ABSTRACT
We have analyzed several cases of Beckwith-Wiedemann syndrome (BWS) with Wilms' tumor in a familial setting, which give insight into the complex controls of imprinting and gene expression in the chromosome 11p15 region. We describe a 2.2-kbp microdeletion in the H19/insulin-like growth factor 2 (IGF2)-imprinting center eliminating three target sites of the chromatin insulator protein CTCF that we believe here is necessary, but not sufficient, to cause BWS and Wilms' tumor. Maternal inheritance of the deletion is associated with IGF2 loss of imprinting and up-regulation of IGF2 mRNA. However, in at least one affected family member a second genetic lesion (a duplication of maternal 11p15) was identified and accompanied by a further increase in IGF2 mRNA levels 35-fold higher than control values. Our results suggest that the combined effects of the H19/IGF2-imprinting center microdeletion and 11p15 chromosome duplication were necessary for manifestation of BWS.
Subject(s)
Beckwith-Wiedemann Syndrome/genetics , Chromosomes, Human, Pair 11 , DNA-Binding Proteins/genetics , Genomic Imprinting , Repressor Proteins/genetics , Sequence Deletion , Wilms Tumor/genetics , Base Sequence , CCCTC-Binding Factor , DNA Methylation , Female , Humans , Insulin-Like Growth Factor II/genetics , Insulin-Like Growth Factor II/metabolism , Male , PedigreeABSTRACT
OBJECTIVE: The different speech sounds are formed by the primary voice signal and by the shape of the articulation tract. With this mechanism, specific overtones, the formants, are generated for each vowel. The objective of this study was to investigate the fundamental frequency (F0) of the voice signal and the first three formants (F1-F3) as a parameter of the articulation in prelingually deafened children at different timepoints after cochlear implantation (CI) compared with children with normal speech development. METHODS: Using the Kay CSL 4300B, the fundamental frequency and the formants F1-F3 of the Swiss-German vowel /a/ were investigated at different timepoints after CI in 20 prelingually deafened children aged 3.8-10.2 years by means of spectrographic and linear predictive coding (LPC) analysis. RESULTS: Children who had been operated before their fourth birthday showed no significant deviation in their fundamental frequency from age- and sex-matched peers, whereas a significant difference was documented in children who were older at the time of implantation. The first formant was very stable in every child and showed only discrete deviations from the normal range. The second and third formants, however, developed a broader scatter, but there was no systematic deviation of these formants to higher or lower values. The F1:F2 ratio was normal in children who were implanted at the age of up to 4 years and more centralized in children who were older at the time of implantation, as is known from the hearing impaired. CONCLUSIONS: Our results indicate that prelingually deaf children who receive a cochlear implant before their fourth birthday attain a better acoustic control over their speech, normalizing their fundamental frequencies and improving their articulatory skills.
Subject(s)
Articulation Disorders/diagnosis , Cochlear Implants , Deafness/surgery , Voice Quality , Child , Child, Preschool , Female , Humans , Male , Phonetics , Postoperative Care , Severity of Illness Index , Speech Intelligibility , Speech Production MeasurementABSTRACT
The purpose of the present study was to test the hypothesis that early detection of regional wall motion abnormalities (WMA) by 2D echocardiography (ECHO) accurately predicts further cardiac events in patients presenting with acute chest pain. A prospective analysis was performed in subjects admitted with the first presentation of acute chest pain and a non-diagnostic ECG for acute ST-elevation myocardial infarction. Patients with known coronary artery disease were excluded. All subjects were contacted by phone for a 30days follow-up regarding cardiac events defined as PCI/CABG, AMI, and death. In 132 consecutive patients (89 male, 43 female) complete data sets consisting of case history (H; abnormal: typical angina), ECG (abnormal: ST-depression, T-inversion, atypical ST-elevation, LBBB), serum markers (TnI; abnormal: elevation of troponin I=0.5 ng/ml), ECHO (abnormal: WMA) and follow-up were available. In 45 patients, 60 cardiac events occurred (three deaths, 24 AMI, 33 PCI/CABG). Positive (PPV; %) and negative predictive values (NPV; %) of ECHO were superior to all other diagnostic tests (P<0.05 each) for adverse cardiac events, evolving AMI or death, and superior to history and ECG for later need of revascularisation (PCI/ACVB). Multivariate analysis revealed that WMA in ECHO predict cardiac events independently of age, gender, and the common combination of investigations (H/ECG/TnI). A significant independent impact of ECHO was also determined for the prediction of AMI/death or PCI/CABG. The study shows that early 2D echocardiography provides superior prognostic information concerning the risk of subsequent complications in patients with acute chest pain and a non-diagnostic ECG for ST-elevation-AMI.
Subject(s)
Chest Pain/diagnosis , Echocardiography , Electrocardiography , Myocardial Infarction/diagnosis , Acute Disease , Adult , Age Factors , Aged , Biomarkers/blood , Chest Pain/blood , Chest Pain/surgery , Cholesterol, LDL/blood , Creatine Kinase/blood , Disease Progression , Female , Follow-Up Studies , Germany , Humans , Male , Middle Aged , Myocardial Infarction/blood , Myocardial Infarction/surgery , Myocardial Revascularization , Predictive Value of Tests , Prognosis , Sex Factors , Troponin I/blood , Ventricular Function, Left/physiologyABSTRACT
The canalicular multidrug resistance protein 2 (MRP2; gene symbol: ABCC2) mediates ATP-dependent biliary excretion of organic anions such as bilirubin diglucuronide, glutathione conjugates and sulfated and glucuronidated bile salts. In chronic cholestatic liver diseases, the biliary excretion of cholephilic organic anions is impaired. While the underlying transport defects have been studied in rat models of cholestasis, little is known about the molecular basis of impaired organic anion excretion in human cholestatic liver disease. Our aim, therefore, was to analyze expression of MRP2 in patients with primary biliary cirrhosis (PBC), a chronic cholestatic liver disease characterized by progressive destruction of small intrahepatic bile ducts. Four patients with PBC stages III (n=1) and IV (n=3) were compared with three non-cholestatic patients with alcoholic liver disease, idiopathic liver cirrhosis and cirrhosis from chronic hepatitis C. Immunohistochemistry was performed on paraffin-embedded tissue slides using a monoclonal antibody to MRP2. MRP2 was detected at the canalicular hepatocyte membrane of all patients. In two PBC patients (stages III and IV, respectively), the degree of immunostaining was comparable with controls, whereas in two other PBC patients with stage IV disease immunostaining was decreased. We conclude that MRP2 expression decreases with progressive cholestasis in PBC.
