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Asymmetry of the craniofacial skeleton in the parents of children with a cleft lip, with or without a cleft palate, or an isolated cleft palate

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EUROPEAN JOURNAL OF ORTHODONTICS 2010年第2期32卷 177-185页

作者： McIntyre, G. T. Mossey, P. A. Univ Dundee Dent Hosp & Sch Dept Orthodont Dundee DD1 4HR Scotland

The postero-anterior (PA) cephalograms of 52 parents of children with CL(P) and 40 parents of children with CP from a sample of 196 children with non-syndromic clefts in the west of Scotland were analysed. A conventional cephalometric asymmetry analysis was used to evaluate size-related right:left asymmetry comprising eight linear distances, nine angular, and three facial area measurements. Right:left ratios of the mean values identified the direction of the asymmetry and two-sample t-tests determined statistical significance. A shape-related asymmetry analysis was also undertaken. The configurations of landmarks were optimally superimposed and scaled using Procrustes algorithms. Euclidean distance matrix analysis (EDMA) was then compared and the shape of the left and the right landmark configurations were statistically tested using a non-parametric bootstrap technique. For the parents of CL(P) children, size-related asymmetry was identified and the area of the craniofacial polygon was statistically significantly larger on the right than on the left side. EDMA detected the presence of shape-related asymmetry (T statistic = 1.304;P = 0.003). For the parents of CP children, although size-related asymmetry was identified, EDMA did not identify shape-related asymmetry (T statistic = 1.281;P = 0.065). Size and shape directional asymmetries are characteristic features of the parental craniofacial skeleton in CL(P). Although directional size asymmetry is present in the parental craniofacial skeleton in CP, shape asymmetry is not a characteristic feature.

关键词： Skeletons CALML3 gene Cleft Lip COTL1 gene Parents Cleft Palate contract laboratory program landmarks Child

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Human CLPP reverts the longevity phenotype of a fungal ClpP deletion strain

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NATURE COMMUNICATIONS 2013年第Jan.期4卷 1397-1402页

作者： Fischer, Fabian Weil, Andrea Hamann, Andrea Osiewacz, Heinz D. Goethe Univ Frankfurt Fac Biosci D-60438 Frankfurt Germany Inst Mol Biosci D-60438 Frankfurt Germany

Mitochondrial maintenance crucially depends on the quality control of proteins by various chaperones, proteases and repair enzymes. While most of the involved components have been studied in some detail, little is known on the biological role of the CLPXP protease complex located in the mitochondrial matrix. Here we show that deletion of PaClpP, encoding the CLP protease proteolytic subunit CLPP, leads to an unexpected healthy phenotype and increased lifespan of the fungal ageing model organism Podospora anserina. This phenotype can be reverted by expression of human ClpP in the fungal deletion background, demonstrating functional conservation of human and fungal CLPP. Our results show that the biological role of eukaryotic CLP proteases can be studied in an experimentally accessible model organism.

关键词： Fungi Phenotype CALML3 gene COTL1 gene Quality Control CLPP gene PATJ gene contract laboratory program

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CpG oligodeoxynucleotide protection in polymicrobial sepsis is dependent on interleukin-17

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JOURNAL OF INFECTIOUS DISEASES 2005年第8期191卷 1368-1376页

作者： Rice, L Orlow, D Ceonzo, K Stahl, GL Tzianabos, AO Wada, H Aird, WC Buras, JA Beth Israel Deaconess Med Ctr Dept Emergency Med Boston MA 02215 USA Beth Israel Deaconess Med Ctr Div Mol & Vasc Med Boston MA 02215 USA Brigham & Womens Hosp Ctr Expt Therapeut & Reperfus Injury Boston MA 02115 USA Brigham & Womens Hosp Channing Lab Boston MA 02115 USA

CpG oligodeoxynucleotides (ODNs) may prevent mortality from infection. We have identified a therapeutic benefit in treating sepsis with phosphorothioate ODN sequences containing the CpG motif. Sepsis was induced in rats by cecal ligation and puncture (CLP), and treatment with CpG ODNs reduced sepsis mortality from 80% to 15% during a 108-h period. Protection from mortality was dose dependent. Bacterial load in peritoneal fluid was reduced in CpG ODN-treated versus non-CpG ODN-treated rats after CLP. Lung injury, as determined by total myeloperoxidase activity, was also reduced in CpG ODN-treated versus non-CpG ODN-treated rats after CLP. Indirect evidence suggests that CpG-induced expression of interleukin (IL)-23 as levels of p40-but not p35-were significantly increased in both plasma and peritoneal lavage fluid in CpG ODN-treated versus nonCpG ODN-treated rats 24 h after CLP. Anti-IL-17 antibody inhibited the CpG-mediated prevention of mortality. These data suggest that IL-17 may mediate CpG-inducible host defenses during intraabdominal sepsis.

关键词： Interleukin-17 Oligodeoxyribonucleotides Sepsis 白细胞介素17 寡脱氧核糖核苷酸类脓毒症 COTL1 gene Sepsis Mortality Oligodeoxyribonucleotides contract laboratory program CPG-ODN CALML3 gene

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Antifreeze proteins in winter rye leaves form oligomeric complexes

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PLANT PHYSIOLOGY 1999年第4期119卷 1361-1369页

作者： Yu, XM Griffith, M Univ Waterloo Dept Biol Waterloo ON N2L 3G1 Canada

Antifreeze proteins (AFPs) similar to three pathogenesis-related proteins, a glucanase-like protein (GLP), a chitinase-like protein (CLP), and a thaumatin-like protein (TLP), accumulate during cold acclimation in winter rye (Secale cereale) leaves, where they are thought to modify the growth of intercellular ice during freezing. The objective of this study was to characterize the rye AFPs in their native forms, and our results show that these proteins form oligomeric complexes in vivo. Nine proteins were separated by nativepolyacrylamide gel electrophoresis from apoplastic extracts of cold-acclimated winter rye leaves. Seven of these proteins exhibited multiple polypeptides when denatured and separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. After isolation of the individual proteins, six were shown by immunoblotting to contain various combinations of GLP, CLP, and TLP in addition to other unidentified proteins. Antisera produced against individual cold-induced winter rye CLP, CLP, and TLP all dramatically inhibited glucanase activity in apoplastic extracts from cold-acclimated winter rye leaves, and each antiserum precipitated all three proteins. These results indicate that each of the polypeptides may be exposed on the surface of the protein complexes. By forming oligomeric complexes, AFPs may form larger surfaces to interact with ice, or they may simply increase the mass of the protein bound to ice. In either case, the complexes of AFPs may inhibit ice growth and recrystallization more effectively than the individual polypeptides.

关键词： Polyacrylamide Gel Electrophoresis Proteins GOLGA6A gene Polypeptides COTL1 gene Protein Ice Immune Sera Rye Antifreeze Proteins contract laboratory program CALML3 gene

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Erythropoietin prevents lymphoid apoptosis but has no effect on survival in experimental sepsis

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PEDIATRIC RESEARCH 2013年第2期74卷 148-153页

作者： Koroglu, Tolga F. Yilmaz, Osman Gokmen, Necati Tugyan, Kazim Baskin, Huseyin Egrilmez, Mehtap Yuksel Dokuz Eylul Univ Dept Pediat Izmir Turkey Dokuz Eylul Univ Div Pediat Crit Care Med Izmir Turkey Dokuz Eylul Univ Inst Hlth Sci Izmir Turkey Dokuz Eylul Univ Dept Anesthesiol & Reanimat Izmir Turkey Dokuz Eylul Univ Dept Histol Izmir Turkey Dokuz Eylul Univ Dept Microbiol Izmir Turkey

BACKGROUND: Lymphoid apoptosis in sepsis is associated with poor outcome, and prevention of apoptosis frequently improves survival in experimental models of sepsis. Recently, erythropoietin (EPO) was shown to protect against lipopolysaccharide (LPS)-induced mortality. As cecal ligation and puncture (CLP) is a clinically more relevant model of sepsis, we evaluated the effect of EPO on CLP-induced lymphoid tissue apoptosis and mortality. METHODS: Young Wistar rats were subjected to polymicrobial sepsis by CLP. EPO (5,000 U/kg intraperitoneal) was administered 30 min before CLP and then 1 and 4h after CLP. Spleen, thymus, and small intestine were harvested at 24 h and assessed for apoptosis by terminal deoxynucleotidyl transferase nick-end labeling (TUNEL) and caspase-3 staining. A separate group of animals was followed up for mortality. RESULTS: Splenic, thymic, and intestinal apoptosis was increased after CLP;administration of EPO significantly decreased apoptosis as determined by TUNEL and caspase-3 staining. Final survival in the CLP mortality study was 30% in both saline and EPO groups. CONCLUSION: Our results provide the first evidence that EPO attenuates lymphoid apoptosis in the CLP model of sepsis. However, EPO is not associated with a survival benefit in the CLP model of sepsis.

关键词： CALML3 gene Caspase 3 COTL1 gene experimental sepsis Erythropoietin Survival experimental model contract laboratory program In Situ Nick-End Labeling

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Myo-inositol, glucose and zinc status as risk factors for non-syndromic cleft lip with or without cleft palate in offspring:: a case-control study

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BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY 2004年第7期111卷 661-668页

作者： Krapels, IPC van Rooij, IALM Wevers, RA Zielhuis, GA Spauwen, PHM Brussel, W Steegers-Theunissen, RPM Univ Nijmegen Ctr Med Dept Epidemiol & Biostat NL-6500 HB Nijmegen Netherlands Univ Nijmegen Ctr Med Dept Oral Biol NL-6500 HB Nijmegen Netherlands Univ Nijmegen Ctr Med Lab Neurol & Paediat NL-6500 HB Nijmegen Netherlands Univ Nijmegen Ctr Med Dept Plast & Reconstruct Surg NL-6500 HB Nijmegen Netherlands Rijnstate Hosp Dept Paediat Arnhem Netherlands Erasmus Univ Ctr Med Dept Obstet & Gynaecol NL-3000 DR Rotterdam Netherlands

Objective To investigate myo-inositol, glucose and zinc status in mothers and their infants on cleft lip with or without cleft palate risk (CLP). Design Case-control study. Setting University Medical Centre Nijmegen, the Netherlands. Population Eighty-four mothers and their CLP child and 102 mothers and their healthy child. Methods Venous blood samples were obtained to determine serum myo-inositol and glucose and red blood cell zinc concentrations in mothers and children. Geometric means were calculated and compared between the groups. The blood parameters were dichotomised with cutoff points based on control values, P90 for glucose concentrations. Main outcome measures Geometric means (P5-P95) and odds ratios (95% confidence intervals). Results The CLP children (P = 0.003) and their mothers (P = 0.02) had significantly lower red blood cell zinc concentrations than controls. A low maternal serum myo-inositol concentration (< 13.5 mumol/L) and a low red blood cell zinc concentration (<189 mumol/L) increased CLP risk [odds ratio 3.0 (95% Cl 1.2-7.4) and 2.0 (95% Cl 0.8-4.8), respectively]. Children with low myo-inositol (<21.5 mumol/L) or low red blood cell zinc concentrations (<118 mumol/L) were more likely to have CLP [odds ratio 3.4 (95% Cl 1.3-8.6) and 3.3 (95% Cl 1.3-8.0), respectively]. Glucose was not a risk factor for CLP in mothers and children. Maternal and child myo-inositol as well as zinc concentrations were slightly, albeit significantly correlated, r(Pearson) = 0.33 (P = 0.0006) and r(Pearson) = 0.23 (P = 0.01), respectively. Conclusion This study demonstrates for the first time that zinc and myo-inositol are important in the aetiology of CLP.

关键词： Zinc Inositol Child Glucose Cephalic index 锌肌醇儿童葡萄糖 Cleft Palate Inositol controlled study contract laboratory program Risk Factors Odds Ratio Blood Glucose Child COTL1 gene Cleft Lip zinc Glucose Mother CALML3 gene

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FOXE1 association with both isolated cleft lip with or without cleft palate, and isolated cleft palate

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HUMAN MOLECULAR GENETICS 2009年第24期18卷 4879-4896页

作者： Moreno, Lina M. Mansilla, Maria Adela Bullard, Steve A. Cooper, Margaret E. Busch, Tamara D. Machida, Junichiro Johnson, Marla K. Brauer, David Krahn, Katherine Daack-Hirsch, Sandy L'Heureux, Jamie Valencia-Ramirez, Consuelo Rivera, Dora Maria Lopez, Ana Moreno, Manuel A. Hing, Anne Lammer, Edward J. Jones, Marilyn Christensen, Kaare Lie, Rolv T. Jugessur, Astanand Wilcox, Allen J. Chines, Peter Pugh, Elizabeth Doheny, Kim Arcos-Burgos, Mauricio Marazita, Mary L. Murray, Jeffrey C. Lidral, Andrew C. Univ Iowa Coll Dent Dept Orthodont Iowa City IA 52242 USA Univ Iowa Coll Dent Dows Inst Dent Res Iowa City IA 52242 USA Univ Iowa Dept Pediat Roy C Carver Coll Med Iowa City IA 52242 USA Univ Pittsburgh Sch Dent Med Dept Oral Biol Ctr Craniofacial & Dent Genet Pittsburgh PA 15260 USA Univ Antioquia Coll Dent Medellin Colombia Lab Genet Forense & Huellas Digitales DNA Medellin Colombia Univ Washington Dept Pediat Seattle WA 98195 USA Childrens Hosp & Reg Med Ctr Craniofacial Ctr Seattle WA 98195 USA Univ Alabama Birmingham Dept Genet Birmingham AL 35294 USA Univ Alabama Birmingham Dept Pediat Birmingham AL 35294 USA Childrens Hosp Oakland Res Inst Oakland CA 94609 USA Univ So Denmark Dept Epidemiol DK-5230 Odense Denmark Univ Bergen Dept Publ Hlth & Primary Hlth Care Sect Epidemiol & Med Stat Bergen Norway Royal Childrens Hosp Murdoch Childrens Res Inst Melbourne Vic 3052 Australia NIEHS Epidemiol Branch Durham NC 27709 USA NHGRI Div Intramural Res Genome Technol Branch NIH Bethesda MD 20892 USA Johns Hopkins Univ Sch Med Inst Med Genet CIDR Baltimore MD 21224 USA Univ Miami Leonard M Miller Sch Med Dept Psychiat & Behav Sci Miami FL 33136 USA Univ Pittsburgh Sch Med Grad Sch Publ Hlth Dept Human Genet Pittsburgh PA 15260 USA Univ Pittsburgh Sch Med Clin & Translat Sci Inst Pittsburgh PA 15260 USA

Nonsyndromic orofacial clefts are a common complex birth defect caused by genetic and environmental factors and/or their interactions. A previous genome-wide linkage scan discovered a novel locus for cleft lip with or without cleft palate (CL/P) at 9q22-q33. To identify the etiologic gene, we undertook an iterative and complementary fine mapping strategy using family-based CL/P samples from Colombia, USA and the Philippines. Candidate genes within 9q22-q33 were sequenced, revealing 32 new variants. Concurrently, 397 SNPs spanning the 9q22-q33 2-LOD-unit interval were tested for association. Significant SNP and haplotype association signals (P = 1.45E - 08) narrowed the interval to a 200 kb region containing: FOXE1, C9ORF156 and HEMGN. Association results were replicated in CL/P families of European descent and when all populations were combined the two most associated SNPs, rs3758249 (P = 5.01E - 13) and rs4460498 (P = 6.51E - 12), were located inside a 70 kb high linkage disequilibrium block containing FOXE1. Association signals for Caucasians and Asians clustered 5' and 3' of FOXE1, respectively. Isolated cleft palate (CP) was also associated, indicating that FOXE1 plays a role in two phenotypes thought to be genetically distinct. Foxe1 expression was found in the epithelium undergoing fusion between the medial nasal and maxillary processes. Mutation screens of FOXE1 identified two family-specific missense mutations at highly conserved amino acids. These data indicate that FOXE1 is a major gene for CL/P and provides new insights for improved counseling and genetic interaction studies.

关键词： birth defect CALML3 gene Cleft Lip COTL1 gene Cleft Palate FOXE1 gene CSRP3 gene contract laboratory program

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DLX4 is associated with orofacial clefting and abnormal jaw development

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HUMAN MOLECULAR GENETICS 2015年第15期24卷 4340-4352页

作者： Wu, Di Mandal, Shyamali Choi, Alex Anderson, August Prochazkova, Michaela Perry, Hazel Gil-Da-Silva-Lopes, Vera L. Lao, Richard Wan, Eunice Tang, Paul Ling-Fung Kwok, Pui-yan Klein, Ophir Zhuan, Bian Slavotinek, Anne M. Univ Calif San Francisco Dept Pediat San Francisco CA 94143 USA Univ Calif San Francisco Dept Orofacial Sci Div Craniofacial Anomalies San Francisco CA 94143 USA Univ Calif San Francisco Inst Human Genet San Francisco CA 94143 USA Univ Calif San Francisco Program Craniofacial Biol San Francisco CA 94114 USA ASCR Vvi Inst Mol Genet Lab Transgen Models Dis Prague Czech Republic Univ Estadual Campinas Dept Med Genet Sao Paulo Brazil Univ Calif San Francisco Cardiovasc Res Inst San Francisco CA 94143 USA Wuhan Univ Sch & Hosp Stomatol Key Lab Oral Biomed Minist Educ Wuhan Peoples R China

Cleft lip and/or palate (CL/P) are common structural birth defects in humans. We used exome sequencing to study a patient with bilateral CL/P and identified a single nucleotide deletion in the patient and her similarly affected son-c. 546_546delG, predicting ***183Argfs*57 in the Distal-less 4 (DLX4) gene. The sequence variant was absent from databases, predicted to be deleterious and was verified by Sanger sequencing. In mammals, there are three Dlx homeobox clusters with closely located gene pairs (Dlx1/Dlx2, Dlx3/Dlx4, Dlx5/Dlx6). In situ hybridization showed that Dlx4 was expressed in the mesenchyme of the murine palatal shelves at E12.5, prior to palate closure. Wild-type human DLX4, but not mutant DLX4_c.546delG, could activate two murine Dlx conserved regulatory elements, implying that the mutation caused haploinsufficiency. We showed that reduced DLX4 expression after short interfering RNA treatment in a human cell line resulted in significant up-regulation of DLX3, DLX5 and DLX6, with reduced expression of DLX2 and significant up-regulation of BMP4, although the increased BMP4 expression was demonstrated only in HeLa cells. We used antisense morpholino oligonucleotides to target the orthologous Danio rerio gene, dlx4b, and found reduced cranial size and abnormal cartilaginous elements. We sequenced DLX4 in 155 patients with non-syndromic CL/P and CP, but observed no sequence variants. From the published literature, Dlx1/Dlx2 double homozygous null mice and Dlx5 homozygous null mice both have clefts of the secondary palate. This first finding of a DLX4 mutation in a family with CL/P establishes DLX4 as a potential cause of human clefts.

关键词： DLX2 gene birth defect human cell lines CALML3 gene Bone Morphogenetic Protein 4 COTL1 gene DLX4 gene CSRP3 gene Morpholinos contract laboratory program

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How useful are clinical, biochemical, and cross-sectional imaging features in predicting potentially malignant or malignant cystic lesions of the pancreas? Results from a single institution experience with 220 surgically treated patients

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JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS 2008年第1期206卷 17-27页

作者： Goh, Brian K. P. Tan, Yu-Meng Thng, Choon-Hua Cheow, Peng-Chung Chung, Yaw-Fui Alexander Chow, Pierce K. H. Wong, Wai-Keong Ooi, London L. P. J. Natl Canc Ctr Dept Surg Oncol Singapore 169610 Singapore Singapore Gen Hosp Dept Surg Singapore 0316 Singapore Natl Canc Ctr Dept Diagnost Imaging Singapore Singapore

BACKGROUND: This study aims to determine the use of preoperative clinical, biochemical, and cross-sectional imaging features for predicting malignancy in cystic lesions of the pancreas (CLP). STUDY DESIGN: Two hundred twenty patients who underwent operations for CLP or suspected CLP were reviewed. Patients were divided into two groups, patients undergoing operations for pseudocysts and patients undergoing operations for suspected cystic neoplasms. The predictive effect of various preoperative factors on the malignant potential of CLP was evaluated. RESULTS: Forty-four patients with a preoperative diagnosis of pseudocysts underwent operations for complications of pseudocyst. Forty-two were confirmed pathologically to have pseudocysts, but two were found, unexpectedly, to harbor malignant lesions. One hundred scventy-six patients underwent operations for suspected pancreatic cystic neoplasms. There were 70 benign, 51 potentially malignant, and 55 malignant CLP. On multivariate analysis, three factors, ie, elevated serum carcinoembryonic antigen (CEA) or carbohydrate antigen 19-9;cyst size > 3 cm;and presence of one or more of three morphologic features, such as solid component;peripheral calcification;and main duct dilation on cross-sectional imaging were independent predictors of malignancy. Presence of two or three of these factors had a positive predictive value of 88% in predicting a premalignant or malignant CLP. CONCLUSIONS: Most pancreatic pseudocysts can be accurately diagnosed preoperatively. In patients with suspected pancreatic cystic neoplasms, elevated serum CEA or carbohydrate antigen 19-9, cyst size > 3 cm, and presence of suspicious morphologic features on imaging are predictors of potentially malignant or malignant CLP. Patients with a high likelihood of a potentially malignant or malignant lesion based on these three factors should undergo operation without additional investigations.

关键词： Adolescent Adult Aged 80 and over CA-19-9 Antigen Carcinoembryonic Antigen 成年人老年人 80以上 CA-19-9抗原癌胚抗原儿童诊断鉴别 Cystic Lesion COTL1 gene CA-19-9 Antigen Surgery pseudocyst CALML3 gene image feature Adolescent dilation of duct Carcinoembryonic Antigen contract laboratory program cysts Pancreas Patients

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Endothelin receptor antagonist attenuates oxidative stress in a neonatal sepsis piglet model

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PEDIATRIC RESEARCH 2012年第6期72卷 600-605页

作者： Goto, Tatenobu Hussein, Mohamed Hamed Kato, Shin Daoud, Ghada Abdel-Hamid Kato, Takenori Sugiura, Takahiro Kakita, Hiroki Nobata, Masanori Kamei, Michi Mizuno, Haruo Imai, Masaki Ito, Tetsuya Kato, Ineko Suzuki, Satoshi Okada, Noriko Togari, Hajime Okada, Hidechika Nagoya City Univ Grad Sch Med Sci Dept Pediat & Neonatol Nagoya Aichi Japan EgyBlood Dept Med Res Giza Egypt EgyBlood Dept Obstet & Gynecol Giza Egypt Nagoya City Univ Grad Sch Med Sci Dept Immunol Nagoya Aichi Japan Saitama Med Univ Saitama Med Ctr Dept Neonatol Ctr Maternal Fetal & Neonatal Med Saitama Japan Fukushimura Hosp Choju Med Inst Dept Immunol Toyohashi Aichi Japan

BACKGROUND: Oxidative stress (oxidant antioxidant imbalance) plays an important role in the pathophysiology of neonatal sepsis. This study evaluated whether an antisense peptide endothelin receptor antagonist, ETR-P1/fl, could attenuate oxidative stress in a neonatal sepsis model. METHODS: A total of 18 3-d-old piglets were anesthetized and mechanically ventilated. Six piglets received cecal ligation and perforation (CLP group) for induction of sepsis. Six piglets also received continuous infusion (0.05 mg/kg/h) of ETR-Pl/fl 30 min after CLP (ETR-Pl/fl group). Six piglets received a sham operation. Serum total hydroperoxide (TH), biological antioxidant potentials (BAPs), oxidative stress index (OSI, calculated as TH/BAP), interleukin (IL)-6, serum glutamic oxaloacetic transaminase (GOT), and creatinine were measured before CLP and at 1, 3, and 6h after CLP. RESULTS: CLP evoked a state of shock resulting in elevated TH, OSI, and IL-6 levels. ETR-P1/fl administration after CLP resulted in lower serum TH at 1 and 3 h after CLP, OSI at 1 and 3 h after CLP, IL-6 at 1 and 3 h after CLP, and GOT at 3 and 6 h after CLP as compared with the CLP group. CONCLUSION: ETR-P1/fl treatment significantly attenuated the elevation of serum oxidative stress markers (TH and OSI), IL-6, and GOT in a progressive neonatal sepsis CLP model.

关键词： Glutamic Oxaloacetic Transaminase piglets CALML3 gene COTL1 gene Neonatal Sepsis open systems interconnection Oxidative Stress Thorium Endothelin Receptor Antagonists contract laboratory program

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