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Phenotypic Heterogeneity (phenotypic + heterogeneity)
Selected AbstractsEvaluation of the genetic basis of phenotypic heterogeneity in north Indian patients with Thalassemia majorEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 6 2010Nidhi Sharma Abstract Objectives: To assess the molecular basis of phenotypic heterogeneity in north Indian patients with thalassemia major (TM). Methods: To determine the clinical severity, 130 patients of TM were studied for the age of first presentation and frequency of blood transfusion. The type of beta mutations, Xmn,1G, polymorphism and G6PD Mediterranean mutation was characterized. Analysis of the phenotypic presentation and the genotype was performed. Results: Majority (83.8%) presented before 1 year of age (mean 8.8 months). The caste distribution showed 41.6% were Aroras and 32.3% were migrants from Pakistan. IVS1-5(G,C) was commonest (32.7%) and the common five Indian mutations comprised of 88.4% of alleles. The mean age of presentation with IVS1-5(G,C), Fr 8/9, (+G) 619-bp del and IVS1-1(G,T) homozygosity was 4.3, 6, 3.4 and 9.1 months respectively. Xmn,1G, status showed ,/, in 66.9%, +/, in 26.1% and +/+ in 6.9% patients. Xmn,1G,,/, presented before 1 year of age. The mean age of presentation with +/+ was 18.3 months. Six hemizygous boys and one heterozygous girl with G6PD Mediterranean were found (prevalence 5.3%). Eight patients could be reclassified as thalassemia intermedia on follow up. Conclusions: This study showed that majority of TM in north India present before 1 year of age and homozygous 619-bp deletion presents the earliest. The presence of Xmn-1G, polymorphism delays the presentation, is associated with the IVS 1-1 (G,T) and shows variable improvement with hydroxyurea therapy. Based on the results of genotyping, reevaluation of patients can improve the outcome in a few patients. [source] Genomic and phenotypic heterogeneity of Acidithiobacillus spp. strains isolated from diverse habitats in ChinaFEMS MICROBIOLOGY ECOLOGY, Issue 2 2008Yong-Qing Ni Abstract The genetic variability among 32 Chinese Acidithiobacillus spp. environmental isolates and four reference strains representing three recognized species of the genus Acidithiobacillus was characterized by using a combination of molecular methods, namely restriction fragment length polymorphisms of PCR-amplified 16S rRNA genes and 16S,23S rRNA gene intergenic spacers, repetitive element PCR, arbitrarily primed PCR and 16S rRNA gene sequence analyses. 16S rRNA gene sequences revealed that all Acidithiobacillus spp. strains could be assigned to seven groups, three of which encompassed the Acidithiobacillus ferrooxidans strains from various parts of the world. A comparative analysis of the phylogenetic Group 1 and 2 was undertaken. Restriction fragment length polymorphism results allowed us to separate the 35 Acidithiobacillus strains into 15 different genotypes. An integrated phenotypic and genotypic analysis indicated that the distribution of A. ferrooxidans strains among the physiological groups were in agreement with their distribution among the genomic groups, and that no clear correlation was found between the genetic polymorphism of the Acidithiobacillus spp. strains and either the geographic location or type of habitats from which the strains were isolated. In addition, five unidentified sulfur-oxidizing isolates may represent one or two novel species of the genus Acidithiobacillus. The results showed that the Chinese Acidithiobacillus spp. isolates exhibited a high degree of genomic and phenotypic heterogeneity. [source] G-substrate gene promoter SNP (,1323T>C) modifies plasma total cholesterol and triglyceride phenotype in familial hypercholesterolemia: Intra-familial association study in an eight-generation hyperlipidemic kindredGERIATRICS & GERONTOLOGY INTERNATIONAL, Issue 2 2004Yukiko Nobe Background: Plasma lipid and lipoprotein generally reflect the complex influences of multiple genetic loci, for instance, even familial hypercholesterolemia (FH), a representative example of monogenic hyperlipidemia, often presents with phenotypic heterogeneity. Methods: In the course of investigating familial coronary artery disease in Utah, we studied 160 members of an eight-generation extended family of FH, to examine possible genetic modification of lipoprotein phenotype by ,modifier locus'. G-substrate (GSBS) is an endogenous substrate for cGMP-dependent protein kinase. We carried out an intrafamilial correlation analysis of modifier effect of ,1323T>C substitution in the GSBS gene among 85 LDLR-mutation carriers and 75 non-carriers. Results: In the LDLR - mutation carriers, the plasma cholesterol levels were highest among ,1323C homozygotes (mean ± SD = 454 ± 101 mg/dL), lowest among ,1323T homozygotes (mean ± SD, 307 ± 72 mg/dL) and intermediate among ,1323T/C heterozygotes (mean ± SD, 314 ± 62 mg/dL; P = 0.015). Similarly, in the LDLR-mutation carriers, the plasma triglyceride levels were highest among ,1323C homozygotes (mean ± SD, 371 ± 381 mg/dL), lowest among ,323T homozygotes (mean ± SD, 171 ± 94 mg/dL), and intermediate among ,1323T/C heterozygotes (mean ± SD, 218 ± 130 mg/dL; P = 0.003). No such gene-interactive effect was observed among non-carriers of the LDLR-mutation. Conclusion: These results indicate a significant modification of the phenotype of FH with defective LDLR allele, by GSBS-1323C allele in the kindred studied. [source] Molecular diagnosis of inherited disorders: lessons from hemoglobinopathies,HUMAN MUTATION, Issue 5 2005George P. Patrinos Abstract Hemoglobinopathies constitute a major health problem worldwide, with a high carrier frequency, particularly in certain regions where malaria has been endemic. These disorders are characterized by a vast clinical and hematological phenotypic heterogeneity. Over 1,200 different genetic alterations that affect the DNA sequence of the human ,-like (HBZ, HBA2, HBA1, and HBQ1) and ,-like (HBE1, HBG2, HBG1, HBD, and HBB) globin genes are mainly responsible for the observed clinical heterogeneity. These mutations, together with detailed information about the resulting phenotype, are documented in the globin locus-specific HbVar database. Family studies and comprehensive hematological analyses provide useful insights for accurately diagnosing thalassemia at the DNA level. For this purpose, numerous techniques can provide accurate, rapid, and cost-effective identification of the underlying genetic defect in affected individuals. The aim of this article is to review the diverse methodological and technical platforms available for the molecular diagnosis of inherited disorders, using thalassemia and hemoglobinopathies as a model. This article also attempts to shed light on issues closely related to thalassemia diagnostics, such as prenatal and preimplantation genetic diagnoses and genetic counseling, for better-quality disease management. Hum Mutat 26(5), 399,412, 2005. © 2005 Wiley-Liss, Inc. [source] The IBD international genetics consortium provides further evidence for linkage to IBD4 and shows gene-environment interactionINFLAMMATORY BOWEL DISEASES, Issue 1 2005Marie Pierik MD Abstract Background and Aims: The inflammatory bowel diseases (IBDs) Crohn's disease (CD) and ulcerative colitis are complex disorders with an important genetic determinant. One gene associated with CD has been identified: NOD2/CARD15. Two independent genome-wide scans found significant evidence (logarithm of odds [LOD] 3.6) and suggestive evidence (LOD 2.8) for linkage on locus 14q11-12, also known as the IBD4 locus. To further characterize this locus, we assessed gene-environment interaction (IBD4 × smoking) and phenotypic heterogeneity in a large cohort of IBD-affected sibling pairs as part of an ongoing international collaborative effort. Patients and Methods: A total of 733 IBD families, comprising 892 affected sibling pairs, were genotyped for microsatellites D14S261, D14S283, D14S972, and D14S275, spanning the IBD4 locus. Information on gender, ethnicity, age at onset, smoking at diagnosis, extraintestinal manifestations, and disease location was available. Results: A significant distortion in the mean allele sharing (MAS) between affected siblings was observed for CD patients only at each of the four markers (54.6%, 52.8%, 50.4%, and 53.3%, respectively). Maximum linkage for CD was observed at marker D14S261 (multipoint nonparametric linkage score 2.36; P , 0.01; MAS 54.6%). MAS was higher in CD families in which all siblings or at least one sibling smoked compared with nonsmoking CD families (MAS, 58.90%, 57.50%, and 52.80%, respectively). Conclusions: The IBD International Genetics Consortium replicated the IBD4 locus on chromosome 14q for CD and also showed evidence for a gene-environment interaction at this locus. Further studies are needed to explore the mechanism by which smoking influences IBD4. [source] Detection of bone marrow-disseminated breast cancer cells using an RT-PCR assay of MUC5B mRNAINTERNATIONAL JOURNAL OF CANCER, Issue 4 2003Nora Berois Abstract The evaluation of disseminated epithelial tumor cells in breast cancer patients has generated considerable interest due to its potential association with disease recurrence. Our work was performed to analyze the usefulness of 5 mucin genes expression (MUC2, MUC3, MUC5B, MUC6 and MUC7), using RT-PCR assays, to detect disseminated cancer cells in patients with operable breast cancer. The highest frequencies of positive RT-PCR tests in breast tumor extracts were observed for MUC5B (7/15) and MUC7 (5/12). The best specificity, negative results on all peripheral blood mononuclear (PBMN) cell samples from healthy donors, were shown for MUC2, MUC5B and MUC6 RT-PCR assays. Thus, we selected MUC5B as a target gene for further evaluation. Using a nested RT-PCR, MUC5B mRNA transcripts were detected in 16/31 primary breast tumors (but not in 36 samples of normal PBMN cells) and in the human MCF-7 breast cancer cell line but not in BT20, MDA, T47D and ZR-75 breast cancer cell lines, indicating that MUC5B mRNA is expressed in a population of breast cancer cells. Using this method, 9/46 patients (19.5%) who underwent curative surgery showed positive MUC5B mRNA in bone marrow aspirates obtained prior to surgery, including 5/24 patients (20.8%) with stage I or II breast cancer, without histopathologic lymph node involvement. These results indicate that MUC5B mRNA could be a specific marker applicable to the molecular diagnosis of breast cancer cell dissemination. A comparative evaluation between MUC5B mRNA, cytokeratin 19 (CK19) mRNA and carcinoembryonic antigen (CEA) mRNA in all bone marrow aspirates suggests a putative complementation for molecular detection of disseminated carcinoma cells. Considering that breast cancer is characterized by a great phenotypic heterogeneity, the use of multimarker approach could contribute to tumor cell detection in bone marrow and blood. © 2002 Wiley-Liss, Inc. [source] Acute myeloid leukaemia with giant granules: association with t(10; 11)(p13; q14) and disseminated intravascular coagulationINTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY, Issue 5 2000S.K. Ma Summary A 16-year-old Chinese girl presented with AML-M5a. A bone marrow examination showed that the myeloblasts which were overwhelming the marrow contained giant granules (pseudo-Chediak,Higashi anomaly). Her karyotype showed a rare translocation t(10; 11)(p13; q14). Molecular delineation of the translocation breakpoints was not possible. Nonetheless, this case further demonstrates the morphological and phenotypic heterogeneity of acute leukaemia with this translocation. In this girl it was associated with disseminated intravascular coagulation. [source] Genotypic and phenotypic heterogeneity among lactococci isolated from traditional Pecorino Sardo cheeseJOURNAL OF APPLIED MICROBIOLOGY, Issue 2 2000L. Mannu Twenty-nine Lactococcus lactis isolates from one traditional 24 h-old Pecorino Sardo cheese were characterized phenotypically, technologically and genotypically in order to assess the biodiversity within this wild microbial population. Two DNA-based techniques, plasmid profiling and PFGE, were used for the genetic typing of the isolates. All 29 isolates were characterized at strain level and eight different genotypes were recognized. In addition, by combining the results from plasmid profile analysis and PFGE, it was possible to identify closely related isolates probably belonging to the same clonal lineage. The dominant biotype was identified in the 24 h-old cheese, as were the strains believed to act as starters for the curd. Atypical lactococci, able to grow in 6·5% NaCl, were isolated. The results suggest that wild bacterial populations should be preserved in order to protect the traditional raw milk cheeses, and to select new starter strains for the dairy industry. [source] Variable phenotype of Alzheimer's disease with spastic paraparesisJOURNAL OF NEUROCHEMISTRY, Issue 3 2008Helena Karlstrom Abstract Pedigrees with familial Alzheimer's disease (AD) show considerable phenotypic variability. Spastic paraparesis (SP), or progressive spasticity of the lower limbs is frequently hereditary and exists either as uncomplicated (paraparesis alone) or complicated (paraparesis and other neurological features) disease subtypes. In some AD families, with presenilin-1 (PSEN1) mutations, affected individuals also have SP. These PSEN1 AD pedigrees frequently have a distinctive and variant neuropathology, namely large, non-cored plaques without neuritic dystrophy called cotton wool plaques (CWP). The PSEN1 AD mutations giving rise to CWP produce unusually high levels of the amyloid , peptide (A,) ending at position 42 or 43, and the main component of CWP is amino-terminally truncated forms of amyloid , peptide starting after the alternative ,-secretase cleavage site at position 11. This suggests a molecular basis for the formation of CWP and an association with both SP and AD. The SP phenotype in some PSEN1 AD pedigrees also appears to be associated with a delayed onset of dementia compared with affected individuals who present with dementia only, suggesting the existence of a protective factor in some individuals with SP. Variations in neuropathology and neurological symptoms in PSEN1 AD raise the prospect that modifier genes may underlie this phenotypic heterogeneity. [source] Investigating the etiology of multiple tooth agenesis in three sisters with severe oligodontiaORTHODONTICS & CRANIOFACIAL RESEARCH, Issue 1 2008S Swinnen Structured Abstract Authors,,, Swinnen S, Bailleul-Forestier I, Arte S, Nieminen P, Devriendt K, Carels C Objectives,,, To describe the dentofacial phenotypes of three sisters with severe non-syndromic oligodontia, to report on the mutation analysis in three genes, previously shown to cause various phenotypes of non-syndromic oligodontia and in two other suspected genes. Based on the phenotypes in the pedigree of this family, the different possible patterns of transmission are discussed. Methods,,, Anamnestic data and a panoramic radiograph were taken to study the phenotype of the three sisters and their first-degree relatives. Blood samples were also taken to obtain their karyotypes and DNA samples. Mutational screening was performed for the MSX1, PAX9, AXIN2, DLX1 and DLX2 genes. Results,,, The probands' pedigree showed evidence for a recessive or multifactorial inheritance pattern. Normal chromosomal karyotypes were found and , despite the severe oligodontia present in all three sisters , no mutation appeared to be present in the five genes studied so far in these patients. Conclusions,,, In the three sisters reported, their common oligodontia phenotype is not caused by mutations in the coding regions of MSX1, PAX9, AXIN2, DLX1 or DLX2 genes, but genetic factors most probably play a role as all three sisters were affected. Environmental and epigenetic factors as well as genes regulating odontogenesis need further in vivo and in vitro investigation to explain the phenotypic heterogeneity and to increase our understanding of the odontogenic processes. [source] Genetic variants in the noncoding region of RPS19 gene in Diamond-Blackfan anemia: Potential implications for phenotypic heterogeneity,AMERICAN JOURNAL OF HEMATOLOGY, Issue 2 2010Aurore Crétien Mutations in the RPS19 gene have been identified in 25% of individuals affected by Diamond-Blackfan anemia (DBA), a congenital erythroblastopenia characterized by an aregenerative anemia and a variety of malformations. More than 60 mutations in the five coding exons of RPS19 have been described to date. We previously reported a mutation (c.-1 + 26G>T) and an insertion at ,631 upstream of ATG (c.-147_-146insGCCA) in the noncoding region. Because DBA phenotype is extremely heterogeneous from silent to severe and because haploinsufficiency seems to play a role in this process, it is likely that genetic variations in the noncoding regions affecting translation of RPS19 can modulate the phenotypic expression of DBA. However, to date, very few studies have addressed this question comprehensively. In this study, we performed detailed sequence analysis of the RPS19 gene in 239 patients with DBA and 110 of their relatives. We found that 6.2% of the patients with DBA carried allelic variations upstream of ATG: 3.3% with c.-1 + 26G>T; 2.5% with c.-147_-146insGCCA; and 0.4% with c.-174G>A. Interestingly, the c.-147_-146insGCCA, which has been found in a black American and French Caribbean control population, was not found in 500 Caucasian control chromosomes we studied. However, it was found in association with the same haplotype distribution of four intronic polymorphisms in our patients with DBA. Although a polymorphism, the frequency of this variant in the patients with DBA and its association with the same haplotype raises the possibility that this polymorphism and the other genetic variations in the noncoding region could play a role in DBA pathogenesis. Am. J. Hematol., 2010. © 2009 Wiley-Liss, Inc. [source] Heterogeneous Disease Modeling for Hardy-Weinberg Disequilibrium in Case-Control Studies: Application to Renal Stones and Calcium-Sensing Receptor PolymorphismsANNALS OF HUMAN GENETICS, Issue 2 2009D. C. Hamilton Summary Renal stone formation due to hypercalciuria is a relatively common disorder with clear evidence for genetic predisposition, but cryptic phenotypic heterogeneity has hampered identification of candidate genes. The R990G single-nucleotide polymorphism (SNP) of the calcium sensing receptor (CASR) gene has been associated with hypercalciuria in stone formers and shows the appropriate functional phenotype in cell culture. In our preliminary association analysis of a case-control cohort, however, we observed significant Hardy-Weinberg disequilibrium (HWD) for the cases (n= 223), but not controls (n= 676) at the R990G locus, pointing us toward the general disease model incorporating HWD. Because there is an adjacent CASR SNP, A986S, which is in negative linkage disequilibrium with R990G, we extended the general disease model to enable testing of a two-site hypothesis. In our data set, there is no lack of fit (P= .345) for the single-locus model for the R990G genotype, and likelihood ratio testing favors a recessive effect with an eight-fold increase in risk (P < .001) for GG homozygotes, relative to wild-type, based on a population prevalence of 2%. Addition of the A986S genotype provides no additional information either by itself or when included in our two-site model. [source] A novel assay based on fluorescence microscopy and image processing for determining phenotypic distributions of rod-shaped bacteriaBIOTECHNOLOGY & BIOENGINEERING, Issue 2 2009Konstantinos Spetsieris Abstract Cell population balance (CPB) models can account for the phenotypic heterogeneity that characterizes isogenic cell populations. To utilize the predictive power of these models, however, we must determine the single-cell reaction and division rates as well as the partition probability density function of the cell population. These functions can be obtained through the Collins,Richmond inverse CPB modeling methodology, if we know the phenotypic distributions of (a) the overall cell population, (b) the dividing cell subpopulation, and (c) the newborn cell subpopulation. This study presents the development of a novel assay that combines fluorescence microscopy and image processing to determine these distributions. The method is generally applicable to rod-shaped cells dividing through the formation of a characteristic constriction. Morphological criteria were developed for the automatic identification of dividing cells and validated through direct comparison with manually obtained measurements. The newborn cell subpopulation was obtained from the corresponding dividing cell subpopulation by collecting information from the two compartments separated by the constriction. The method was applied to E. coli cells carrying the genetic toggle network with a green fluorescent marker. Our measurements for the overall cell population were in excellent agreement with the distributions obtained via flow cytometry. The new assay constitutes a powerful tool that can be used in conjunction with inverse CPB modeling to rigorously quantify single-cell behavior from data collected from highly heterogeneous cell populations. Biotechnol. Bioeng. 2009;102: 598,615. © 2008 Wiley Periodicals, Inc. [source] Personality: is it a viable endophenotype for genetic studies of bipolar affective disorder?BIPOLAR DISORDERS, Issue 4 2006Jonathan B Savitz Progress in identifying the genetic basis of bipolar affective disorder has been disappointing, most probably because of the genetic and phenotypic heterogeneity of the condition. These setbacks have led to the adoption of alternative strategies such as the use of endophenotypes or intermediate traits to identify those individuals at genetic risk for developing the disorder. Gottesman and Gould [Am J Psychiatry (2003), 160:636], in a review of the endophenotypic concept, have suggested five criteria that should be characteristic of a trait in order for it to qualify as an endophenotype. These five criteria are used in order to assess the viability of using personality traits as endophenotypes for genetic analyses of bipolar disorder. A review of the literature suggests that certain personality traits or temperaments are associated with the illness in a state independent manner, that personality is at least partly heritable, and that various temperaments aggregate in the non-affected relatives of bipolar probands. Nevertheless, it is unclear whether specific personality traits co-segregate with affectively ill individuals. We conclude that personality profiling of probands and their relatives may facilitate molecular genetic work, but given the fact that personality is itself a complex trait, its use as an endophenotype has certain limitations. [source] Age at onset in bipolar affective disorders: a reviewBIPOLAR DISORDERS, Issue 2 2005Marion Leboyer Bipolar affective disorder (BPAD) is a multifactorial disorder with various clinical presentations. Etiologic heterogeneity may partly underlie the phenotypic heterogeneity. Efforts to dissect BPAD have been based on the course of the disorders (BP I versus BP II or rapid cycling), cormorbidity pattern (panic attacks, suicide attempts, addiction or hyperactivity), differences between the sexes, and clinical pattern (cycloid and puerperal psychosis). The present article provides a comprehensive review of the existing data, showing that age at onset (AAO) identifies homogeneous sub-groups of patients with BPAD. Recent work has demonstrated the existence of three , early, intermediate and late , onset bipolar sub-groups based on AAO, following Kendell's criteria for validity (The American Journal of Psychiatry 2003; 160: 999). We will also show how these distinctions may be of use in the search for genetic vulnerability factors and other pathogenic influences. Following Kendell's criteria, we show that AAO of bipolar disorders has been tested with most of the available strategies for establishing the validity of clinical syndromes. We also present data from genetic epidemiologic studies in bipolar disorder, showing that AAO sub-groups may reduce the underlying genetic heterogeneity. No accurate AAO thresholds to define valid sub-groups have been identified precisely. Until recently, studies defined early- and late-onset as corresponding to early or mid-adulthood, not taking into account juvenile-onset bipolar disorder. A recently proposed theoretical model with three AAO sub-groups (onset age 17, 27 and 46) is discussed. [source] Creutzfeldt,Jakob disease with PRNP G114V mutation in a Chinese familyACTA NEUROLOGICA SCANDINAVICA, Issue 6 2010Z. Liu Liu Z, Jia L, Piao Y, Lu D, Wang F, Lv H, Lu Y, Jia J. Creutzfeldt,Jakob disease with PRNP G114V mutation in a Chinese family. Acta Neurol Scand: 2010: 121: 377,383. © 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Background,,, Recent evidence has shown clinical phenotypic heterogeneity of inherited prion diseases, even between patients harbouring the same mutation in the PRNP gene. Objective and methods,,, We collected clinical data from a Chinese family with autosomal dominant dementia and screened the PRNP gene on 28 living members. A stereotactic biopsy of the right frontal lobe of the proband was performed. Results,,, The family comprised four affected individuals within two successive generations. The age of onset was in 30 or 40 s, and the duration was about 2,3 years. Clinical features of the affected members included neuropsychiatric disturbances, progressive dementia and extrapyramidal symptoms. Immunostaining for prion protein showed fine granular deposits of PrPsc in the neuropil. The PRNP gene analysis demonstrated a heterozygous G114V mutation in 15 family members. The proband was diagnosed as familial Creutzfeldt,Jakob disease (fCJD). Conclusion,,, This study strengthens the linkage of the G114V mutation to CJD. It supports the worldwide distribution of fCJD despite differences in genetic background. [source] Pseudodominant Friedreich's ataxia with phenotypic heterogeneityACTA NEUROLOGICA SCANDINAVICA, Issue 5 2007M. Panas Objective,,, A family with a clinically heterogeneous progressive ataxia in two generations is presented. Methods ,, Having eliminated mutations within the known dominant spinocerebellar ataxia genes, the family was investigated for expansion at the Friedreich's gene. Results,,, The affected members (father, son and daughter) were homozygous for the mutation at the Friedreich's gene, while the unaffected (the mother and her sister) were heterozygous. Conclusion,,, This pseudodominant form of Friedreich's ataxia should be considered in families with an apparently autosomal dominant progressive ataxia in conjunction with sensory neuropathy and pyramidal signs. [source] Differential mitogenic responses of human macrovascular and microvascular endothelial cells to cytokines underline their phenotypic heterogeneityCELL PROLIFERATION, Issue 3 2001I. Lang A variety of growth factors promote the complex multistep process of angiogenesis. The mitogenic activity of vascular endothelial growth factors (VEGFs) and placental growth factors (PlGFs), known as cytokines acting predominantly on endothelial cells, was tested on human umbilical vein endothelial cells (HUVEC) and microvascular endothelial cells (MIEC) and compared with the potency of the universally acting basic fibroblast growth factor (FGF-2). The cells were seeded at different cell numbers and incubated with various doses of growth factors for a period of 24,72 h in culture medium ± serum. Proliferation was determined by measuring the optical density after staining the cells with the tetrazolium salt WST-1. VEGF121 and VEGF165 increased the number of HUVEC and MIEC at low and high seeding densities various doses and incubation times. The efficiency of FGF-2 was less pronounced at high seeding densities of the cells under serum-free conditions. PlGF-1 and PlGF-2 stimulated mitogenesis on HUVEC only at low cell numbers and after a short incubation time by 125 ± 3% and 102 ± 5% (P < 0.001), respectively. Longer incubation times with the lower seeding density in the absence of FCS did not induce a significant stimulatory effect of the PlGFs. MIEC responded stronger to all growth factors. In particular under serum free conditions, PlGF-1 and PlGF-2 effectively stimulated cell proliferation by 247 ± 54% (P < 0.01) and 288 ± 40% (P < 0.05) at low cell numbers, and by 81 ± 13% (P < 0.05) and 49 ± 13% (P < 0.01), respectively, at high cell numbers. The addition of fetal calf serum caused a reduced proliferative response of all growth factors on both cell types related to the controls. In conclusion, MIEC and HUVEC differ in their proliferative response to VEGFs, PlGFs and FGF-2. [source] 2464: Phenotype/genotype evolution in corneal dystrophiesACTA OPHTHALMOLOGICA, Issue 2010F CHIAMBARETTA Purpose The corneal dystrophies are a group of genetically determined diseases usually characterized by loss of corneal transparency, which may be caused by a progressive accumulation of abnormal material within the cornea. The genetic characterization of corneal dystrophies revealed both genetic heterogeneity, that is, different genes (KRT3 and KRT12) causing a single dystrophy phenotype (Meesmann dystrophy), and phenotypic heterogeneity with a single gene (TGFBI) causing different allelic dystrophy phenotypes (RBCD, TBCD, granular type 1, granular type 2, and lattice type 1). But less is known about the evolution of the phenotype during life. Methods We were interesting in following the corneal phénotype progressive evolution during childhood. During several years we analyzed corneal phénotype of families of Lattice type 1 and granular type 1, using Scheimpflug camera. Results We were able to follow the accumulation of abnormal material, his corneal localisation and evolution during years. Conclusion The phenotype of both Lattice type 1 and granular type 1 is totally different in childhood, with subepithelial localization. [source] Early therapeutic intervention in females with Fabry disease?ACTA PAEDIATRICA, Issue 2008Derralynn A Hughes Abstract Anderson,Fabry disease is an X-linked lysosomal storage disorder resulting from deficiency of ,-galactosidase A. The subsequent accumulation of globotriaosylceramide (Gb3) in cells and tissues of the body has multisystemic effects and significantly impacts upon quality of life and survival of individuals with this condition. In general, Anderson,Fabry disease is more severe in male patients; however, despite X-linkage, females may develop severe signs and symptoms of the disease, although there is considerable phenotypic heterogeneity, which correlates most closely with age. Histological analyses of biopsies have shown evidence of Gb3 storage in the kidney and heart in female patients. Gb3 levels are also elevated in the urine of females, although plasma Gb3 levels are not reliably elevated. The efficacy of enzyme replacement therapy (ERT) with recombinant human ,-galactosidase A has been demonstrated in females in a clinical trial and in observational studies, including those using data from outcome surveys. Benefits include a reduction in left ventricular mass, stabilization of renal function and improvements in pain and quality of life. Conclusion: If early intervention with ERT in females is to be advocated, it is necessary to demonstrate not only that females with Anderson,Fabry disease have clinical and biochemical features of ,-galactosidase A deficiency and respond to ERT, but also that early intervention prevents the onset of the later manifestations of the disorder. Any strategy for early therapy should also balance future advantages against any impact on quality of life. [source] Clinical and Molecular diagnosis of the skeletal dysplasias associated with mutations in the gene encoding Fibroblast Growth Factor Receptor 3 (FGFR3) in PortugalCLINICAL GENETICS, Issue 2 2009MR Almeida Mutations in the gene that encodes Fibroblast Growth Factor Receptor 3 (FGFR3) are associated with Achondroplasia (MIM 100800), Hypochondroplasia (MIM 146000), Muenke Syndrome (MIM 602849), Thanatophoric Dysplasia (MIM 187600, MIM 187601) and Lacrimo-Auriculo-Dento-Digital Syndrome (MIM 149730). Here we report a clinical and molecular study in a large cohort of 125 Portuguese patients with these skeletal disorders. The identification of the P250R mutation allowed the confirmation of the Muenke Syndrome in 9 out of the 52 cases referred. Two known mutations were found in the Thanatophoric Dysplasia referred cases. No mutations were identified in the LADD syndrome patient. In Achondroplasia and Hypochondroplasia, genetic heterogeneity was present amongst the 70 clinically diagnosed patients with 5 different mutations identified. As in other studies, complex phenotypic heterogeneity amongst patients carrying the same gene defect was observed. In several cases, the new amino acids encoded, as a consequence of mutations, were related to the severity of patients' phenotype. The presence of 10 misdiagnosed cases emphasizes the importance of performing mutation analysis of the hotspot regions responsible for both dysplasias (Ach and Hch). For patients with an unquestionable clinical diagnosis, lacking the most common mutations, a complete screening of FGFR3 is necessary. [source] | |||||||||||||