers] and their neuropsychological performance across the time point (T1 = baseline/ admission vs. T2 = 6th month follow-up. Minor A allele carriers in this study generally performed more poorly on neuropsychological testing in comparison wildtype G allele group at both time points. Significant mean differences were observed among the wildtype group in the domains of memory (M = -11.44, SD = 10.0, p = .01, d = 1.22, executive function (M = -11.56, SD = 11.7, p = .02, d = 1.05 and overall performance (M = -6.89 SD = 5.3, p = .00, d = 1.39, while the minor A allele carriers showed significant mean differences in the domains of attention (M = -11.0, SD = 13.1, p = .00, d = .86 and overall cognitive performance (M = -5.25, SD = 8.1, p = .01, d = .66.The minor A allele carriers in comparison to the wildtype G allele group, showed considerably lower scores at

  10. The visibility of cancer on previous mammograms in retrospective review

    International Nuclear Information System (INIS)

    Saarenmaa, I.; Salminen, T.; Geiger, U.; Heikkinen, P.; Hyvarinen, S.; Isola, J.; Kataja, V.; Kokko, M.-L.; Kokko, R.; Kumpulainen, E.; Karkkainen, A.; Pakkanen, J.; Peltonen, P.; Piironen, A.; Salo, A.; Talviala, M.-L.; Hakama, M.

    2001-01-01

    AIM: To study how many tumours were visible in restrospect on mammograms originally reported as normal or benign in patients coming to surgery with proven breast cancer. The effect of making the pre--operative mammogram available was also assessed. MATERIALS AND METHODS: Three hundred and twenty initial mammograms of consecutive new breast cancer cases were analysed by a group of radiologists in the knowledge that all patients were later diagnosed with breast cancer. The films were read twice, first without and then with the later (pre-operative) mammograms available. The parenchymal density in the location of the tumour was classified as fatty, mixed or dense, and the tumours were classified as visible or not visible. The reasons for the invisibility of the tumour in the earlier examination were analysed. RESULTS: Fourteen per cent (45) of cancers were retrospectively visible in earlier mammograms without the pre-operative mammograms having been shown, and 29% (95) when pre-operative mammograms were shown. Breast parenchymal density decreased with age and the visibility of tumours increased with age. When considered simultaneously, the effect of age (over 55 vs under 55) was greater (OR = 2.9) than the effect of density (fatty vs others) (OR = 1.5). The most common reasons for non-detection were that the lesion was overlooked (55%), diagnosed as benign (33%) or was visible only in one projection (26%). Growing density was the most common (37%) feature of those lesions originally overlooked or regarded as benign. CONCLUSIONS: Tumours are commonly visible in retrospect, but few of them exhibit specific signs of cancer, and are recognized only if they grow or otherwise change. It is not possible to differentiate most of them from normal parenchymal densities. Saaremaa, I. (2001)

  11. Nocturnal Wakefulness as a Previously Unrecognized Risk Factor for Suicide.

    Science.gov (United States)

    Perlis, Michael L; Grandner, Michael A; Brown, Gregory K; Basner, Mathias; Chakravorty, Subhajit; Morales, Knashawn H; Gehrman, Philip R; Chaudhary, Ninad S; Thase, Michael E; Dinges, David F

    2016-06-01

    Suicide is a major public health problem and the 10th leading cause of death in the United States. The identification of modifiable risk factors is essential for reducing the prevalence of suicide. Recently, it has been shown that insomnia and nightmares significantly increase the risk for suicidal ideation, attempted suicide, and death by suicide. While both forms of sleep disturbance may independently confer risk, and potentially be modifiable risk factors, it is also possible that simply being awake at night represents a specific vulnerability for suicide. The present analysis evaluates the frequency of completed suicide per hour while taking into account the percentage of individuals awake at each hour. Archival analyses were conducted estimating the time of fatal injury using the National Violent Death Reporting System for 2003-2010 and the proportion of the American population awake per hour across the 24-hour day using the American Time Use Survey. The mean ± SD incident rate from 06:00-23:59 was 2.2% ± 0.7%, while the mean ± SD incident rate from 00:00-05:59 was 10.3% ± 4.9%. The maximum incident rate was from 02:00-02:59 (16.3%). Hour-by-hour observed values differed from those that would be expected by chance (P < .001), and when 6-hour blocks were examined, the observed frequency at night was 3.6 times higher than would be expected by chance (P < .001). Being awake at night confers greater risk for suicide than being awake at other times of the day, suggesting that disturbances of sleep or circadian neurobiology may potentiate suicide risk. © Copyright 2016 Physicians Postgraduate Press, Inc.

  12. Urinary tract infections in hospital pediatrics: many previous antibiotherapy and antibiotics resistance, including fluoroquinolones.

    Science.gov (United States)

    Garraffo, A; Marguet, C; Checoury, A; Boyer, S; Gardrat, A; Houivet, E; Caron, F

    2014-02-01

    We studied antibiotic resistance in pediatric UTIs and we evaluated the impact of antibiotic exposure in the previous 12 months, very little French data being available for this population. We conducted a multicenter prospective study including children consulting for, or admitted in 2 hospitals. Prior antibiotic exposure was documented from their health record. One hundred and ten patients (73 girls), 11 days to 12 years of age, were included in 10 months. Ninety-six percent presented with pyelonephritis, associated to uropathy for 25%. Escherichia coli was predominant (78%), followed by Proteus spp. and Enterococcus spp. The antibiotic resistance rate of E. coli was high and close to that reported for adults with complicated UTIs: amoxicillin 60%, amoxicillin-clavulanate 35%, cefotaxim 5%, trimethoprim-sulfametoxazole 26%, nalidixic acid 9%, ciprofloxacin 7%, gentamycin 1%, nitrofurantoin and fosfomycin 0%. The antibiotic exposure in the previous 12 months involved 62 children (56%) most frequently with β-lactams (89%) for a respiratory tract infection (56%). A clear relationship between exposure and resistance was observed for amoxicillin (71% vs. 46%), first generation (65% vs. 46%) and third generation (9% vs. 3%) cephalosporins, or trimethoprim-sulfamethoxazole (36% vs. 15%). However, antibiotic exposure could not account alone for the results, as suggested by the 7% of ciprofloxacin resistance, observed without any identified previous treatment. Bacterial species and antibiotic resistance level in children are similar to those reported for adults. Antibiotic exposure in the previous 12 months increases the risk of resistance but other factors are involved (previous antibiotic therapies and fecal-oral or mother-to-child transmission). Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  13. Milky Way Past Was More Turbulent Than Previously Known

    Science.gov (United States)

    2004-04-01

    Results of 1001 observing nights shed new light on our Galaxy [1] Summary A team of astronomers from Denmark, Switzerland and Sweden [2] has achieved a major breakthrough in our understanding of the Milky Way, the galaxy in which we live. After more than 1,000 nights of observations spread over 15 years, they have determined the spatial motions of more than 14,000 solar-like stars residing in the neighbourhood of the Sun. For the first time, the changing dynamics of the Milky Way since its birth can now be studied in detail and with a stellar sample sufficiently large to allow a sound analysis. The astronomers find that our home galaxy has led a much more turbulent and chaotic life than previously assumed. PR Photo 10a/04: Distribution on the sky of the observed stars. PR Photo 10b/04: Stars in the solar neigbourhood and the Milky Way galaxy (artist's view). PR Video Clip 04/04: The motions of the observed stars during the past 250 million years. Unknown history Home is the place we know best. But not so in the Milky Way - the galaxy in which we live. Our knowledge of our nearest stellar neighbours has long been seriously incomplete and - worse - skewed by prejudice concerning their behaviour. Stars were generally selected for observation because they were thought to be "interesting" in some sense, not because they were typical. This has resulted in a biased view of the evolution of our Galaxy. The Milky Way started out just after the Big Bang as one or more diffuse blobs of gas of almost pure hydrogen and helium. With time, it assembled into the flattened spiral galaxy which we inhabit today. Meanwhile, generation after generation of stars were formed, including our Sun some 4,700 million years ago. But how did all this really happen? Was it a rapid process? Was it violent or calm? When were all the heavier elements formed? How did the Milky Way change its composition and shape with time? Answers to these and many other questions are 'hot' topics for the

  14. Total hip arthroplasty after a previous pelvic osteotomy: A systematic review and meta-analysis.

    Science.gov (United States)

    Shigemura, T; Yamamoto, Y; Murata, Y; Sato, T; Tsuchiya, R; Wada, Y

    2018-06-01

    There are several reports regarding total hip arthroplasty (THA) after a previous pelvic osteotomy (PO). However, to our knowledge, until now there has been no formal systematic review and meta-analysis published to summarize the clinical results of THA after a previous PO. Therefore, we conducted a systematic review and meta-analysis of results of THA after a previous PO. We focus on these questions as follows: does a previous PO affect the results of subsequent THA, such as clinical outcomes, operative time, operative blood loss, and radiological parameters. Using PubMed, Web of Science, and Cochrane Library, we searched for relevant original papers. The pooling of data was performed using RevMan software (version 5.3, Cochrane Collaboration, Oxford, UK). A p-value50%, significant heterogeneity was assumed and a random-effects model was applied for the meta-analysis. A fixed-effects model was applied in the absence of significant heterogeneity. Eleven studies were included in this meta-analysis. The pooled results indicated that there was no significant difference in postoperative Merle D'Aubigne-Postel score (I 2 =0%, SMD=-0.15, 95% CI: -0.36 to 0.06, p=0.17), postoperative Harris hip score (I 2 =60%, SMD=-0.23, 95% CI: -0.50 to 0.05, p=0.10), operative time (I 2 =86%, SMD=0.37, 95% CI: -0.09 to 0.82, p=0.11), operative blood loss (I 2 =82%, SMD=0.23, 95% CI: -0.17 to 0.63, p=0.25), and cup abduction angle (I 2 =43%, SMD=-0.08, 95% CI: -0.25 to 0.09, p=0.38) between THA with and without a previous PO. However, cup anteversion angle of THA with a previous PO was significantly smaller than that of without a previous PO (I 2 =77%, SMD=-0.63, 95% CI: -1.13 to -0.13, p=0.01). Systematic review and meta-analysis of results of THA after a previous PO was performed. A previous PO did not affect the results of subsequent THA, except for cup anteversion. Because of the low quality evidence currently available, high-quality randomized controlled trials are required

  15. Summary of Previous Chamber or Controlled Anthrax Studies and Recommendations for Possible Additional Studies

    Energy Technology Data Exchange (ETDEWEB)

    Piepel, Gregory F.; Amidan, Brett G.; Morrow, Jayne B.

    2010-12-29

    This report and an associated Excel file(a) summarizes the investigations and results of previous chamber and controlled studies(b) to characterize the performance of methods for collecting, storing and/or transporting, extracting, and analyzing samples from surfaces contaminated by Bacillus anthracis (BA) or related simulants. This report and the Excel are the joint work of the Pacific Northwest National Laboratory (PNNL) and the National Institute of Standards and Technology (NIST) for the Department of Homeland Security, Science and Technology Directorate. The report was originally released as PNNL-SA-69338, Rev. 0 in November 2009 with limited distribution, but was subsequently cleared for release with unlimited distribution in this Rev. 1. Only minor changes were made to Rev. 0 to yield Rev. 1. A more substantial update (including summarizing data from other studies and more condensed summary tables of data) is underway

  16. Adolescents' physical activity is associated with previous and current physical activity practice by their parents

    Directory of Open Access Journals (Sweden)

    Diego Giulliano Destro Christofaro

    Full Text Available Abstract Objective: The purpose of this study was to determine whether parents' current and previous physical activity practice is associated with adolescents' physical activity. Methods: The sample was composed of 1231 adolescents (14-17 years, and 1202 mothers and 871 fathers were interviewed. Weight and height of the adolescents were measured. Self-reported parents' weight and height were obtained. The current and previous physical activity levels (Baecke's questionnaire of parents (during childhood and adolescence and adolescents' physical activity levels were obtained using a questionnaire. The magnitude of the associations between parent and adolescent physical activity levels was determined by binary logistic regression (adjusted by sex, age, and socioeconomic level of adolescents and education level of parents. Results: The current physical activity practice by parents was associated with adolescents' physical activity (p < 0.001. The physical activities reported by parents in their childhood and adolescence were also associated with higher physical activity levels among adolescents. Adolescents whose parents were both physically active in the past and present were six times (OR = 6.67 [CI = 1.94-22.79] more likely to be physically active compared to adolescents with no parents who were physically active in the past. Conclusions: The current and previous physical activities of parents were associated with higher levels of physical activity in adolescents, even after controlling for confounding factors.

  17. Adolescents' physical activity is associated with previous and current physical activity practice by their parents.

    Science.gov (United States)

    Christofaro, Diego Giulliano Destro; Andersen, Lars Bo; Andrade, Selma Maffei de; Barros, Mauro Virgílio Gomes de; Saraiva, Bruna Thamyres Ciccotti; Fernandes, Rômulo Araújo; Ritti-Dias, Raphael Mendes

    The purpose of this study was to determine whether parents' current and previous physical activity practice is associated with adolescents' physical activity. The sample was composed of 1231 adolescents (14-17 years), and 1202 mothers and 871 fathers were interviewed. Weight and height of the adolescents were measured. Self-reported parents' weight and height were obtained. The current and previous physical activity levels (Baecke's questionnaire) of parents (during childhood and adolescence) and adolescents' physical activity levels were obtained using a questionnaire. The magnitude of the associations between parent and adolescent physical activity levels was determined by binary logistic regression (adjusted by sex, age, and socioeconomic level of adolescents and education level of parents). The current physical activity practice by parents was associated with adolescents' physical activity (p<0.001). The physical activities reported by parents in their childhood and adolescence were also associated with higher physical activity levels among adolescents. Adolescents whose parents were both physically active in the past and present were six times (OR=6.67 [CI=1.94-22.79]) more likely to be physically active compared to adolescents with no parents who were physically active in the past. The current and previous physical activities of parents were associated with higher levels of physical activity in adolescents, even after controlling for confounding factors. Copyright © 2017 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

  18. Differences between previously married and never married 'gay' men: family background, childhood experiences and current attitudes.

    Science.gov (United States)

    Higgins, Daryl J

    2004-01-01

    Despite a large body of literature on the development of sexual orientation, little is known about why some gay men have been (or remain) married to a woman. In the current study, a self-selected sample of 43 never married gay men ('never married') and 26 gay men who were married to a woman ('previously married') completed a self-report questionnaire. Hypotheses were based on five possible explanations for gay men's marriages: (a) differences in sexual orientation (i.e., bisexuality); (b) internalized homophobia; (c) religious intolerance; (d) confusion created because of childhood/adolescent sexual experiences; and/or (e) poor psychological adjustment. Previously married described their families' religious beliefs as more fundamentalist than never married. No differences were found between married' and never married' ratings of their sexual orientation and identity, and levels of homophobia and self-depreciation. Family adaptability and family cohesion and the degree to which respondents reported having experienced child maltreatment did not distinguish between previously married and never married. The results highlight how little is understood of the reasons why gay men marry, and the need to develop an adequate theoretical model.

  19. Validation of the Online version of the Previous Day Food Questionnaire for schoolchildren

    Directory of Open Access Journals (Sweden)

    Raquel ENGEL

    Full Text Available ABSTRACT Objective To evaluate the validity of the web-based version of the Previous Day Food Questionnaire Online for schoolchildren from the 2nd to 5th grades of elementary school. Methods Participants were 312 schoolchildren aged 7 to 12 years of a public school from the city of Florianópolis, Santa Catarina, Brazil. Validity was assessed by sensitivity, specificity, as well as by agreement rates (match, omission, and intrusion rates of food items reported by children on the Previous Day Food Questionnaire Online, using direct observation of foods/beverages eaten during school meals (mid-morning snack or afternoon snack on the previous day as the reference. Multivariate multinomial logistic regression analysis was used to evaluate the influence of participants’ characteristics on omission and intrusion rates. Results The results showed adequate sensitivity (67.7% and specificity (95.2%. There were low omission and intrusion rates of 22.8% and 29.5%, respectively when all food items were analyzed. Pizza/hamburger showed the highest omission rate, whereas milk and milk products showed the highest intrusion rate. The participants who attended school in the afternoon shift presented a higher probability of intrusion compared to their peers who attended school in the morning. Conclusion The Previous Day Food Questionnaire Online possessed satisfactory validity for the assessment of food intake at the group level in schoolchildren from the 2nd to 5th grades of public school.

  20. Do attitudes of families concerned influence features of children who claim to remember previous lives?

    Science.gov (United States)

    Pasricha, Satwant K

    2011-01-01

    Reported cases of nearly 2600 children (subjects) who claim to remember previous lives have been investigated in cultures with and without belief in reincarnation. The authenticity in most cases has been established. To study the influence of attitudes of parents of the subjects, families of the deceased person with whom they are identified and attention paid by others on the features of the cases. The study is based on field investigations. Data is derived from analysis of a larger series of an ongoing project. Information on initial and subsequent attitudes of subjects' mothers was available for 292 and 136 cases, respectively; attitudes of 227 families of deceased person (previous personality) with whom he is identified, and the extent of attention received from outsiders for 252 cases. Observations and interviews with multiple firsthand informants on both sides of the case as well as some neutral informants supplemented by examination of objective data were the chief methods of investigation. The initial attitude of mothers varied from encouragement (21%) to neutral or tolerance (51%) to discouragement (28%). However, it changed significantly from neutrality to taking measures to induce amnesia in their children for previous life memories due to various psychosocial pressures and prevalent beliefs. Families of the previous personalities, once convinced, showed complete acceptance in a majority of cases. Outside attention was received in 58% cases. The positive attitude of parents might facilitate expression of memories but subsequently attitudes of persons concerned do not seem to alter features of the cases.

  1. Identification of novel missense mutations in the Norrie disease gene associated with one X-linked and four sporadic cases of familial exudative vitreoretinopathy.

    Science.gov (United States)

    Shastry, B S; Hejtmancik, J F; Trese, M T

    1997-01-01

    X-linked Familial Exudative Vitreoretinopathy (XLFEVR) is a hereditary eye disorder that affects both the retina and the vitreous body. It is characterized by an abnormal vascularization of the peripheral retina. It has been previously shown by linkage and candidate gene analysis that XLFEVR and Norrie disease are allelic. In this report we describe four novel mutations (R41K, H42R, K58N, and Y120C) in the Norrie disease gene associated with one X-linked and four sporadic cases of FEVR. One mutation (H42R) was found to be segregating with the disease in three generations (X-linked family), and the others are sporadic. These sequence alterations changed the encoded amino acids in the Norrie disease protein and were not found in 17 unaffected family members or in 36 randomly selected normal individuals. This study provides additional evidence that mutations in the same gene can result in FEVR and Norrie disease. It also demonstrates that it may be beneficial for clinical diagnosis to screen for mutations in the Norrie disease gene in sporadic FEVR cases.

  2. Association of a missense mutation in the positional candidate gene glutamate receptor-interacting protein 1 with backfat thickness traits in pigs

    Directory of Open Access Journals (Sweden)

    Jae-Bong Lee

    2017-08-01

    Full Text Available Objective Previously, we reported quantitative trait loci (QTLs affecting backfat thickness (BFT traits on pig chromosome 5 (SW1482–SW963 in an F2 intercross population between Landrace and Korean native pigs. The aim of this study was to evaluate glutamate receptor-interacting protein 1 (GRIP1 as a positional candidate gene underlying the QTL affecting BFT traits. Methods Genotype and phenotype analyses were performed using the 1,105 F2 progeny. A mixed-effect linear model was used to access association between these single nucleotide polymorphism (SNP markers and the BFT traits in the F2 intercross population. Results Highly significant associations of two informative SNPs (c.2442 T>C, c.3316 C>G [R1106G] in GRIP1 with BFT traits were detected. In addition, the two SNPs were used to construct haplotypes that were also highly associated with the BFT traits. Conclusion The SNPs and haplotypes of the GRIP1 gene determined in this study can contribute to understand the genetic structure of BFT traits in pigs.

  3. Novel rare missense variations and risk of autism spectrum disorder: whole-exome sequencing in two families with affected siblings and a two-stage follow-up study in a Japanese population.

    Directory of Open Access Journals (Sweden)

    Jun Egawa

    Full Text Available Rare inherited variations in multiplex families with autism spectrum disorder (ASD are suggested to play a major role in the genetic etiology of ASD. To further investigate the role of rare inherited variations, we performed whole-exome sequencing (WES in two families, each with three affected siblings. We also performed a two-stage follow-up case-control study in a Japanese population. WES of the six affected siblings identified six novel rare missense variations. Among these variations, CLN8 R24H was inherited in one family by three affected siblings from an affected father and thus co-segregated with ASD. In the first stage of the follow-up study, we genotyped the six novel rare missense variations identified by WES in 241 patients and 667 controls (the Niigata sample. Only CLN8 R24H had higher mutant allele frequencies in patients (1/482 compared with controls (1/1334. In the second stage, this variation was further genotyped, yet was not detected in a sample of 309 patients and 350 controls (the Nagoya sample. In the combined Niigata and Nagoya samples, there was no significant association (odds ratio = 1.8, 95% confidence interval = 0.1-29.6. These results suggest that CLN8 R24H plays a role in the genetic etiology of ASD, at least in a subset of ASD patients.

  4. Homozygous missense mutation (G56R in glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPI-HBP1 in two siblings with fasting chylomicronemia (MIM 144650

    Directory of Open Access Journals (Sweden)

    Hegele Robert A

    2007-09-01

    Full Text Available Abstract Background Mice with a deleted Gpihbp1 gene encoding glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPI-HBP1 develop severe chylomicronemia. We screened the coding regions of the human homologue – GPIHBP1 – from the genomic DNA of 160 unrelated adults with fasting chylomicronemia and plasma triglycerides >10 mmol/L, each of whom had normal sequence of the LPL and APOC2 genes. Results One patient with severe type 5 hyperlipoproteinemia (MIM 144650, fasting chylomicronemia and relapsing pancreatitis resistant to standard therapy was found to be homozygous for a novel GPIHBP1 missense variant, namely G56R. This mutation was absent from the genomes of 600 control subjects and 610 patients with hyperlipidemia. The GPIHBP1 G56 residue has been conserved throughout evolution and the G56R mutation was predicted to have compromised function. Her homozygous brother also had refractory chylomicronemia and relapsing pancreatitis together with early coronary heart disease. G56R heterozygotes in the family had fasting mild hypertriglyceridemia. Conclusion Thus, a very rare GPIHBP1 missense mutation appears to be associated with severe hypertriglyceridemia and chylomicronemia.

  5. Spontaneous Fundal Uterine Rupture in a Pregnant Woman at 32 Weeks Gestation who had Two Previous Cesarean Sections

    Directory of Open Access Journals (Sweden)

    Metin Kaba

    2017-08-01

    Full Text Available Spontaneous uterine rupture during pregnancy can cause severe complications, even maternal and fetal demise. We report successful management of a spontaneous fundal uterine rupture in a 32 week pregnant who had undergone two previous cesarean sections due to preterm delivery. We explain causes of spontaneous uterine rupture and the management of this rare event in the presented case report.

  6. Poly-epiphyseal overgrowth: description of a previously unreported skeletal dysplasia

    Energy Technology Data Exchange (ETDEWEB)

    Pazzaglia, Ugo E.; Bonaspetti, Giovanni [University of Brescia, Orthopaedic Clinic, Brescia (Italy); Beluffi, Giampiero [Fondazione IRCCS Policlinico San Matteo, Department of Paediatric Radiology, Pavia (Italy); Marchi, Antonietta; Bozzola, Mauro; Savasta, Salvatore [Fondazione IRCCS Policlinico San Matteo, Paediatric Clinic, University of Pavia, Pavia (Italy)

    2007-10-15

    A skeletal dysplasia with previously unreported features is presented. Its evolution was characterized by growth abnormalities of bones without involvement of other organs. Advanced bone age, increased stature and irregular epiphyseal ossification with stippling of the main long bones were documented. Physeal overgrowth was massive in the left proximal humerus and femur. Furthermore, the hip joint appeared fused with an abundant mass of pathological calcific tissue extending from the femur to the ilium. Pathological epiphyses were characterized by anarchic cartilaginous proliferation with multiple ossification centres, while lamellar bone apposition and remodelling were normal. The observed bone changes were different from those in any previously reported syndrome, metabolic defect or bone dysplasia. However, they clearly indicated a defect of endochondral ossification with some resemblance to phenotypes observed in dysplasia epiphysealis hemimelica. (orig.)

  7. Previous experience in manned space flight: A survey of human factors lessons learned

    Science.gov (United States)

    Chandlee, George O.; Woolford, Barbara

    1993-01-01

    Previous experience in manned space flight programs can be used to compile a data base of human factors lessons learned for the purpose of developing aids in the future design of inhabited spacecraft. The objectives are to gather information available from relevant sources, to develop a taxonomy of human factors data, and to produce a data base that can be used in the future for those people involved in the design of manned spacecraft operations. A study is currently underway at the Johnson Space Center with the objective of compiling, classifying, and summarizing relevant human factors data bearing on the lessons learned from previous manned space flights. The research reported defines sources of data, methods for collection, and proposes a classification for human factors data that may be a model for other human factors disciplines.

  8. Streptococcus agalactiae endocarditis presenting as acalculous cholecystitis in a previously well woman.

    LENUS (Irish Health Repository)

    Brewer, Linda

    2013-01-01

    This case report describes the unusual presentation of a previously very well woman with Streptococcus agalactiae endocarditis in the emergency department. History, examination and preliminary laboratory and radiological investigations supported a diagnosis of acalculous cholecystitis, for which she was given intravenous broad spectrum antimicrobial therapy. One day following admission, the patient deteriorated and became unresponsive. Subsequent MRI of the brain revealed multiple bihemispheric cerebral emboli and a large, mobile mitral valve thrombus was visualised on her transoesophageal echocardiogram. S agalactiae was cultured from venous blood samples and her antimicrobial cover was adjusted accordingly. Despite her presumed guarded prognosis, this patient made a remarkable recovery. To our knowledge, the association of S agalactiae endocarditis with acalculous cholecystitis has not been previously described.

  9. Poly-epiphyseal overgrowth: description of a previously unreported skeletal dysplasia

    International Nuclear Information System (INIS)

    Pazzaglia, Ugo E.; Bonaspetti, Giovanni; Beluffi, Giampiero; Marchi, Antonietta; Bozzola, Mauro; Savasta, Salvatore

    2007-01-01

    A skeletal dysplasia with previously unreported features is presented. Its evolution was characterized by growth abnormalities of bones without involvement of other organs. Advanced bone age, increased stature and irregular epiphyseal ossification with stippling of the main long bones were documented. Physeal overgrowth was massive in the left proximal humerus and femur. Furthermore, the hip joint appeared fused with an abundant mass of pathological calcific tissue extending from the femur to the ilium. Pathological epiphyses were characterized by anarchic cartilaginous proliferation with multiple ossification centres, while lamellar bone apposition and remodelling were normal. The observed bone changes were different from those in any previously reported syndrome, metabolic defect or bone dysplasia. However, they clearly indicated a defect of endochondral ossification with some resemblance to phenotypes observed in dysplasia epiphysealis hemimelica. (orig.)

  10. 75 FR 39143 - Airworthiness Directives; Arrow Falcon Exporters, Inc. (previously Utah State University); AST...

    Science.gov (United States)

    2010-07-08

    ... (previously Precision Helicopters, LLC); Robinson Air Crane, Inc.; San Joaquin Helicopters (previously Hawkins... (Previously Hawkins & Powers Aviation); S.M. &T. Aircraft (Previously Us Helicopter Inc., UNC Helicopters, Inc...

  11. 75 FR 66009 - Airworthiness Directives; Cessna Aircraft Company (Type Certificate Previously Held by Columbia...

    Science.gov (United States)

    2010-10-27

    ... Company (Type Certificate Previously Held by Columbia Aircraft Manufacturing (Previously the Lancair... Company (Type Certificate Previously Held by Columbia Aircraft Manufacturing (Previously The Lancair...-15895. Applicability (c) This AD applies to the following Cessna Aircraft Company (type certificate...

  12. Micrococcus sedentarius bacteraemia presenting with haemophagocytic syndrome in previously healthy boy.

    Science.gov (United States)

    Kuskonmaz, Baris; Kara, Ates; Ozen, Maide; Cengiz, A Bülent; Ozen, Metehan; Seçmeer, Gülten; Gürgey, Aytemiz

    2006-01-01

    Haemophagocytic syndromes are the clinical manifestation of an increased macrophagic activity with haemophagocytosis. Infection-associated HS was originally described by Risdall in 1979, in viral disease. Since the initial description HS has also been documented in patients with bacterial, parasitic or fungal infections. We describe a case of Micrococcus sedentarius bacteraemia in a previously healthy 10-y-old boy with haemophagocytic syndrome. Species of micrococci are generally considered as non-pathogenic commensals that colonize the skin, mucosae and oropharynx. We report the first case of Microccoccus sedentarius bacteraemia in an immunocompetent host and first case of HS associated with Micrococcus species.

  13. Delayed vaginal reconstruction in the fibrotic pelvis following radiation or previous reconstruction

    International Nuclear Information System (INIS)

    Berek, J.S.; Hacker, N.F.; Lagasse, L.D.; Smith, M.L.

    1983-01-01

    Vaginal reconstruction was performed in 14 patients who had developed vaginal stenosis secondary to extensive pelvic fibrosis after pelvic radiation therapy (12 patients) or prior vaginal reconstruction (2 patients). Sixteen procedures were performed using a split-thickness skin graft. All patients had satisfactory vaginal restoration, and 12 patients reported good vaginal function. No fistula developed as a result of the operative procedure, but one patient later developed a rectovaginal fistula resulting from tumor recurrence. Successful vaginal reconstruction can be achieved even years after initial therapy in patients who develop an obliterated vagina from previous radiation or surgery

  14. [Renal oncocytoma in the single kidney after previous surgery of renal carcinoma. Apropos of 2 cases].

    Science.gov (United States)

    Veneroni, L; Canclini, L; Berti, G L; Giola, V; Leidi, G L; Maccaroni, A; Raimoldi, A; Sironi, M; Assi, A; Bacchioni, A M

    1997-12-01

    Renal oncocytoma is a neoplasm which rarely occurs in patients with solitary kidney, the other being absent because of a previous nephrectomy performed for renal cancer. We present two case reports and a literature review. We have studied some important problems such as the histogenesis, the potential for malignancy, the diagnosis, the treatment and the follow up. The high incidence of coexistence of renal oncocytoma and renal cell carcinoma has important clinical implications. We would like to emphasize the importance of preoperatory FNAB, nephron sparing surgery and very careful follow up.

  15. Congenital costo-vertebral fibrous band and congenital kyphoscoliosis: a previously unreported combination.

    Science.gov (United States)

    Eid, Tony; Ghostine, Bachir; Kreichaty, Gaby; Daher, Paul; Ghanem, Ismat

    2013-05-01

    Congenital kyphoscoliosis (CKS) results from abnormal vertebral chondrification. Congenital fibrous bands occur in several locations with variable impact on vertebral development. We report a previously unreported case of a female infant with CKS presenting with an L2 hypoplastic vertebra and a costo-vertebral fibrous band extending to the skin in the form of a dimple. We also describe the therapeutic approach, consisting of surgical excision of the fibrous band and postoperative fulltime bracing, with a 7-year follow-up. We recommend a high index of suspicion in any unusual presentation of CKS and insist on case by case management in such cases.

  16. Echinocandin Failure Case Due to a Previously Unreported FKS1 Mutation in Candida krusei

    DEFF Research Database (Denmark)

    Jensen, Rasmus Hare; Justesen, Ulrik Stenz; Rewes, Annika

    2014-01-01

    Echinocandins are the preferred therapy for invasive infections due to Candida krusei. We present here a case of clinical failure involving C. krusei with a characteristic FKS1 hot spot mutation not previously reported in C. krusei that was isolated after 14 days of treatment. Anidulafungin MICs...... were elevated by ≥5 dilution steps above the clinical breakpoint but by only 1 step for a Candida albicans isolate harboring the corresponding mutation, suggesting a notable species-specific difference in the MIC increase conferred by this mutation....

  17. Data from studies of previous radioactive waste disposal in Massachusetts Bay

    International Nuclear Information System (INIS)

    Curtis, W.R.; Mardis, H.M.

    1984-12-01

    This report presents the results of studies conducted in Massachusetts Bay during 1981 and 1982. Included are data from: (1) a side scan sonar survey of disposal areas in the Bay that was carried out by the National Oceanic and Atmospheric Administration (NOAA) for EPA; (2) Collections of sediment and biota by NOAA for radiochemical analysis by EPA; (3) collections of marketplace seafood samples by the Food and Drug Administration (FDA) for radioanalysis by both FDA and EPA; and (4) a radiological monitoring survey of LLW disposal areas by EPA to determine whether there should be any concern for public health resulting from previous LLW disposals in the Bay

  18. Secondary Myelitis in Dermal Sinus Causing Paraplegia in a Child with Previously Normal Neurological Function

    Directory of Open Access Journals (Sweden)

    Sakina Rashid

    2016-01-01

    Full Text Available Neural tube defects result from failure of neural tube fusion during early embryogenesis, the fourth week after conception. The spectrum of severity is not uniform across the various forms of this congenital anomaly as certain presentations are not compatible with extrauterine life (anencephaly while, on the other hand, other defects may remain undiagnosed as they are entirely asymptomatic (occult spina bifida. We report a child with previously normal neurological development, a devastating clinical course following superinfection of a subtle spina bifida defect which resulted in a flaccid paralysis below the level of the lesion and permanent neurological deficits following resolution of the acute infection and a back closure surgery.

  19. Previous induced abortion among young women seeking abortion-related care in Kenya: a cross-sectional analysis.

    Science.gov (United States)

    Kabiru, Caroline W; Ushie, Boniface A; Mutua, Michael M; Izugbara, Chimaraoke O

    2016-05-14

    Unsafe abortion is a leading cause of death among young women aged 10-24 years in sub-Saharan Africa. Although having multiple induced abortions may exacerbate the risk for poor health outcomes, there has been minimal research on young women in this region who have multiple induced abortions. The objective of this study was therefore to assess the prevalence and correlates of reporting a previous induced abortion among young females aged 12-24 years seeking abortion-related care in Kenya. We used data on 1,378 young women aged 12-24 years who presented for abortion-related care in 246 health facilities in a nationwide survey conducted in 2012. Socio-demographic characteristics, reproductive and clinical histories, and physical examination assessment data were collected from women during a one-month data collection period using an abortion case capture form. Nine percent (n = 98) of young women reported a previous induced abortion prior to the index pregnancy for which they were receiving care. Statistically significant differences by previous history of induced abortion were observed for area of residence, religion and occupation at bivariate level. Urban dwellers and unemployed/other young women were more likely to report a previous induced abortion. A greater proportion of young women reporting a previous induced abortion stated that they were using a contraceptive method at the time of the index pregnancy (47 %) compared with those reporting no previous induced abortion (23 %). Not surprisingly, a greater proportion of young women reporting a previous induced abortion (82 %) reported their index pregnancy as unintended (not wanted at all or mistimed) compared with women reporting no previous induced abortion (64 %). Our study results show that about one in every ten young women seeking abortion-related care in Kenya reports a previous induced abortion. Comprehensive post-abortion care services targeting young women are needed. In particular, post

  20. Pregnancy in a Previously Conjoined Thoracopagus Twin with a Crisscross Heart

    Directory of Open Access Journals (Sweden)

    Bassam H. Rimawi

    2015-01-01

    Full Text Available Background. Crisscross heart (CCH is a complex, rare, congenital, rotational, cardiac abnormality that accounts for <0.1% of congenital heart defects (CHD. CCH is characterized by the crossing of the inflow streams of the two ventricles due to an abnormal twisting of the heart. A case of maternal CCH has not been previously reported. Case. We report a case of a primigravida with a CCH, who was separated at birth from her thoracopagus conjoined twin. Pregnancy was managed by congenital cardiology, maternal-fetal medicine, anesthesiology, and obstetrics. She underwent a 39-week vaginal delivery without maternal or neonatal complication. Conclusion. A successful term pregnancy outcome was achieved in a patient with CCH using a multidisciplinary approach to address her cardiac condition.

  1. Vaginal prostaglandin gel to induce labour in women with one previous caesarean section.

    LENUS (Irish Health Repository)

    Agnew, G

    2012-02-01

    This retrospective study reviewed the mode of delivery when vaginal prostaglandins were used to induce labour in women with a single previous lower segment caesarean section. Over a 4-year period, PGE 2 gel was used cautiously in low doses in 54 women. Induction with PGE 2 gel was associated with an overall vaginal birth after caesarean section (VBAC) rate of 74%, which compared favourably with the 74% VBAC rate in women who went into spontaneous labour (n = 1969). There were no adverse outcomes recorded after the prostaglandin inductions but the number reported are too small to draw any conclusions about the risks, such as uterine rupture. We report our results because they may be helpful in assessing the chances of a successful VBAC in the uncommon clinical circumstances where prostaglandin induction is being considered.

  2. Incidence of cancer in adolescent idiopathic scoliosis patients treated 25 years previously

    DEFF Research Database (Denmark)

    Simony, Ane; Hansen, Emil Jesper; Christensen, Steen Bach

    2016-01-01

    , is comparable to modern equipment. This is to our knowledge the first study to report increased rates of endometrial cancers in a cohort of AIS patients, and future attention is needed to reduce the radiation dose distributed to the AIS patients both pre-operatively and during surgery.......PURPOSE: To report the incidence of cancer in a cohort of adolescent idiopathic scoliosis (AIS) patients treated 25 years previously. METHODS: 215 consecutive AIS patients treated between 1983 and 1990 were identified and requested to return for clinical and radiographic examination. The incidence....... RESULTS: From the original cohort of 215 consecutive AIS patients, radiation information was available in 211 of the patients, and medical charts were available in 209 AIS patients. 170 (83 %) of the 205 AIS patients participated in the follow-up study with questionnaires. The calculated mean total...

  3. Gestational Diabetes in Korea: Incidence and Risk Factors of Diabetes in Women with Previous Gestational Diabetes

    Directory of Open Access Journals (Sweden)

    Hak Chul Jang

    2011-02-01

    Full Text Available Korean women with a history of gestational diabetes mellitus (GDM have a 3.5 times greater risk of developing postpartum diabetes than the general population. The incidence of type 2 diabetes mellitus in early postpartum is reported as 10-15% in Korean women. A prospective follow-up study on Korean women with GDM showed that approximately 40% of women with previous GDM were expected to develop diabetes within 5 years postpartum. Independent risk factors for the development of diabetes in Korean women with previous GDM are pre-pregnancy body weight, gestational age at diagnosis, antepartum hyperglycemia on oral glucose tolerance test, low insulin response to oral glucose load, and family history of diabetes. Women with postpartum diabetes have greater body mass indexes, body weight, and waist circumferences than women with normal glucose tolerance. Multiple logistic regression analysis has revealed that waist circumference is the strongest obesity index along with systolic blood pressure and that triglyceride levels are a major independent risk factor for developing diabetes. These results in Korean women with previous GDM underline the importance of postpartum testing in Korean women diagnosed with GDM, and demonstrate that impaired B-cell function, obesity, and especially visceral obesity, are associated with the development of diabetes.

  4. Previously unidentified changes in renal cell carcinoma gene expression identified by parametric analysis of microarray data

    International Nuclear Information System (INIS)

    Lenburg, Marc E; Liou, Louis S; Gerry, Norman P; Frampton, Garrett M; Cohen, Herbert T; Christman, Michael F

    2003-01-01

    Renal cell carcinoma is a common malignancy that often presents as a metastatic-disease for which there are no effective treatments. To gain insights into the mechanism of renal cell carcinogenesis, a number of genome-wide expression profiling studies have been performed. Surprisingly, there is very poor agreement among these studies as to which genes are differentially regulated. To better understand this lack of agreement we profiled renal cell tumor gene expression using genome-wide microarrays (45,000 probe sets) and compare our analysis to previous microarray studies. We hybridized total RNA isolated from renal cell tumors and adjacent normal tissue to Affymetrix U133A and U133B arrays. We removed samples with technical defects and removed probesets that failed to exhibit sequence-specific hybridization in any of the samples. We detected differential gene expression in the resulting dataset with parametric methods and identified keywords that are overrepresented in the differentially expressed genes with the Fisher-exact test. We identify 1,234 genes that are more than three-fold changed in renal tumors by t-test, 800 of which have not been previously reported to be altered in renal cell tumors. Of the only 37 genes that have been identified as being differentially expressed in three or more of five previous microarray studies of renal tumor gene expression, our analysis finds 33 of these genes (89%). A key to the sensitivity and power of our analysis is filtering out defective samples and genes that are not reliably detected. The widespread use of sample-wise voting schemes for detecting differential expression that do not control for false positives likely account for the poor overlap among previous studies. Among the many genes we identified using parametric methods that were not previously reported as being differentially expressed in renal cell tumors are several oncogenes and tumor suppressor genes that likely play important roles in renal cell

  5. Urinary incontinence and vaginal squeeze pressure two years post-cesarean delivery in primiparous women with previous gestational diabetes mellitus

    OpenAIRE

    Barbosa, Angélica Mércia Pascon; Dias, Adriano; Marini, Gabriela; Calderon, Iracema Mattos Paranhos; Witkin, Steven; Rudge, Marilza Vieira Cunha

    2011-01-01

    OBJECTIVE: To assess the prevalence of urinary incontinence and associated vaginal squeeze pressure in primiparous women with and without previous gestational diabetes mellitus two years post-cesarean delivery. METHODS: Primiparous women who delivered by cesarean two years previously were interviewed about the delivery and the occurrence of incontinence. Incontinence was reported by the women and vaginal pressure evaluated by a Perina perineometer. Sixty-three women with gestational diabetes ...

  6. Outcomes after radical prostatectomy in men receiving previous pelvic radiation for non-prostate malignancies.

    Science.gov (United States)

    Masterson, Timothy A; Wedmid, Alexei; Sandhu, Jaspreet S; Eastham, James A

    2009-08-01

    To report the perioperative and functional outcomes of nine patients treated at our institution who had radical prostatectomy (RP) after previous pelvic radiotherapy (RT) for non-prostate malignancies. From 1993 to 2007, nine patients had RP after external beam RT for testicular seminoma (six), anorectal cancer (two) and colon cancer (one). Clinical information was obtained from a prospective prostate cancer database. RP was completed with no identifiable injury to adjacent structures in all nine patients. Four patients had significant pelvic fibrosis, and three required bilateral neurovascular bundle (NVB) resection. The NVB was preserved in the remaining six patients, four with good preoperative erectile function. However, no patient recovered erectile function after RP at a median (range) follow-up of 75 (12-172) months. Of seven men continent before RP, four required one or fewer pads daily and three were completely dry, achieving complete urinary control at a median (range) time of 7.5 (2-20) months. Two patients developed an anastomotic stricture, one being associated with concomitant ureteric stricture. RP after pelvic RT for non-prostate malignancies was not associated with increased intraoperative morbidity. However, rates of anastomotic stricture, erectile dysfunction and urinary incontinence appeared to be higher than those reported after RP in men with no previous RT, and comparable with those seen in the salvage RP setting.

  7. [Meningitis and white matter lesions due to Streptococcus mitis in a previously healthy child].

    Science.gov (United States)

    Yiş, Reyhan; Yüksel, Ciğdem Nükhet; Derundere, Umit; Yiş, Uluç

    2011-10-01

    Streptococcus mitis, an important member of viridans streptococci, is found in the normal flora of the oropharynx, gastrointestinal tract, female genital tract and skin. Although it is of low pathogenicity and virulence, it may cause serious infections in immunocompromised patients. Meningitis caused by S.mitis has been described in patients with previous spinal anesthesia, neurosurgical procedure, malignancy, bacterial endocarditis with neurological complications and alcoholics, but it is rare in patients who are previously healthy. In this report, a rare case of meningoencephalitis caused by S.mitis developed in a previously healthy child has been presented. A previously healthy eight-year-old girl who presented with fever, altered state of consciousness, and headache was hospitalized in intensive care unit with the diagnosis of meningitis. Past history revealed that she was treated with amoxicillin-clavulanate for acute sinusitis ten days before her admission. Whole blood count revealed the followings: hemoglobin 13 g/dl, white blood cell count 18.6 x 109/L (90% neutrophils), platelet count 200 x 109/L and 150 leucocytes were detected on cerebrospinal fluid (CSF) examination. Protein and glucose levels of CSF were 80 mg/dl and 40 mg/dl (concomitant blood glucose 100 mg/dl), respectively. Brain magnetic resonance imaging (MRI) revealed widespread white matter lesions, and alpha-hemolytic streptococci were grown in CSF culture. The isolate was identified as S.mitis with conventional methods, and also confirmed by VITEK2 (bioMerieux, France) and API 20 STREP (bioMerieux, France) systems. Isolate was found susceptible to penicillin, erythromycin, clindamycin, tetracycline, cefotaxime, vancomycin and chloramphenicol. Regarding the etiology, echocardiography revealed no vegetation nor valve pathology, and peripheral blood smear showed no abnormality. Immunoglobulin and complement levels were within normal limits. Ongoing inflammation in maxillary sinuses detected in

  8. The frequency of previously undetectable deletions involving 3' Exons of the PMS2 gene.

    Science.gov (United States)

    Vaughn, Cecily P; Baker, Christine L; Samowitz, Wade S; Swensen, Jeffrey J

    2013-01-01

    Lynch syndrome is characterized by mutations in one of four mismatch repair genes, MLH1, MSH2, MSH6, or PMS2. Clinical mutation analysis of these genes includes sequencing of exonic regions and deletion/duplication analysis. However, detection of deletions and duplications in PMS2 has previously been confined to Exons 1-11 due to gene conversion between PMS2 and the pseudogene PMS2CL in the remaining 3' exons (Exons 12-15). We have recently described an MLPA-based method that permits detection of deletions of PMS2 Exons 12-15; however, the frequency of such deletions has not yet been determined. To address this question, we tested for 3' deletions in 58 samples that were reported to be negative for PMS2 mutations using previously available methods. All samples were from individuals whose tumors exhibited loss of PMS2 immunohistochemical staining without concomitant loss of MLH1 immunostaining. We identified seven samples in this cohort with deletions in the 3' region of PMS2, including three previously reported samples with deletions of Exons 13-15 (two samples) and Exons 14-15. Also detected were deletions of Exons 12-15, Exon 13, and Exon 14 (two samples). Breakpoint analysis of the intragenic deletions suggests they occurred through Alu-mediated recombination. Our results indicate that ∼12% of samples suspected of harboring a PMS2 mutation based on immunohistochemical staining, for which mutations have not yet been identified, would benefit from testing using the new methodology. Copyright © 2012 Wiley Periodicals, Inc.

  9. Revision and simplification of the boarding previous minimum of the lumbar column

    International Nuclear Information System (INIS)

    Lazannec, JY; Del Vecchio, R; Ramare, S; Saillant, G

    2001-01-01

    This paper describes the boarding retroperineal previous minimum, which provides access at any level discal and vertebral between T12 and S1. It is carried out a technique of dissection retroperineal that facilitates the renal and duodenum-pancreatic mobilization to consent to the face previous left of the whole lumbar column and of the thoracic-lumbar union. They were carried out careful anatomical dissections in fresh cadavers and preserved to determine the topography and the anatomical relationships of interest and this way to develop a sure boarding and easily reproducible. Special attention has been paid to the description of the lumbar veins and the anastomosis between the vein renal left and the hemiacigos system for the exhibition of the expensive left anterolateral of T12 and L1. A series of 94 patients is reported with lesions caused by traumas or degenerative processes. For all the lumbar levels, even in-patient with antecedents of surgery intraperitoneal, the boarding minimum retroperitoneal, was safe for the kidneys, ureters, spleen, hypo gastric plexus and duodenum-pancreatic union. Better cosmetic results are reported, decrease of the time surgical, scarce bled intraoperatory and easiness for the decortications and placement of implants. The previous boarding minimum retro peritoneal of the column developed starting from the boarding classic retroperineals, offers significant advantages on the endoscopic techniques, which require sophisticated machinery and they are technically plaintiffs. The exhibition of all the lumbar levels, as well as the reduction maneuvers and placement of implants, they can be carried out with easiness without causing muscular damage

  10. Emergency diagnosis of cancer and previous general practice consultations: insights from linked patient survey data.

    Science.gov (United States)

    Abel, Gary A; Mendonca, Silvia C; McPhail, Sean; Zhou, Yin; Elliss-Brookes, Lucy; Lyratzopoulos, Georgios

    2017-06-01

    Emergency diagnosis of cancer is common and aetiologically complex. The proportion of emergency presenters who have consulted previously with relevant symptoms is uncertain. To examine how many patients with cancer, who were diagnosed as emergencies, have had previous primary care consultations with relevant symptoms; and among those, to examine how many had multiple consultations. Secondary analysis of patient survey data from the 2010 English Cancer Patient Experience Survey (CPES), previously linked to population-based data on diagnostic route. For emergency presenters with 18 different cancers, associations were examined for two outcomes (prior GP consultation status; and 'three or more consultations' among prior consultees) using logistic regression. Among 4647 emergency presenters, 1349 (29%) reported no prior consultations, being more common in males (32% versus 25% in females, P <0.001), older (44% in ≥85 versus 30% in 65-74-year-olds, P <0.001), and the most deprived (35% versus 25% least deprived, P = 0.001) patients; and highest/lowest for patients with brain cancer (46%) and mesothelioma (13%), respectively ( P <0.001 for overall variation by cancer site). Among 3298 emergency presenters with prior consultations, 1356 (41%) had three or more consultations, which were more likely in females ( P <0.001), younger ( P <0.001), and non-white patients ( P = 0.017) and those with multiple myeloma, and least likely for patients with leukaemia ( P <0.001). Contrary to suggestions that emergency presentations represent missed diagnoses, about one-third of emergency presenters (particularly those in older and more deprived groups) have no prior GP consultations. Furthermore, only about one-third report multiple (three or more) consultations, which are more likely in 'harder-to-suspect' groups. © British Journal of General Practice 2017.

  11. Retrospective analysis on malignant calcification previously misdiagnosed as benign on screening mammography

    International Nuclear Information System (INIS)

    Ha, Su Min; Cha, Joo Hee; Kim, Hak Hee; Shin, Hee Jung; Chae, Eun Young; Choi, Woo Jung

    2017-01-01

    The purpose of our study was to investigate the morphology and distribution of calcifications initially interpreted as benign or probably benign, but proven to be malignant by subsequent stereotactic biopsy, and to identify the reason for misinterpretation or underestimation at the initial diagnosis. Out of 567 women who underwent stereotactic biopsy for calcifications at our hospital between January 2012 and December 2014, 167 women were diagnosed with malignancy. Forty-six of these 167 women had previous mammography assessed as benign or probably benign which was changed to suspicious malignancy on follow-up mammography. Of these 46 women, three women with biopsy-proven benign calcifications at the site of subsequent cancer were excluded, and 43 patients were finally included. The calcifications (morphology, distribution, extent, associated findings) in the previous and follow-up mammography examinations were analyzed according to the Breast Imaging Reporting and Data System (BI-RADS) lexicon and assessment category. We classified the patients into two groups: 1) group A patients who were still retrospectively re-categorized as less than or equal to BI-RADS 3 and 2) group B patients who were re-categorized as equal to or higher than BI-RADS 4a and whose results should have prompted previous diagnostic assessment. In the follow-up mammography examinations, change in calcification morphology (n = 27, 63%) was the most frequent cause of assessment change. The most frequent previous mammographic findings of malignant calcification were amorphous morphology (n = 26, 60%) and grouped distribution (n = 36, 84%). The most frequent calcification findings at reassessment were amorphous morphology (n = 4, 9%), fine pleomorphic calcification (n = 30, 70%), grouped distribution (n = 23, 53%), and segmental calcification (n = 12, 28%). There were 33 (77%) patients in group A, and 10 patients (23%) in group B. Amorphous morphology and grouped distribution were the most frequent

  12. Determination of the Boltzmann constant with cylindrical acoustic gas thermometry: new and previous results combined

    Science.gov (United States)

    Feng, X. J.; Zhang, J. T.; Lin, H.; Gillis, K. A.; Mehl, J. B.; Moldover, M. R.; Zhang, K.; Duan, Y. N.

    2017-10-01

    We report a new determination of the Boltzmann constant k B using a cylindrical acoustic gas thermometer. We determined the length of the copper cavity from measurements of its microwave resonance frequencies. This contrasts with our previous work (Zhang et al 2011 Int. J. Thermophys. 32 1297, Lin et al 2013 Metrologia 50 417, Feng et al 2015 Metrologia 52 S343) that determined the length of a different cavity using two-color optical interferometry. In this new study, the half-widths of the acoustic resonances are closer to their theoretical values than in our previous work. Despite significant changes in resonator design and the way in which the cylinder length is determined, the value of k B is substantially unchanged. We combined this result with our four previous results to calculate a global weighted mean of our k B determinations. The calculation follows CODATA’s method (Mohr and Taylor 2000 Rev. Mod. Phys. 72 351) for obtaining the weighted mean value of k B that accounts for the correlations among the measured quantities in this work and in our four previous determinations of k B. The weighted mean {{\\boldsymbol{\\hat{k}}}{B}} is 1.380 6484(28)  ×  10-23 J K-1 with the relative standard uncertainty of 2.0  ×  10-6. The corresponding value of the universal gas constant is 8.314 459(17) J K-1 mol-1 with the relative standard uncertainty of 2.0  ×  10-6.

  13. Retrospective analysis on malignant calcification previously misdiagnosed as benign on screening mammography

    Energy Technology Data Exchange (ETDEWEB)

    Ha, Su Min [Dept. of Radiology, Research Institute of Radiology, Chung Ang University Hospital, Seoul(Korea, Republic of); Cha, Joo Hee; Kim, Hak Hee; Shin, Hee Jung; Chae, Eun Young; Choi, Woo Jung [Dept. of Radiology, Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of)

    2017-04-15

    The purpose of our study was to investigate the morphology and distribution of calcifications initially interpreted as benign or probably benign, but proven to be malignant by subsequent stereotactic biopsy, and to identify the reason for misinterpretation or underestimation at the initial diagnosis. Out of 567 women who underwent stereotactic biopsy for calcifications at our hospital between January 2012 and December 2014, 167 women were diagnosed with malignancy. Forty-six of these 167 women had previous mammography assessed as benign or probably benign which was changed to suspicious malignancy on follow-up mammography. Of these 46 women, three women with biopsy-proven benign calcifications at the site of subsequent cancer were excluded, and 43 patients were finally included. The calcifications (morphology, distribution, extent, associated findings) in the previous and follow-up mammography examinations were analyzed according to the Breast Imaging Reporting and Data System (BI-RADS) lexicon and assessment category. We classified the patients into two groups: 1) group A patients who were still retrospectively re-categorized as less than or equal to BI-RADS 3 and 2) group B patients who were re-categorized as equal to or higher than BI-RADS 4a and whose results should have prompted previous diagnostic assessment. In the follow-up mammography examinations, change in calcification morphology (n = 27, 63%) was the most frequent cause of assessment change. The most frequent previous mammographic findings of malignant calcification were amorphous morphology (n = 26, 60%) and grouped distribution (n = 36, 84%). The most frequent calcification findings at reassessment were amorphous morphology (n = 4, 9%), fine pleomorphic calcification (n = 30, 70%), grouped distribution (n = 23, 53%), and segmental calcification (n = 12, 28%). There were 33 (77%) patients in group A, and 10 patients (23%) in group B. Amorphous morphology and grouped distribution were the most frequent

  14. First report of bilateral pheochromocytoma in the clinical spectrum of HIF2A-related polycythemia-paraganglioma syndrome.

    Science.gov (United States)

    Taïeb, David; Yang, Chunzhang; Delenne, Blandine; Zhuang, Zhengping; Barlier, Anne; Sebag, Fréderic; Pacak, Karel

    2013-05-01

    Molecular genetic research has so far resulted in the identification of 10 well-characterized susceptibility genes for hereditary pheochromocytoma (PHEO) or paraganglioma (PGL). Recently, a new syndrome characterized by multiple PGLs and somatostatinomas associated with congenital polycythemia due to somatic mutations in HIF2A has been reported. The aim of the study was to define the genetic defect in a new case of bilateral PHEO and multiple PGLs associated with congenital polycythemia. A female patient presented with neonatal polycythemia (treated by phlebotomies, 1 session approximately every 4 mo), mildly enlarged cerebral ventricles, and bilateral PHEO and multiple PGLs. There was no family history of any neuroendocrine tumor or polycythemia. Surgical removal of the tumors only temporarily normalized plasma erythropoietin (Epo) levels and discontinued phlebotomies. No germline mutations were initially detected in the SDHB, SDHC, SDHD, VHL, and PHD2 genes, known to be associated with polycythemia. The PHEOs presented with a typical noradrenergic biochemical phenotype. A heterozygous missense mutation (c.1589C>T) was identified in exon 12 of HIF2A, resulting in an alanine 530 substitution in the HIF-2α protein with valine (A530V). This somatic mutation was detected in the tissue from 1 PHEO and 1 PGL, with no HIF2A germline mutation found. This mutation led to stabilization of HIF-2α and hence a gain-of-function phenotype, as in previously published studies. This case represents the first association of a somatic HIF2A gain-of-function mutation with PHEO and congenital polycythemia, and it alerts physicians to perform proper genetic screening in patients presenting with multiple norepinephrine-producing PHEOs and polycythemia. This report also extends the previous findings of a new syndrome of only multiple PGLs, somatostatinomas, and polycythemia to multiple PHEOs.

  15. Systemic vascular phenotypes of Loeys-Dietz syndrome in a child carrying a de novo R381P mutation in TGFBR2: a case report.

    Science.gov (United States)

    Uike, Kiyoshi; Matsushita, Yuki; Sakai, Yasunari; Togao, Osamu; Nagao, Michinobu; Ishizaki, Yoshito; Nagata, Hazumu; Yamamura, Kenichiro; Torisu, Hiroyuki; Hara, Toshiro

    2013-11-12

    Loeys-Dietz syndrome, also known as Marfan syndrome type II, is a rare connective tissue disorder caused by dominant mutations in transforming growth factor-beta receptors (TGFBR1 and 2). We report a 7-year-old Japanese boy with Loeys-Dietz syndrome who carried a novel, de novo missense mutation in TGFBR2 (c.1142g > c, R381P). He showed dysmorphic faces and skeletal malformations that were typical in previous cases with Loeys-Dietz syndrome. The cardiac studies disclosed the presence of markedly dilated aortic root and patent ductus aorteriosus. The cranial magnetic resonance imaging (MRI) and angiography (MRA) detected the tortuous appearances of the bilateral middle cerebral and carotid arteries. This study depicts the systemic vascular phenotypes of a child with Loeys-Dietz syndrome that were caused by a novel heterozygous mutation of TGFR2. A large cohort with serial imaging studies for vascular phenotypes will be useful for delineating the genotype-phenotype correlations of Loeys-Dietz syndrome.

  16. Alternative splicing of exon 17 and a missense mutation in exon 20 of the insulin receptor gene in two brothers with a novel syndrome of insulin resistance (congenital fiber-type disproportion myopathy)

    DEFF Research Database (Denmark)

    Vorwerk, P; Christoffersen, C T; Müller, J

    1999-01-01

    to be compound heterozygotes for mutations in the IR gene. The maternal allele was alternatively spliced in exon 17 due to a point mutation in the -1 donor splice site of the exon. The abnormal skipping of exon 17 shifts the amino acid reading frame and leads to a truncated IR, missing the entire tyrosine kinase......The insulin receptor (IR) in two brothers with a rare syndrome of congenital muscle fiber type disproportion myopathy (CFTDM) associated with diabetes and severe insulin resistance was studied. By direct sequencing of Epstein-Barr virus-transformed lymphocytes both patients were found...... domain. In the correct spliced variant, the point mutation is silent and results in a normally translated IR. The paternal allele carries a missense mutation in the tyrosine kinase domain. All three cDNA variants were present in the lymphocytes of the patients. Purified IR from 293 cells overexpressing...

  17. Insights into the Molecular Mechanisms of Alzheimer’s and Parkinson’s Diseases with Molecular Simulations: Understanding the Roles of Artificial and Pathological Missense Mutations in Intrinsically Disordered Proteins Related to Pathology

    Directory of Open Access Journals (Sweden)

    Orkid Coskuner-Weber

    2018-01-01

    Full Text Available Amyloid-β and α-synuclein are intrinsically disordered proteins (IDPs, which are at the center of Alzheimer’s and Parkinson’s disease pathologies, respectively. These IDPs are extremely flexible and do not adopt stable structures. Furthermore, both amyloid-β and α-synuclein can form toxic oligomers, amyloid fibrils and other type of aggregates in Alzheimer’s and Parkinson’s diseases. Experimentalists face challenges in investigating the structures and thermodynamic properties of these IDPs in their monomeric and oligomeric forms due to the rapid conformational changes, fast aggregation processes and strong solvent effects. Classical molecular dynamics simulations complement experiments and provide structural information at the atomic level with dynamics without facing the same experimental limitations. Artificial missense mutations are employed experimentally and computationally for providing insights into the structure-function relationships of amyloid-β and α-synuclein in relation to the pathologies of Alzheimer’s and Parkinson’s diseases. Furthermore, there are several natural genetic variations that play a role in the pathogenesis of familial cases of Alzheimer’s and Parkinson’s diseases, which are related to specific genetic defects inherited in dominant or recessive patterns. The present review summarizes the current understanding of monomeric and oligomeric forms of amyloid-β and α-synuclein, as well as the impacts of artificial and pathological missense mutations on the structural ensembles of these IDPs using molecular dynamics simulations. We also emphasize the recent investigations on residual secondary structure formation in dynamic conformational ensembles of amyloid-β and α-synuclein, such as β-structure linked to the oligomerization and fibrillation mechanisms related to the pathologies of Alzheimer’s and Parkinson’s diseases. This information represents an important foundation for the successful and

  18. Impact of previous virological treatment failures and adherence on the outcome of antiretroviral therapy in 2007.

    Directory of Open Access Journals (Sweden)

    Marie Ballif

    Full Text Available BACKGROUND: Combination antiretroviral treatment (cART has been very successful, especially among selected patients in clinical trials. The aim of this study was to describe outcomes of cART on the population level in a large national cohort. METHODS: Characteristics of participants of the Swiss HIV Cohort Study on stable cART at two semiannual visits in 2007 were analyzed with respect to era of treatment initiation, number of previous virologically failed regimens and self reported adherence. Starting ART in the mono/dual era before HIV-1 RNA assays became available was counted as one failed regimen. Logistic regression was used to identify risk factors for virological failure between the two consecutive visits. RESULTS: Of 4541 patients 31.2% and 68.8% had initiated therapy in the mono/dual and cART era, respectively, and been on treatment for a median of 11.7 vs. 5.7 years. At visit 1 in 2007, the mean number of previous failed regimens was 3.2 vs. 0.5 and the viral load was undetectable (4 previous failures compared to 1 were 0.9 (95% CI 0.4-1.7, 0.8 (0.4-1.6, 1.6 (0.8-3.2, 3.3 (1.7-6.6 respectively, and 2.3 (1.1-4.8 for >2 missed cART doses during the last month, compared to perfect adherence. From the cART era, odds ratios with a history of 1, 2 and >2 previous failures compared to none were 1.8 (95% CI 1.3-2.5, 2.8 (1.7-4.5 and 7.8 (4.5-13.5, respectively, and 2.8 (1.6-4.8 for >2 missed cART doses during the last month, compared to perfect adherence. CONCLUSIONS: A higher number of previous virologically failed regimens, and imperfect adherence to therapy were independent predictors of imminent virological failure.

  19. 75 FR 20933 - Airworthiness Directives; Arrow Falcon Exporters, Inc. (previously Utah State University...

    Science.gov (United States)

    2010-04-22

    ... Hawkins and Powers Aviation, Inc.); S.M.&T. Aircraft (previously US Helicopters, Inc., UNC Helicopter, Inc... Joaquin Helicopters (previously Hawkins and Powers Aviation, Inc.); S.M.&T. Aircraft (previously US...

  20. The Affordable Care Act, Insurance Coverage, and Health Care Utilization of Previously Incarcerated Young Men: 2008-2015.

    Science.gov (United States)

    Winkelman, Tyler N A; Choi, HwaJung; Davis, Matthew M

    2017-05-01

    To estimate health insurance and health care utilization patterns among previously incarcerated men following implementation of the Affordable Care Act's (ACA's) Medicaid expansion and Marketplace plans in 2014. We performed serial cross-sectional analyses using data from the National Survey of Family Growth between 2008 and 2015. Our sample included men aged 18 to 44 years with (n = 3476) and without (n = 8702) a history of incarceration. Uninsurance declined significantly among previously incarcerated men after ACA implementation (-5.9 percentage points; 95% confidence interval [CI] = -11.5, -0.4), primarily because of an increase in private insurance (6.8 percentage points; 95% CI = 0.1, 13.3). Previously incarcerated men accounted for a large proportion of the remaining uninsured (38.6%) in 2014 to 2015. Following ACA implementation, previously incarcerated men continued to be significantly less likely to report a regular source of primary care and more likely to report emergency department use than were never-incarcerated peers. Health insurance coverage improved among previously incarcerated men following ACA implementation. However, these men account for a substantial proportion of the remaining uninsured. Previously incarcerated men continue to lack primary care and frequently utilize acute care services.