The future of genomic profiling of neurological diseases using blood

Sequencing of the human genome and new microarray technology make it possible to assess all genes on a single chip or array. Recent studies show different patterns of gene expression related to different tissues and diseases, and these patterns of gene expression are beginning to be used for diagnosis and treatment decisions in various types of lymphoid and solid malignancies. Because of obvious problems obtaining brain tissue, progress in genomics of neurological diseases has been slow. To address this, we demonstrated that different types of acute injury in rodent brain produced different patterns of gene expression in peripheral blood. These animal studies have now been extended to human studies. Two groups have shown that there are specific genomic profiles in the blood of patients after ischemic stroke that are highly sensitive and specific for predicting stroke. Other recent studies demonstrate specific genomic profiles in the blood of patients with Down syndrome, neurofibromatosis, tuberous sclerosis, Huntington disease, multiple sclerosis, Tourette syndrome, and others. In addition, data demonstrate specific profiles of gene expression in the blood related to different drugs, toxins, and infections. Although all of these studies are still preliminary basic scientific endeavors, they suggest that this approach will have clinical applications to neurological diseases in humans.     

A proteomic study of serum from children with autism showing differential expression of apolipoproteins and complement proteins

Modern methods that use systematic, quantitative and unbiased approaches are making it possible to discover proteins altered by a disease. To identify proteins that might be differentially expressed in autism, serum proteins from blood were subjected to trypsin digestion followed by liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) on time-of-flight (TOF) instruments to identify differentially expressed peptides. Children with autism 4-6 years of age (n=69) were compared to typically developing children (n=35) with similar age and gender distributions. A total of 6348 peptide components were quantified. Of these, five peptide components corresponding to four known proteins had an effect size >0.99 with a P<0.05 and a Mascot identification score of 30 or greater for autism compared to controls. The four proteins were: Apolipoprotein (apo) B-100, Complement Factor H Related Protein (FHR1), Complement C1q and Fibronectin 1 (FN1). In addition, apo B-100 and apo A-IV were higher in children with high compared to low functioning autism. Apos are involved in the transport of lipids, cholesterol and vitamin E. The complement system is involved in the lysis and removal of infectious organisms in blood, and may be involved in cellular apoptosis in brain. Despite limitations of the study, including the low fold changes and variable detection rates for the peptide components, the data support possible differences of circulating proteins in autism, and should help stimulate the continued search for causes and treatments of autism by examining peripheral blood.     

Genotype of the cystic fibrosis population of the Hunter Region of New South Wales

Objective : To determine the genotype of patients attending the cystic fibrosis clinic at John Hunter Hospital, Newcastle, Australia.
Methodology : Seventy-five of the 76 patients attending the clinic over a 6 month period had blood collected for genetic analysis of 17 of the cystic fibrosis (CF) gene mutations.
Results : Sixty-one per cent of the patients were homozygous for the ΔF508 mutation and all except one child had at least one ΔF508 mutation.
Discussion : Nearly 80% of the CF genes were the ΔF508 mutation. This prevalence suggests that the obligatory false negative rate of a newborn screening programme for CF based on a combination of immunoreactive trypsin and the ΔF508 gene may be as low as 4-5%.     

Increasing dialysate flow and dialyzer mass transfer area coefficient to increase the clearance of protein-bound solutes

Clinical hemodialysis systems achieve high single pass extraction of small solutes that are not bound to plasma proteins. But they clear protein-bound solutes much less effectively. This study examines the extent to which clearance of a protein-bound test solute is improved by increasing the dialyzer mass transfer area coefficient (KoA) and the dialysate flow rate (Qd). A reservoir containing test solutes and artificial plasma with albumin concentration approximately 4 g/dl was dialyzed with a standard clinical dialysate delivery system. The clearance of phenol red (ClPR) was compared with the clearances of urea and creatinine at a plasma flow rate (Qp) of 200 ml/min with varying values of KoA and Qd. ClPR increased from 11 +/- 2 ml/min to 23 +/- 2 ml/min when KoA for phenol red, KoAPR, was increased from 238 to 640 ml/min and Qd was increased from 286 +/- 6 ml/min to 734 +/- 9 ml/min. Increasing either KoAPR or Qd alone had lesser effects. Clearance values for phenol red were much lower than clearance values for the unbound solutes urea and creatinine, which ranged from 150 to 200 ml/min and were less affected by varying KoA and Qd. A mathematical model was developed to predict ClPR from values of Qp, Qd, the fraction of phenol red bound to albumin (94% +/- 1%) and KoAPR. The model accurately predicts the pattern of measured results and shows further that ClPR can be made to approach Qp only by very large increases in both KoAPR and Qd.     

妊娠诱发先天异常输尿管结石梗阻1例

1病例报告女,26岁.因孕5 mo余,右腰腹部间断性疼痛3 d伴高烧,于2004-05-27急诊入本院泌尿外科.患者疼痛难忍,向右下腹放射,间歇性,无恶心呕吐,无尿急、尿频、尿痛,伴发热,体温最高可达40℃,既往无泌尿系患病史.查体: T 40℃,P 110次/min,BP 16/10 kPa,R 21次/min.痛苦面容,心肺正常,右肾区及右输尿管走行区扣击痛.     

阿司匹林与埃索美拉唑合用较氯吡格雷减少高危患者再次溃疡出血的发生

问题：在有阿司匹林诱发溃疡出血史的患者中，用氯毗格雷预防溃疡出血复发，是否不次于小剂量阿司匹林加埃索美拉唑？[编者按]     

Mutations in the C-terminal domain of Sonic Hedgehog cause holoprosencephaly

Holoprosencephaly (HPE) is the most common brain anomaly in humans, involving abnormal formation and septation of the developing central nervous system. Among the heterogeneous causes of HPE, mutations in the Sonic Hedgehog (SHH) gene have been shown to result in an autosomal dominant form of the disorder. Here we describe a total of five different mutations in the processing domain encoded by exon 3 of SHH in familial and sporadic HPE. This is the first instance in humans where SHH mutations in the domain responsible for autocatalytic cleavage and cholesterol modification of the N-terminal signaling domain of the protein have been observed.