Further delineation of the KBG syndrome caused by ANKRD11 aberrations

Loss-of-function variants in ANKRD11 were identified as the cause of KBG syndrome, an autosomal dominant syndrome with specific dental, neurobehavioural, craniofacial and skeletal anomalies. We present the largest cohort of KBG syndrome cases confirmed by ANKRD11 variants reported so far, consisting of 20 patients from 13 families. Sixteen patients were molecularly diagnosed by Sanger sequencing of ANKRD11, one familial case and three sporadic patients were diagnosed through whole-exome sequencing and one patient was identified through genomewide array analysis. All patients were evaluated by a clinical geneticist. Detailed orofacial phenotyping, including orthodontic evaluation, intra-oral photographs and orthopantomograms, was performed in 10 patients and revealed besides the hallmark feature of macrodontia of central upper incisors, several additional dental anomalies as oligodontia, talon cusps and macrodontia of other teeth. Three-dimensional (3D) stereophotogrammetry was performed in 14 patients and 3D analysis of patients compared with controls showed consistent facial dysmorphisms comprising a bulbous nasal tip, upturned nose with a broad base and a round or triangular face. Many patients exhibited neurobehavioural problems, such as autism spectrum disorder or hyperactivity. One-third of patients presented with (conductive) hearing loss. Congenital heart defects, velopharyngeal insufficiency and hip anomalies were less frequent. On the basis of our observations, we recommend cardiac assessment in children and regular hearing tests in all individuals with a molecular diagnosis of KBG syndrome. As ANKRD11 is a relatively common gene in which sequence variants have been identified in individuals with neurodevelopmental disorders, it seems an important contributor to the aetiology of both sporadic and familial cases.     

Activated protein C decreases plasminogen activator-inhibitor activity in endothelial cell-conditioned medium

Confluent cultures of endothelial cells from human umbilical cord were used to study the effect of activated human protein C (APC) on the production of plasminogen activators, plasminogen activator-inhibitor, and factor VIII-related antigen. Addition of APC to the cells in a serum-free medium did not affect the production of tissue-type plasminogen activator (t-PA) or factor VIII-related antigen; under all measured conditions, no urokinase activity was found. However, less plasminogen activator-inhibitor activity accumulated in the conditioned medium in the presence of APC. This decrease was dose dependent and could be prevented by specific anti-protein C antibodies. No decrease was observed with the zymogen protein C or with diisopropylfluorophosphate-inactivated APC. APC also decreased the t-PA inhibitor activity in endothelial cell-conditioned medium in the absence of cells, which suggests that the effect of APC is at least partly due to a direct effect of APC on the plasminogen activator- inhibitor. High concentrations of thrombin-but not of factor Xa or IXa-- had a similar effect on the t-PA inhibitor activity. The effect of APC on the plasminogen activator-inhibitor provides a new mechanism by which APC may enhance fibrinolysis. The data suggest that activation of the coagulation system may lead to a secondary increase of the fibrinolytic activity by changing the balance between plasminogen activator(s) and its (their) fast-acting inhibitor.     

TEL gene is involved in myelodysplastic syndromes with either the typical t(5;12)(q33;p13) translocation or its variant t(10;12)(q24;p13)

A t(5;12)(q33;p13) translocation is a recurrent chromosome abnormality in a subgroup of myeloid malignancies with features of both myeloproliferative disorders and myelodysplastic syndromes (MDSs). The molecular consequence of a t(5;12) is a fusion between the platelet- derived growth factor receptor-B gene on chromosome 5 and a novel ETS- like gene, TEL, on chromosome 12. We report on three patients with a t(5;12)(q33;p13) diagnosed as chronic myelomonocytic leukemia, and one case of a t(10;12)(q24;p13) in a progressive MDS, with eosinophilia and monocytosis. Involvement of the TEL gene in these chromosome translocations was investigated by fluorescence in situ hybridization (FISH) with cosmid probes containing selectively the 5' end or 3' end of TEL. Hybridization of these cosmids to the der(5)/der(10) or a der(12), respectively, demonstrated a rearrangement of TEL in both translocations, showing that the t(10;12) is a variant translocation of the t(5;12). Cloning of the fusion cDNA of one case of t(5;12) showed that the breakpoint occurred at the RNA level at exactly the same position as reported by Golub et al (Cell 77:307, 1994). In addition, the TEL gene on chromosome 12 could be localized between two probes previously mapped to 12p13, namely PRB1 and D12S178, leading to a better definition of the position of TEL in this chromosome region. Moreover, in the case involving chromosome 10, the breakpoint occurred between cKTN206 and cKTN312/LYT-10 at 10q24. Clinicohematological data in these studies as well as the restriction mapping of chromosomal breakpoints strongly suggest that (1) common features in MDSs involving the TEL gene are monocytosis and eosinophilia, (2) chromosomes other than no. 5 may be involved and at least a t(10;12)(q24;p13) variant chromosome translocation does exist in these MDSs, and (3) both standard and variant 12p/TEL translocations may be identified by FISH with appropriate probes.     

Breastfeeding attenuates the effect of low birthweight on abdominal adiposity in adolescents: the HELENA study

The aim of this study was to examine whether breastfeeding may reduce the programming effect of birthweight on abdominal adiposity. Abdominal (in three regions: R1, R2 and R3) adiposity was measured by dual energy x‐ray absorptiometry in 314 adolescents. Breastfeeding duration, birthweight, duration of gestation and maternal educational level were obtained from questionnaire. Physical activity was objectively measured. We detected significant interactions between breastfeeding and birthweight on abdominal adiposity (Ps = 0.02–0.07). We observed that birthweight was associated with abdominal adiposity in the group who had never been breastfed (β = ?0.19 to ?0.23; Ps < 0.05), while no association was found in adolescents who had breastfeeding for ≥3 months (β = ?0.03 to ?0.07). The results were independent of duration of gestation, age, sex, maternal educational level and physical activity. Breastfeeding may reduce the adverse influence conferred by low birthweight on abdominal adiposity in adolescents.     

A power series beta Weibull regression model for predicting breast carcinoma

The postmastectomy survival rates are often based on previous outcomes of large numbers of women who had a disease, but they do not accurately predict what will happen in any particular patient's case. Pathologic explanatory variables such as disease multifocality, tumor size, tumor grade, lymphovascular invasion, and enhanced lymph node staining are prognostically significant to predict these survival rates. We propose a new cure rate survival regression model for predicting breast carcinoma survival in women who underwent mastectomy. We assume that the unknown number of competing causes that can influence the survival time is given by a power series distribution and that the time of the tumor cells left active after the mastectomy for metastasizing follows the beta Weibull distribution. The new compounding regression model includes as special cases several well‐known cure rate models discussed in the literature. The model parameters are estimated by maximum likelihood. Further, for different parameter settings, sample sizes, and censoring percentages, some simulations are performed. We derive the appropriate matrices for assessing local influences on the parameter estimates under different perturbation schemes and present some ways to assess local influences. The potentiality of the new regression model to predict accurately breast carcinoma mortality is illustrated by means of real data. Copyright © 2015 John Wiley & Sons, Ltd.     

Association of Resistance Exercise With the Incidence of Hypercholesterolemia in Men

Objective

To examine the associations of resistance exercise, independent of and combined with aerobic exercise, with the risk of development of hypercholesterolemia in men.