PRRT2-related phenotypes in patients with a 16p11.2 deletion

We studied the presence of benign infantile epilepsy (BIE), paroxysmal kinesigenic dyskinesia (PKD), and PKD with infantile convulsions (PKD/IC) in patients with a 16p11.2 deletion including PRRT2 or with a PRRT2 loss-of-function sequence variant. Index patients were recruited from seven Dutch university hospitals. The presence of BIE, PKD and PKD/IC was retrospectively evaluated using questionnaires and medical records. We included 33 patients with a 16p11.2 deletion: three (9%) had BIE, none had PKD or PKD/IC. Twelve patients had a PRRT2 sequence variant: BIE was present in four (p?=?0.069), PKD in six (p?<?0.001) and PKD/IC in two (p?=?0.067). Most patients with a deletion had undergone genetic testing because of developmental problems (87%), whereas all patients with a sequence variant were tested because of a movement disorder (55%) or epilepsy (45%). BIE, PKD and PKD/IC clearly showed incomplete penetrance in patients with 16p11.2 deletions, but were found in all and 95% of patients with a PRRT2 sequence variant in our study and a large literature cohort, respectively. Deletions and sequence variants have the same underlying loss-of-function disease mechanism. Thus, differences in ascertainment have led to overestimating the frequency of BIE, PKD and PKD/IC in patients with a PRRT2 sequence variant. This has important implications for counseling if genome-wide sequencing shows such variants in patients not presenting the PRRT2-related phenotypes.     

Exchange transfusion the hard way: massive hemolysis following transplantation of bone marrow with minor ABO incompatibility

BACKGROUND: Bone marrow transplantation using donors with minor ABO incompatibility may result in the rapid production of donor-derived red cell isohemagglutinins, causing hemolysis of recipient red cells. CASE REPORT: The transplant of sibling-donor marrow with minor ABO incompatibility (group O donor marrow to group A recipient), using FK- 506 as an immunosuppressant to prevent graft-versus-host disease, is reported. Following early myeloid engraftment, the recipient developed hemolysis of her entire A red cell population between Day 8 and Day 11. This brisk hemolytic anemia was due to rapid donor lymphoid engraftment that resulted in the explosive production of donor-derived anti-A. CONCLUSION: Patients undergoing the transplantation of marrow from donors with minor ABO incompatibility in which the donor cells can produce isohemagglutinins against the recipient's red cells must be kept under vigilant observation for the possible development of severe hemolysis, particularly in the setting of profound T-cell suppression without B-cell suppression.     

THE DURATION OF ACTION OF INHALED FORMOTEROL DRY POWDER

SUMMARY The duration of action of formoterol inhaled as a dry powder formulation is compared with placebo and a reference treatment of salbutamol dry powder in patients with bronchial asthma. This single-centre, double-blind, cross-over study recruited 23 outpatients with clinically stable asthma. These patients were treated with 12μg formoterol, 400μg salbutamol or placebo in a randomly allocated sequence, with at least 2 days between treatments. Forced expiratory volume in 1s of expiration (FEV₁) was measured at specified time points from 15 min to 15 hours post-treatment. Formoterol produced significantly higher values of FEV₁ at the primary endpoint of 12 hours compared with placebo and salbutamol. No differences between FEV₁ values were seen for the active treatments of formoterol and salbutamol for the first 5 hours post-inhalation. Formoterol was significantly superior to placebo at all time points, whereas salbutamol was significantly superior to placebo for the first 5 hours.This study demonstrates that formoterol, when given as a dry powder inhalation, has a significantly longer duration of acute bronchodilator action than 400μg salbutamol inhaled as a dry powder. The duration of action of formoterol of at least 12 hours seen in this study is at least as long as that reported following administration from a metered dose inhaler (MDI) at the same dose level. The study also demonstrates that 12μg formoterol dry powder is well tolerated by patients.     

人视网膜色素上皮细胞增殖与川芎嗪的影响

目的:观察糖基化终产物(advanced glycation end products,AGEs)对人视网膜色素上皮细胞增殖的影响,以及川芎嗪对AGEs诱导的人视网膜色素上皮细胞增殖的拮抗作用。方法:实验于2003-09/2004-07在中南大学湘雅二医院中心实验室完成。①实验分组:原代培养人视网膜色素上皮细胞,第3￣8代用于实验,设空白对照组,DMEM培养基中不加入任何药物;AGEs对照物组,培养液中含100mg/L的AGEs对照物;AGEs组,培养液中含10,50,100,200,400mg/L的AGEs,分别干预视网膜色素上皮细胞24h及48h。②实验操作:川芎嗪干预实验:也设空白对照组;AGEs对照物组;AGEs组,培养液中含100mg/L的AGEs;AGEs 川芎嗪组,培养液中加入10,20,40,80,160,320,640mg/L川芎嗪30min后加入100mg/L的AGEs,分别干预视网膜色素上皮细胞24h。③实验评估:MTT微量酶比色法检测视网膜色素上皮细胞增殖情况。结果:①视网膜色素上皮细胞增殖情况:不同浓度AGEs组细胞增殖率均高于对照物组(P<0.01),100mg/LAGEs组增殖率(24,48h分别为39.45%,31.97%)高于其他组(P<0.01),48h与24h结果一致。②川芎嗪的抑制效应:与AGEs组比较,10,20,40,80,160mg/L川芎嗪对AGEs诱导的视网膜色素上皮细胞增殖无抑制作用(P>0.05),320及640mg/L川芎嗪有抑制作用,其抑制率为8.96%,15.08%(P<0.01)。结论:①AGEs可诱导人视网膜色素上皮细胞增殖。②低浓度川芎嗪对AGEs诱导的人视网膜色素上皮细胞增殖无抑制作用,高浓度川芎嗪具有抑制作用。     

Molecular basis of intrahepatic cholestasis

Intrahepatic cholestasis, or impairment of bile flow, is an important manifestation of inherited and acquired liver disease. In recent years, human genetic and molecular studies have identified several genes, the disruption of which results in cholestasis. ATP8B1 (FIC1), ABCB11 (BSEP), and ABCB4 (MDR3) are disrupted in forms of progressive familial intrahepatic cholestasis (PFIC) and related disorders. Mutations in BAAT, TJP2 (ZO‐2), and EPHX1 have been identified in patients with hypercholanemia. A CLDN1 mutation was recently reported in patients with ichthyosis, leukocyte vacuoles, alopecia and sclerosing cholangitis (ILVASC), and North American Indian childhood cirrhosis (NAIC) is associated with a missense mutation in CIRH1A. Alagille syndrome patients carry mutations in JAG1, and mutations in VPS33B have been identified in patients with arthrogryposis, renal dysfunction and cholestasis syndrome (ARC). Identification of these genes, and characterization of the proteins they encode, is enhancing our understanding of the biology of the enterohepatic circulation in health and disease.     

Social responsiveness scale-aided analysis of the clinical impact of copy number variations in autism

Recent array-based studies have detected a wealth of copy number variations (CNVs) in patients with autism spectrum disorders (ASD). Since CNVs also occur in healthy individuals, their contributions to the patient's phenotype remain largely unclear. In a cohort of children with symptoms of ASD, diagnosis of the index patient using ADOS-G and ADI-R was performed, and the Social Responsiveness Scale (SRS) was administered to the index patients, both parents, and all available siblings. CNVs were identified using SNP arrays and confirmed by FISH or array CGH. To evaluate the clinical significance of CNVs, we analyzed three families with multiple affected children (multiplex) and six families with a single affected child (simplex) in which at least one child carried a CNV with a brain-transcribed gene. CNVs containing genes that participate in pathways previously implicated in ASD, such as the phosphoinositol signaling pathway (PIK3CA, GIRDIN), contactin-based networks of cell communication (CNTN6), and microcephalin (MCPH1) were found not to co-segregate with ASD phenotypes. In one family, a loss of CNTN5 co-segregated with disease. This indicates that most CNVs may by themselves not be sufficient to cause ASD, but still may contribute to the phenotype by additive or epistatic interactions with inherited (transmitted) mutations or non-genetic factors. Our study extends the scope of genome-wide CNV profiling beyond de novo CNVs in sporadic patients and may aid in uncovering missing heritability in genome-wide screening studies of complex psychiatric disorders.