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This is an electrocardiological study, based on electrocardiographic analysis of new cases as well as on a review of some features, hitherto unrecognized or not stressed, in subjects with these disorders, that may help throw more light on them. In six cases studied personally using intracardiac electrography - the technique of His bundle electrography - the contribution and relevance of this method will be analysed, and the results compared with the conclusions drawn from other contemporary work in this field. Thus, the clinical presentation of the cases, and of these syndromes, receives secondary attention, and more detailed analysis only when appropriate to substantiate the main burdens of the thesis. These case reports appear separately in Section c. The mechanism of production of arrhythmias is becoming much better understood, and some of the diagnostic measures that are discussed in this work provide a clearer picture of their genesis. It is not proposed to embark upon a detailed consideration of anti-arrhythmic therapy in these syndromes, but the general principles will be discussed, and special reference will also be made to some new developments in this field.

No description available.

Germline mutations in the tumor suppressor gene PTEN (phosphatase and tensin homology deleted on chromosome 10) cause Cowden and Bannayan-Riley- Ruvalcaba (BRR) syndromes, two dominantly inherited disorders characterized by mental retardation, multiple hamartomas, and variable cancer risk. Here, we modeled three sentinel mutant alleles of PTEN identified in patients with Cowden syndrome and show that the nonsense PtenΔ4-5 and missense PtenC124R and PtenG129E alleles lacking lipid phosphatase activity cause similar developmental abnormalities but distinct tumor spectrawith varying severity and age of onset. Allele-specific differences may be accounted for by loss of function for PtenΔ4-5, hypomorphic function for PtenC124R, and gain of function for Pten G129E. These data demonstrate that the variable tumor phenotypes observed in patients with Cowden and BRR syndromes can be attributed to specificmutations in PTEN that alter protein function through distinct mechanisms.

Indiana University-Purdue University Indianapolis (IUPUI) / The mongoloid face and craniofacial skeleton has been characterized by many investigators using clinical impressions and soft tissue measurements on living and autopsy material. Few studies have included data derived from cephalometric radiographs. The present study was designed to describe the mongoloid face and cranial base and to analyze the data. Twenty mongoloid children ranging in age from three years to 12 years, and their siblings were selected for study. A control group of children were selected on the basis of their essentially normal occlusion and facial skeleton. The data obtained from the cephalometric radiographs were analyzed in three ways. Each of the three groups of children, normal, mongoloid and their siblings were divided into four age groups, approximately three, five, seven and 11 years of age and means for the individual measurements were calculated. The sibling measurements were "corrected” to the age of the mongoloid child using the growth progression data from the normal children. The mean measurements of the “corrected” siblings and mongoloids were then compared using “t” tests for statistical significance. All children were then divided into three comparison pairs, normal-sibling, normal-mongoloid, and mongoloid-sibling, and the cephalometric measurements subjected to a multivariate, step-wise regression analysis. The growth of the maxillae and mandible were retarded in the Mongoloid children. The maxilla and mandible were positioned anteriorly under the cranial base.

Indiana University-Purdue University Indianapolis (IUPUI) / The relationship between gene copy number and protein expression levels has not thoroughly been examined in humans or mouse models of Down syndrome (DS) in relationship to developmental changes in the trisomic brain. Found on human chromosome 21 (Hsa21) and triplicated in DS, Dual-specificity tyrosine-phosphorylated regulated kinase 1A (DYRK1A) has been linked in DS to neurological deficits by restricting cell growth and proliferation. Little information exists regarding DYRK1A during perinatal development and how its expression may lead to cognitive deficits, and none exists that explores the gene-to-protein relationship during these critical time periods. This study aims to 1) Quantify variable DYRK1A expression across development as a function of age, sex, and brain region in trisomic Ts65Dn mice compared to euploid counterparts and 2) establish that the spatiotemporal pattern of developmental DYRK1A in the brain is not influenced solely by gene copy number, and that reduction of Dyrk1a in euploid and trisomic mice does not result in a corresponding global reduction of DYRK1A expression. DYRK1A was quantified in three areas of the postnatal brain at seven ages using the Ts65Dn mouse, the most studied model of DS, and found that trisomic expression is significantly increased on postnatal day ([P]6), declining by the third week to near euploid levels. We also uncovered a sexual dimorphic expression of DYRK1A when comparing animals of different sexes within the same genotype. Data from Dyrk1a knockdown mice indicated that reducing only Dyrk1a in euploid and in otherwise trisomic animals yields highly variable levels of DYRK1A, dependent on sex and tissue type, supporting the non-intuitive relationship between gene dosage and protein expression. These data emphasize the need to understand the age-dependent regulation of antecedent conditions that are causing changes in Dyrk1a expression in the brain.

The purpose of this study was to examine whether cut-points developed for the general population provide different estimates of physical activity (PA) levels in adults with Down syndrome (DS) compared to cut-points developed specifically in adults with DS. This study also attempted to objectively measure the PA levels of adults with DS and to determine if they meet the recommended amount of PA to obtain health benefits. Thirteen adults with DS wore an accelerometer to determine time spent in moderate, vigorous, and moderate-to-vigorous PA. Results indicated that different sets of cut-points responded differently in classifying moderate and vigorous PA levels, as well as in classifying whether participants met the recommended amount of PA for health benefits, as evidenced by the different estimates of moderate-to-vigorous PA in 10 minute bouts. Results also indicated that population specific cut-points should be used for assessment of PA levels in persons with DS.

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