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.     

Postoperative survival for patients with thymoma complicating myasthenia gravis—preliminary retrospective results of the ChART database

Background

It is so far not clear that how myasthenia gravis (MG) affected the prognosis of thymoma patients. The aim of this assay is to compare the postoperative survival between patients with thymoma only and those with both thymoma and MG.

Methods

The Chinese Alliance for Research in Thymomas (ChART) registry recruited patients with thymoma from 18 centers over the country on an intention to treat basis from 1992 to 2012. Two groups were formed according to whether the patient complicated MG. Demographic and clinical data were reviewed, patients were followed and their survival status were analyzed.

Results

There were 1,850 patients included in this study, including 421 with and 1,429 without MG. Complete thymectomy were done in 91.2% patients in MG group and 71.0% in non-MG group (P<0.05). There were more percentage of patients with the histology of thymoma AB, B1, or B2 (P<0.05) in MG group, and more percentage of patients with MG were in Masaoka stage I and II. The 5- and 10-year overall survival (OS) rates were both higher in MG group (93% vs. 88%; 83% vs. 81%, P=0.034) respectively. The survival rate was significantly higher in patients with MG when the Masaoka staging was 3/4 (P=0.003). Among patients with advanced stage thymoma (stage 3, 4a, 4b), the constituent ratios of 3, 4a, 4b were similar between MG and non-MG group. Histologically, however, there were significantly more proportion of AB/B1/B2/B3 in the MG group while there were more C in the non-MG group (P=0.000). Univariate analyses for all patients showed that MG, WHO classification, Masaoka stage, surgical approach, chemotherapy and radiotherapy and resectability were significant factors, and multivariate analysis showed WHO classification, Masaoka stage, and resectability were strong independent prognostic indicators.

Conclusions

Although MG is not an independent prognostic factor, the survival of patients with thymoma was superior when MG was present, especially in late Masaoka stage patients. Possible reasons included early diagnosis of the tumor, better histologic types, an overall higher R0 resection and less recurrence.     

改良扩张方法对兔静脉移植物内皮细胞保护作用研究

目的:观察不同扩张方法对兔静脉移植物内皮细胞保护作用。方法:健康纯种新西兰兔72只,按扩张液(空白对照、罂粟碱和罂粟碱+维拉帕米)随机分为A组、B组、C组,每组24只。每组又分为4个亚组,用相同扩张液分别以30mmHg、40mmHg、50mmHg和100mmHg扩张2min,再保存30min。实验终了取静脉,测量扩张后单位面积血管内皮细胞死亡数目,测定内皮细胞功能。结果:相同扩张压力下,扩张后各组均有内皮细胞死亡,但C组明显低于A组和B组(P<0.01);各组内皮细胞功能均有降低,C组明显高于A组、B组(P<0.01)。A组和B组扩张压力在50mmHg时,内皮细胞损伤最轻;而C组以40mmHg最佳(P<0.01)。结论:新的扩张方法可减轻兔静脉移植物内皮细胞损伤。     

Dual Antiplatelet Therapy Duration Determines Outcome After 2- But Not 1-Stent Strategy in Left Main Bifurcation Percutaneous Coronary Intervention

Objectives

The aim of this study was to investigate clinical outcomes after left main coronary artery (LM) bifurcation percutaneous coronary intervention (PCI) and the impact of the duration of dual antiplatelet therapy (DAPT) according to treatment strategy.

Influence of graft size matching on outcomes of infantile living donor liver transplantation

We aimed to assess the impact of size mismatching between grafts and recipients on outcomes of infants or small children after LDLT. Between October 2006 and December 2014, 129 LDLT recipients weighing no more than 8 kg were retrospectively analyzed. The entire cohort was categorized into three groups by GRWR: GRWR<3.0% (group A, n = 38), 3.0%≤GRWR<4.0% (group B, n = 61), and GRWR≥4.0% (group C, n = 30). Baseline characteristics were similar among groups A, B, and C. Compared with groups A and B, post‐transplant alanine aminotransferase and aspartate aminotransferase within seven days were significantly higher in group C; however, differences between total bilirubin and albumin after transplantation were not prominent. Moreover, incidences of surgical complications, perioperative deaths, infections, and acute rejections were all comparable among the three groups. Five‐yr patient survival rates for groups A, B, and C were 89.5%, 88.9%, and 81.6%, respectively (p = 0.872), and the graft survival rates were 89.5%, 86.6%, and 81.6%, respectively (p = 0.846). In conclusion, GRWR between 1.9% and 5.8% would not cause noticeable adverse events for infantile LDLT recipients ≤8 kg. However, there is still a role for considering reduction in the graft mass as an applicable strategy in selected cases.     

Fraxiparin, a low-molecular-weight heparin, stimulates megakaryocytopoiesis in vitro and in vivo in mice

Summary. The effect of a low-molecular-weight heparin, faxiparin (Nadroparinŕ;), on murine megakaryocytopoiesis in vitro and in vivo was studied in comparison with unfractionated heparin. The addition of fraxiparin at 1–20 IU/ml into plasma clot cultures but not serum-free agar culture significantly enhanced MK colony growth. Furthermore, fraxiparin was found to potentiate the stimulating activity of aplastic anaemia serum (AAS) but not stem cell factor (SCF), interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin (Epo), on MK colony growth in vitro , and to neutralize the inhibitory effect of platelet factor 4 (PF4) in vitro and in vivo . Fraxiparin also acted synergistically with heparin confactor II and antithrombin III to promote megakaryocyte colony formation. Intraperitoneal administration of fraxiparin twice daily for 4d at 0.1–25IU/injection increased in mice the level of blood platelet counts and the number of single MKs and CFU-MK in bone marrow. These data demonstrate that fraxiparin is able to positively regulate megakaryocytopoiesis.     

Effect of adrenocorticotropin administration on the biosynthesis of corticosteroid-binding globulin in fetal sheep

Parturition in sheep is initiated by the fetus through activation of the fetal hypothalamic-pituitary-adrenal axis and is associated with increased concentrations of ACTH, cortisol, and corticosteroid-binding globulin (CBG) in the fetal circulation during the final 10-15 days of pregnancy. Premature parturition and a precocious elevation in fetal plasma CBG are produced by intrafetal ACTH administration, but the possible sources of CBG in the ovine fetus are not known. To determine these sites, CBG mRNA was measured in tissues from fetal sheep in late pregnancy and after intrafetal ACTH treatment, using a sheep CBG cDNA. Fetal ACTH treatment caused a significant increase in the fetal plasma corticosteroid-binding capacity (CBC), although there was no significant difference in CBC between umbilical arterial and umbilical venous plasma. After ACTH treatment, CBC was elevated in fetal liver and kidney. Cortisol binding in these tissues had characteristics similar to those of cortisol binding in fetal sheep plasma. By Northern blot analysis a single mRNA (1.7 kilobases) for CBG was detected in fetal liver, kidney, lung, and adrenal, but not in placenta. The abundance of CBG mRNA in the fetal liver was greater than that in other tissues, but was unchanged by ACTH treatment. The level of CBG mRNA in the fetal kidney, but not in other tissues, increased 3-fold after ACTH. We conclude that the elevation in plasma CBC after intrafetal ACTH, and presumably also at term pregnancy, does not reflect production of CBC by the placenta or transfer from the mother. Rather, it results from production primarily in the fetal liver and kidney, although only in the latter tissue is CBG mRNA accumulation increased by intrafetal ACTH treatment.     

The C9 methyl group of retinal interacts with glycine-121 in rhodopsin

The visual pigment rhodopsin is a prototypical G protein-coupled receptor. These receptors have seven transmembrane helices and are activated by specific receptor–ligand interactions. Rhodopsin is unusual in that its retinal prosthetic group serves as an antagonist in the dark in the 11-cis conformation but is rapidly converted to an agonist on photochemical cis to trans isomerization. Receptor–ligand interactions in rhodopsin were studied in the light and dark by regenerating site-directed opsin mutants with synthetic retinal analogues. A progressive decrease in light-dependent transducin activity was observed when a mutant opsin with a replacement of Gly¹²¹ was regenerated with 11-cis-retinal analogues bearing progressively larger R groups (methyl, ethyl, propyl) at the C9 position of the polyene chain. A progressive decrease in light activity was also observed as a function of increasing size of the residue at position 121 for both the 11-cis-9-ethyl- and the 11-cis-9-propylretinal pigments. In contrast, a striking increase of receptor activity in the dark—i.e., without chromophore isomerization—was observed when the molecular volume at either position 121 of opsin or C9 of retinal was increased. The ability of bulky replacements at either position to hinder ligand incorporation and to activate rhodopsin in the dark suggests a direct interaction between these two sites. A molecular model of the retinal-binding site of rhodopsin is proposed that illustrates the specific interaction between Gly¹²¹ and the C9 methyl group of 11-cis-retinal. Steric interactions in this region of rhodopsin are consistent with the proposal that movement of transmembrane helices 3 and 6 is concomitant with receptor activation.