Description of two new ABCB11 mutations responsible for type 2 benign recurrent intrahepatic cholestasis in a French-Canadian family

Benign recurrent intrahepatic cholestasis is a rare clinical entity that is caused by mutations in the canalicular transport genes. The present report describes two individuals from the same family whose symptoms were typical of the clinical characteristics of type 2 benign recurrent intrahepatic cholestasis. Sequencing of the ABCB11 gene revealed two previously unreported mutations that predict the absence of expression of the protein. The clinical presentation of the current cases are discussed, as are the differential diagnosis and genetic characteristics of the hereditary cholestatic disorders, overemphasizing the possibility of making a definite genetic diagnosis.     

Buspirone: pharmacological and clinical properties of the first member of a new anxiolytic drug family

Buspirone is a new anxiolytic agent with an original chemical structure. Its activity in doses of 15 to 30 mg per day has been demonstrated in patients presenting with manifestations of generalized anxiety. Its mode of action is still imperfectly known; in animals, it influences several neuromediator systems but does not act on benzodiazepine receptors. Its main pharmacokinetic features are: complete absorption when given orally, short half-life (4 to 8 h), reduced plasma clearance in patients with hepatic cirrhosis or renal impairment and no major interaction with most of the other psychotropic drugs. Controlled clinical studies have provided evidence of its anxiolytic properties; against anxiety symptoms buspirone has proved more effective than placebo and as effective as several reference benzodiazepine derivatives, with a lesser incidence of sedative effects. However, it is not effective in the treatment of benzodiazepine withdrawal. Gastrointestinal disorders and moderate headache have been reported in less than 10 p. 100 of the patients treated. Administered acutely, buspirone does not seem to alter cognitive mechanisms. Unlike benzodiazepines, it does not potentiate the effects of alcohol and does not lead to drug-dependence. Its usefulness in panic disorders, anxious-depressive states and obsessional symptoms remains to be determined.     

FLRG, member of the follistatin family, a new player in hematopoiesis

Several years ago, we cloned and characterized from a B cell leukemia a new secreted protein which, on the basis of its high degree of structural homology with follistatin, was defined as a member of the follistatin family and accordingly named follistatin-related gene (FLRG). However, follistatin and FLRG revealed non-overlapping patterns of expression in various tissues thereby indicating the existence of non-redundant functional roles for these proteins throughout the organism. As known for a long time, follistatin is a biological regulator of activin and bone morphogenetic protein (BMP) function in various cellular systems: in particular, it inhibits the effects of activin on hematopoiesis. We therefore investigated the expression and effects of FLRG during human hematopoiesis with particular focus on the effect of this soluble glycoprotein in the regulation of erythropoiesis. For this purpose, we have for the first time, compared the role of Activin A, BMP2 and BMP4 during erythropoiesis, in primary human cells. Our results indicate that, BMP2 acts on early erythroid cells while Activin A acts on a more differentiated population. We report the induction by Activin A and BMP2 of cell commitment towards erythropoiesis in the absence of EPO. This induction involves two key events: increase of EPO-R and the decrease of GATA2 expression. Our results indicate that despite their high structural homology, follistatin and FLRG do not regulate the same signaling targets, therefore highlighting distinct functions and mechanisms for these two proteins in the human hematopoietic system. We thus propose a working model for the regulation of activin or BMP-induced human erythropoiesis by follistatin/FLRG.     

Araguari virus, a new member of the family Orthomyxoviridae: serologic, ultrastructural, and molecular characterization

This paper reports the results of serologic, structural, biochemical, and genetic studies indicating that Araguari virus, a previously unassigned viral agent, is a member of the family Orthomyxoviridae and genus Thogotovirus. Araguari virus has six RNA fragments; biologically, it shares several properties with other viruses in the family Orthomyxoviridae. Nucleotide sequencing of the RNA segments 4 (glycoprotein) and 5 (nucleoprotein) of Araguari virus aligned with the orthomyxoviruses, showing the closest relationship with Thogoto virus (sequence similarity = 61.9% and 69.1%, respectively, for glycoprotein and nucleoprotein), but also sharing a more distant similarity with Dhori and Influenza C viruses, especially for the glycoprotein gene. Based on these results, we propose that Araguari virus should be assigned as a new member of the family Orthomyxoviridae and genus Thogotovirus.     

LR11, a mosaic LDL receptor family member, mediates the uptake of ApoE-rich lipoproteins in vitro

Since the molecular identification of the low density lipoprotein receptor (LDLR), an ever increasing number of related proteins have been discovered. These receptors belonging to the LDLR family are thought to play key roles in lipoprotein metabolism in a variety of tissues, including the arterial wall. We have discovered that the expression of a 250-kDa mosaic LDLR-related protein, which we termed LR11 for the presence of 11 LDLR ligand-binding repeats, is markedly induced in smooth muscle cells in the hyperplastic intima of animal models used for the study of atherosclerosis. Here, we demonstrate that the human LR11, when overexpressed in hamster cells, binds and internalizes 39-kDa receptor-associated protein (RAP), an in vitro ligand for all receptors belonging to the LDLR family. Furthermore, LR11 binds the apolipoprotein E (apoE)-rich lipoproteins, beta-very low density lipoproteins (VLDLs), with a high affinity similar to that of other members, such as the LDLR and VLDL receptor. RAP and beta-VLDL compete with each other; however, other serum lipoproteins are not able to inhibit their binding. LR11 shows specific binding of apoE-enriched HDL prepared from human cerebrospinal fluid as well as of beta-VLDL, suggesting that the apoE content of lipoproteins is most likely important for mediating the high-affinity binding to the receptor. LR11-overexpressing cells are able to internalize and degrade the bound beta-VLDL; these cells also show increased accumulation of cholesteryl esters when incubated with beta-VLDL. Incubation for 48 hours with beta-VLDL of LR11-overexpressing cells, but not of control cells, promotes the appearance of numerous intracellular lipid droplets. Taken together, LR11, a mosaic LDLR family member whose expression in smooth muscle cells is markedly induced in atheroma, has all the properties of a receptor for the endocytosis of lipoproteins, particularly for the incorporation of apoE-rich lipoproteins.     

Serum cystatin C and the incidence of type 2 diabetes mellitus

Aims/hypothesis  

To examine the association of serum cystatin C with the incidence of type 2 diabetes mellitus over a 15 year follow-up period.     

Characterization of CD33 as a new member of the sialoadhesin family of cellular interaction molecules

CD33 is a member of the Ig superfamily that is restricted to cells of the myelomonocytic lineage but whose functions and binding properties are unknown. It shares sequence similarity with sialoadhesin, CD22, and the myelin-associated glycoprotein, which constitute the Sialoadhesin family of sialic acid-dependent cell adhesion molecules. In the present study, we show that CD33 is a fourth member of this family. As a model for sialic acid-dependent binding, human erythrocytes were derivatized with N-acetylneuraminic acid (NeuAc) in different linkages. A recombinant soluble form of CD33, Fc-CD33, bound red blood cells with a specificity similar to that of sialoadhesin, preferring NeuAc alpha 2,3Gal in N- and O-glycans over NeuAc alpha 2,6Gal in N-glycans. Fc- CD33 also bound selectively to the myeloid cell lines HL-60 and U937. However, CD33 was unable to mediate cell binding after transient expression in COS cells, despite high levels of surface expression. Pretreatment of the CD33-transfected cells with sialidase rendered them capable of mediating sialic acid-dependent binding. These results show that CD33 can function as a sialic acid-dependent cell adhesion molecule and that binding can be modulated by endogenous sialoglycoconjugates when CD33 is expressed in a plasma membrane.     

Molecular nature of aldosterone synthase, a member of cytochrome P-450(11 beta) family

The molecular nature of the aldosterone synthesizing enzymes of cattle and rat is discussed. In bovine adrenal cortex, one molecular species of cytochrome P-450(11 beta) catalyzes aldosterone synthesis as well as 11 beta-hydroxylation. The intactness of the mitochondrial membrane surrounding P-450(11 beta) in the zonae fasciculata-reticularis is essential to keep the aldosterone synthesizing activity of the cytochrome in these zones latent. In rat adrenal cortex, two distinct molecules belonging to a P-450(11 beta) family exist. One is 11 beta-hydroxylase, and the other aldosterone synthase.     

建立家属参与的糖尿病患者管理教育新模式

目的探索建立家属以监管身份参与糖尿病教育管理的新模式。方法建立以医生为总管理者、患者家属为督促者、患者为自我管理者、护士为施教者的MUST糖尿病管理模式,采用改良的Deborah糖尿病自我管理评价表进行依从性判定。对2010年6至7月收治的180例2型糖尿病患者采用区组随机的方法分为干预组和对照组（各90例）进行1年的观察。干预组男47例,女43例,平均年龄（52±12）岁,病程（10±3）年。对照组男46例,女44例,平均年龄（52±12）岁,病程（114-4）年。其中干预组进入MUST管理模式,对照组采用传统的糖尿病教育模式,分析比较两组依从性的改进情况。两组均数比较用配对或独立样本t检验,计数资料用卡方检验。结果干预组患者完全从医行为观察结束时比观察开始时提高超过1倍（75．6％比34．4％,）（2：30．ol,P〈0．05）,而且从进入MUST模式的第3个月依从性改善就有明显提高（67．8％比34．4％,X^2：20．01,P〈0．05）,半年后依从性改善维持高水平,直到观察结束,但在观察后期略有下降。从第3个月开始,完全从医人数干预组与同时期对照组比较差异均有统计学意义（均P〈0．01）。对依从性五大分项的分析显示影响对照组依从性的主要因素是饮食和运动。两组观察结束后,合理的运动强度（OR：2．555,P=0．000）、胰岛素合理使用（OR=4．812,P：0．002）、低盐低脂饮食（OR=5．028,P=0．029）、合理血糖监测频率（OR=20．656,P=0．000）以及合理运动频率（OR=6．560,P=0．001）5个单项对依从性改善影响最大。结论MUST模式强调家属作为监督者的身份参与糖尿病教育的重要性,可显著提高患者的依从性。     

Identification of another member of the transforming growth factor type beta gene family.

We report here the complete amino acid sequence of another member of the type beta transforming growth factor gene family, deduced from the nucleotide sequence of three overlapping cDNA clones. The C-terminal 112 amino acids share approximately 80% sequence identity with type beta 1 and beta 2 transforming growth factors, with many of the remaining differences being conservative substitutions. By analogy to type beta 1 and type beta 2 transforming growth factors, we predict the protein to be synthesized as a 412 amino acid precursor that undergoes proteolytic cleavage to produce the mature polypeptide.     

Identification, chromosomal mapping, and partial characterization of mouse InsI6: a new member of the insulin family

A new member of the mouse insulin family, InsI6, was identified from mouse expressed sequence tags through the use of bioinformatics. A full length cDNA was sequenced and predicts a protein of 191 amino acids. The protein contains a signal peptide and has A and B peptides as well as a connecting peptide consistent with the contention that it is a member of the insulin family. Northern analysis demonstrates that the primary site of expression is the testis, but message is also found in the kidney, small bowel, heart, brain and thymus. The gene was mapped to mouse chromosome 19 by radiation hybrid mapping. The chromosomal location and primary structure of this protein suggest a functional relationship to relaxin and relaxin-related proteins.