Pseudolesion in segment II of the liver observed on CT during arterial portography caused by the aberrant left gastric venous drainage

A rare case with a pseudolesion in segment II of the liver observed on computed tomography (CT) during arterial portography caused by the aberrant left gastric venous drainage is presented. Close observation of the celiac angiography was helpful in recognizing this pseudolesion. Selective catheterization of the left gastric artery and CT during its venous phase confirmed the etiology of the pseudolesion. Received: 11 June 1998/Revision accepted: 9 September 1998     

A hidden layer of structural variation in transposable elements reveals potential genetic modifiers in human disease-risk loci

Genome-wide association studies (GWAS) have been highly informative in discovering disease-associated loci but are not designed to capture all structural variations in the human genome. Using long-read sequencing data, we discovered widespread structural variation within SINE-VNTR-Alu (SVA) elements, a class of great ape-specific transposable elements with gene-regulatory roles, which represents a major source of structural variability in the human population. We highlight the presence of structurally variable SVAs (SV-SVAs) in neurological disease–associated loci, and we further associate SV-SVAs to disease-associated SNPs and differential gene expression using luciferase assays and expression quantitative trait loci data. Finally, we genetically deleted SV-SVAs in the BIN1 and CD2AP Alzheimer''s disease–associated risk loci and in the BCKDK Parkinson''s disease–associated risk locus and assessed multiple aspects of their gene-regulatory influence in a human neuronal context. Together, this study reveals a novel layer of genetic variation in transposable elements that may contribute to identification of the structural variants that are the actual drivers of disease associations of GWAS loci.

Discovering the genetic variation underlying human diseases is a common goal in human genetics, and the rapid increase of genome-wide association studies (GWAS) has generated a vast catalog of single-nucleotide polymorphisms (SNPs) associated with specific traits and diseases (MacArthur et al. 2017). In most cases, GWAS do not identify the genetic variation that drives the trait but use SNPs as markers to highlight trait-associated loci through linkage disequilibrium (LD) (Edwards et al. 2013). This calls for elaborate post-GWAS analysis to shed light on the genes and mechanisms involved in specific traits (Backman et al. 2021; Mortezaei and Tavallaei 2021). A comprehensive view of the genetic structural variants that exist within loci containing trait-associated SNPs is an essential first step to assessing how these variants may lead to disease susceptibility on both genetic and functional levels (Eichler 2019).One source of structural variation that has not been sufficiently considered comes from transposable elements (TEs), which together constitute >42% of the human genome (Smit 1999; International Human Genome Sequencing Consortium 2001; Audano et al. 2019; Linthorst et al. 2020). Although the vast majority of TEs do not alter coding regions of our genome, some TE classes harbor strong gene regulatory potential that can directly affect gene expression levels (Jacobs et al. 2014; Wang et al. 2014; Chuong et al. 2016; Fuentes et al. 2018; Pontis et al. 2019). The TE-mediated regulatory effect on genes is highly tissue-specific and has been shown to be particularly prominent in a neuronal environment (Jacob-Hirsch et al. 2018; Trizzino et al. 2018; Pontis et al. 2019; Miao et al. 2020; Sundaram and Wysocka 2020). TEs are activated during aging, neurodegeneration, and neurological diseases, but whether this is a cause or a consequence of the disease pathology remains unknown in many cases (Frank et al. 2005; Li et al. 2013; Van Meter et al. 2014; Guo et al. 2018; Shpyleva et al. 2018).Only TEs of the Alu, L1, and SVA (SINE-VNTR-Alu) families can still actively spread through the genome, and new insertions cause variation between individuals in the form of presence/absence TE-insertional polymorphisms (Kazazian et al. 1988; Batzer et al. 1991; Brouha et al. 2003; Ostertag et al. 2003). TEs can alter gene regulation in the locus in which they insert, such that the presence or absence of a TE can lead to inter-individual differences in gene expression. There are approximately 60,475 Alu, 10,018 L1, and 6417 SVA TE-insertional polymorphisms known, with new insertions occurring every 40, 63, and 63 births, respectively (Feusier et al. 2019; Collins et al. 2020). Some of these new insertions have been linked to diseases (Makino et al. 2007; Hancks and Kazazian 2016; Sekar et al. 2016; Payer et al. 2017; Payer and Burns 2019; Pfaff et al. 2021). Next to presence/absence TE polymorphisms, structural variation within fixed TEs (TE insertions observed in all individuals in the human population) has also been reported (Savage et al. 2013, 2014), although the prevalence of this type of structural variation has remained elusive. The repetitive nature of TEs increases the propensity for unequal crossover events or DNA polymerase slippage during meiosis, for which variable number of tandem repeats (VNTRs) are especially susceptible (Brookes 2013). SVA elements harbor unusually large VNTRs as their internal segment and have a unique sequence composition compared to other VNTRs in our genome. The structural variation in VNTRs is particularly interesting because they are often associated with gene-regulatory functions, and many genes have accrued VNTRs as essential regulatory elements for their expression (International Human Genome Sequencing Consortium 2001; Fondon et al. 2008).It is becoming increasingly clear that gene-regulatory properties of TEs were co-opted during evolution, leading to the integration of TEs as novel gene-regulatory elements in preexisting gene expression networks (Cordaux and Batzer 2009; Chuong et al. 2016). As such, TEs have become an integral part of normal human gene regulation. Because our genome has become dependent on TEs for specific aspects of gene regulation, structural variation within fixed TEs could account for inter-individual differences in temporal or spatial aspects of gene expression. Despite the possible roles structurally variable TEs may play in human health or disease, this level of structural variation has remained largely undocumented. This is mainly a result of technical limitations associated with the highly repetitive DNA sequences within TEs, which makes identifying structural variations in TEs using short-read sequencing strategies extremely challenging. The development of long-read sequencing techniques provides, for the first time, the opportunity to accurately assess the level of structural variation (Eichler 2019). This allows for the evaluation of possible associations between disease susceptibility and specific structural variations found in fixed TEs in our genome (Audano et al. 2019; Chaisson et al. 2019; Sulovari et al. 2019; Ewing et al. 2020; Ebert et al. 2021; Porubsky et al. 2021).In this study we discovered that SVA retrotransposons, a great ape-specific class of TEs, constitutes a major source of hidden genetic variation that is not taken into account by conventional genetic case-control studies. We set out to investigate the biological consequences of structural variability in SVAs, focusing on SV-SVAs in Alzheimer''s disease (AD)– and Parkinson''s disease (PD)–associated GWAS loci. We assessed the gene-regulatory influence of SV-SVAs in a human neuronal context by genetic deletion of SVAs in three disease-associated loci. Our findings highlight the importance of careful mapping of structural variations within fixed TEs in the human population and argue for their inclusion in complex trait genetics as a layer of genetic variation that may, in some cases, confer the actual disease susceptibility to a GWAS-identified locus.     

Mechanism of Action of Gemfibrozil on HDL Metabolism and Atherosclerosis in WHHL Rabbits

We investigated the mechanism of action of gemfibrozil on high-density lipoproteins (HDL) and apolipoprotein (apo) A-I metabolism and atherogenesis in homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model of familial hypercholesterolemia and HDL deficiency. Two-month-old WHHL rabbits were fed either a normal control diet or a diet containing 0.5% gemfibrozil for 12 months. In vivo apo A-I kinetics, the fractional rate of cholesterol esterification in HDL (FER_HDL), which reflects the reactivity of HDL to lecithin:cholesterol acyltransferase, and a morphometrical analysis of atherosclerotic lesions in the descending thoracic aorta, were examined. At12 months, the mean levels of serum total cholesterol, LDL cholesterol (LDL-C), and HDL cholesterol (HDL-C) in both groups had decreased to approximately 53%, 57%, and 87% of the initial levels (at 0 month), respectively, which is characteristic of homozygous WHHL rabbits of the physiologic influence of aging, and no differences in the levels of serum LDL-C, HDL-C, and triglycerides were found between the two groups. Rabbits treated with gemfibrozil exhibited a decreased FER_HDL (38% of the controls, P = 0.039). Gemfibrozil induced a significant increase in the total mass of apo A-I (1.7-fold, P < 0.05) and in the rate of apo A-I synthesis (1.6-fold, P< 0.05). The atherosclerotic intimal area was positively correlated with serum LDL-C (P = 0.02) in both groups, but gemfibrozil did not affect the atherosclerotic intimal area. These results indicate that 12 months of treatment with gemfibrozil did not protect against atherosclerosis despite a significant increase in apo A-I synthesis and enhanced HDL function through FER_HDL. It is possible that both the qualitative and quantitative improvement in HDL by gemfibrozil cannot overcome the massive and long-term exposure of the vascular wall to LDL in these animals. This revised version was published online in July 2006 with corrections to the Cover Date.     

Circulating immune complexes in Beh?et's disease

The levels of circulating immune complexes (CICs) were investigated in the patients with Beh?et's disease by Clq solid-phase enzyme immunoassay. A significantly higher level of CICs was observed in the patients than in the control group. Concerning the correlation between the levels of CICs and the stages of the ocular attack, the levels were significantly higher in the preattack stage and the early stage of the attack than in the late stage and the remission phase. A high level of CICs was associated with the patients of the fulminant form of ocular attacks. These results suggest that immune complexes may play a role in the development of the ocular attack of Beh?et's disease.     

廊坊世纪协和医院:平价为旗

平价医院虽是注意力经济的产物，却也代表了社会的共同价值取向和未来发展趋势，尽管以平价求发展在现阶段并不容易。     

Histopathological evidence of poor prognosis in patients with vesicoureteral reflux

Patients with vesicoureteral reflux (VUR) often develop reflux nephropathy with focal segmental glomerular sclerosis (FSGS), although the exact mechanisms leading to the development of this complication are unknown. To determine the early changes in glomeruli of VUR patients that ultimately cause poor renal outcome, we examined morphometrically renal biopsies of 16 young patients (age 10–20 years) with VUR at baseline pre-operatively. Patients were divided into two groups, those who subsequently showed good prognosis and those with poor renal prognosis at the end of a 10-year follow-up period. Patients with poor prognosis had worse proteinuria and lower creatinine at baseline than those with good prognosis. We also examined 40 age-matched control cases with previous temporal microhematuria and/or proteinuria but normal renal function and histology. Although the mean diameter of glomerular capillary did not change in VUR cases irrespective of prognosis, glomerular capillary length increased by 125% in cases with good prognosis, and 335% in cases with poor prognosis (P<0.01). Cystically expanded capillaries, with diameter ≥95% of that in age-matched control, were detected in five of eight patients with poor prognosis, but only in one of eight patients with good prognosis. In VUR, the number of podocytes/capillary diminished with increased length of the capillaries. Tuft adhesion to Bowman’s capsule and podocyte detachment were primarily found in patients with poor prognosis. Our results suggest that lengthening of glomerular capillaries in young patients with VUR is a compensatory reaction to hyperfiltration. The appearance of cystic capillary expansion, podocyte detachment and/or tuft adhesion to Bowman’s capsule in such glomeruli may be important indicators of renal prognosis in patients with VUR. These changes may lead to FSGS due to podocyte injury in patients with VUR, with subsequent deterioration of renal function. Received: 3 January 2000 / Revised: 18 January 2001 / Accepted: 18 January 2001