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Ophthalmic complications of slit-ventricle syndrome in children.

OBJECTIVE: To present the ophthalmic features and visual prognosis of patients with slit-ventricle syndrome (SVS). DESIGN: Observational case series. PARTICIPANTS: Six patients diagnosed and treated with SVS at the Montreal Children's Hospital between 1985 and 1999. METHODS: Patients were included in this study if they had an appropriate ophthalmologic follow-up and if they fulfilled the criteria for the diagnosis of SVS based on intracranial pressure monitoring and neuroimaging studies. MAIN OUTCOME MEASURES: Features studied included patients' baseline ophthalmologic evaluation, visual outcome, and neurosurgical characteristics. RESULTS: The follow-up ranged from 1 to 14 years. The average number of shunting procedures was 3.7. Ocular examination performed on the initial visit revealed a normal visual acuity in four patients, esotropia in three of six patients, and nystagmus in two of six patients. Cycloplegic refraction was normal in all the subjects. Initial funduscopic evaluation revealed optic atrophy in a 4-month-old infant, whereas two children developed optic atrophy later in the course of the disease. One child developed severe visual field defects. The two children with optic atrophy had moderate to severe loss of visual acuity associated with SVS. CONCLUSIONS: A prompt recognition of patients with SVS is crucial, because these individuals are at an increased risk for significant visual loss.

Cerebral Ventricles↗

Characterization of endothelin receptors in human varicose veins.

PURPOSE: Experiments were designed to characterize endothelin receptors in human varicose veins. Three groups of veins were studied: (1) varicose vein (VV) tributaries of the greater saphenous vein from patients who were undergoing vein stripping for primary varicosity; (2) greater saphenous veins (SVs) from the same patients; and (3) greater saphenous veins from patients without varicosity who were undergoing arterial reconstruction (control). METHODS: Veins were either cut into rings and suspended in organ chambers for measurement of isometric force, prepared for receptor binding of membrane proteins, or were prepared for measurement of preproendothelin mRNA by reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: Endothelin-1 (10(-11) to 10(-7) mol/L) produced similar concentration-dependent contractions in rings with or without endothelium. Maximal tensions were significantly greater in control veins compared with either SVs or VVs. Sarafotoxin S6c (10(-11) to 3 x 10(-7) mol/L), which is selective for the endothelin-B receptor, also produced concentration-dependent increases in tension in all veins. Sarafotoxin S6c responses in VVs were shifted significantly rightward compared with either SVs or control. Maximal tensions to sarafotoxin S6c also were significantly greater in control veins compared with either SVs or VVs. In receptor binding studies, the number of binding sites as defined by competitive inhibition of 125I-endothelin-1 by endothelin-1 was less in VVs than control veins. Competitive inhibition of 125I-endothelin-1 with endothelin-3 (both A and B receptors) or sarafotoxin S6c (B receptors only) suggests that the difference in receptor number between varicose and nonvaricose veins is attributable to differences in the endothelin-B receptor subtype. Binding affinities were not significantly different for either of the receptor subtypes in all veins studied. Preproendothelin mRNA as quantitated by RT-PCR tended to be higher in VVs compared with either SVs or control veins. CONCLUSIONS: Decreased contractions to endothelin-1 in both varicose and saphenous veins of patients with primary varicosity may be associated with a decrease in the number of receptors. These receptors may be downregulated in response to increased production of endothelin-1, which is regulated at the transcriptional level.

Aged↗

Effect of antibodies against seminal vesicle secretion on fertility in the rat.

Fertile female Wistar rats were immunised against rat and mouse seminal vesicle secretion (SVS) to test the production of allo-antibodies and the effect of the antibodies elicited on fertility. Twenty-six per cent of the rat and mouse SVS-immunised females were infertile after the treatment. The sera were titrated by ELISA and used in Western blots to detect the proteins recognised. Although neither the antibody titres nor the proteins recognised by the sera showed a close relation with the degree of fertility, in all females the highest antibody titre in the fluids from the genital tract was found in the oviductal fluid and during the night of oestrus. This fact suggested that the site of action of the antibody could be the oviduct. Similar results were obtained using mouse SVS as immunogen--a fact that can be related to the antigenic similarity between the SVS of the two species. The antibodies react with the spermatozoa but not with eggs or embryos. Analyses performed on embryos collected from sterile females showed that there was a delay in fertilisation and normal embryogenesis. Our results suggest that SVS proteins are antigenic and that these antigens are bound to the spermatozoa and could take part in early pre-fertilisation events such as capacitation or sperm transport.

Animals↗

Analysis of deep-resequencing data of 984 soybean accessions reveals structural variations underlying agronomic traits.

Genomic structural variants (SVs) are major sources of genetic variation and have profound impacts on phenotypic traits. However, their functional effects remain largely unexplored in soybean. Here, we resequence 940 soybean accessions. Together with 44 publicly available datasets, we identify 602,281 SVs. Using a graph-based genome, we detect an additional 58,760 presence/absence variations (PAVs) that broadly affect gene expression. Population genomic analyses reveal that SVs serve as a core driving force for soybean domestication and improvement. Integrating SVs with QTLs for oil and protein content, and performing GWAS on 27 traits, we identify key functional SVs. These include transposable element insertions altering seed coat color, multiple insertions within a cytochrome P450 gene modifying flower and hypocotyl color, and a GmMATE1 deletion enhancing seed size. Together, our study establishes a comprehensive SV map of soybean, offering a valuable resource for dissecting the genetic basis of complex traits to accelerate molecular breeding.

Glycine max↗

Characteristics of successful and unsuccessful completers of 3 postacute brain injury rehabilitation pathways.

OBJECTIVE: To determine whether successful participants along different postacute brain injury rehabilitation pathways differ on demographic, injury-related, disability, and outcome variables. DESIGN: Secondary analysis of pre- and posttreatment, and 1-year follow-up data obtained in a previous study of specialized vocational services (SVS) for persons with brain injury. SETTING: Outpatient brain injury rehabilitation clinic. PARTICIPANTS: One hundred fourteen persons with acquired brain injury. INTERVENTIONS: Participants in 3 distinct rehabilitation pathways were studied: SVS only; SVS and a 3-h/wk community reintegration outpatient group; and SVS and 6-h/d comprehensive day treatment (CDT). MAIN OUTCOME MEASURES: Mayo-Portland Adaptability Inventory (MPAI); Vocational Independence Scale; and "success," as defined by community-based employment (CBE) at 1-year follow-up. RESULTS: The percentage (77%-85%) of participants in CBE at 1-year follow-up did not differ among the 3 pathways. CDT participants had more limited educational backgrounds, were less recently injured, and showed greater disability and more impaired self-awareness than those receiving limited intervention (ie, SVS or community reintegration outpatient group). MPAI scores for limited-intervention participants who were unsuccessful were similar in level to successful participants in CDT. Logistic regression models were developed to predict the probability of success with limited intervention and CDT. CONCLUSION: Different rehabilitation pathways result in CBE for a large percentage of persons with brain injury if the intensity of service is appropriately matched to the severity of the disability, the time since injury, and other participant characteristics.

Adult↗

Enhancement of Mdr2-mediated phosphatidylcholine translocation by the bile salt taurocholate. Implications for hepatic bile formation.

Expression of the Mdr2-protein in secretory vesicules (SVs) from the yeast mutant sec6-4 causes a time- and temperature-dependent enhancement of phosphatidylcholine (PC) translocation from the outer to the inner leaflet of the SV lipid bilayer. We show that this activity is independent of changes either in the membrane potential or the pH gradient (inside positive) generated in these SVs by the yeast proton-translocating PMA1 ATPase. However, loading of the SVs with the primary bile salt taurocholate results in an apparent enhancement of Mdr2-mediated PC translocation activity. Reducing the intravesicular taurocholate (TC) concentration by dissipating the electrochemical potential across the SV membranes eliminates the enhancing effect of TC. Three lines of evidence suggest that the enhanced Mdr2-mediated PC translocation activity is not caused by a regulatory effect of TC on Mdr2 but rather reflected the formation of TC/PC aggregates or micelles in the lumen of SVs. First, significantly higher detergent concentrations are required to reveal the fluorescence of (7-nitro-2-1,3-benzoxadiazol-4-yl)amino-PC molecules translocated in Mdr2-SV under conditions of TC stimulation than under control conditions; second, the nonmicelle-forming bile salt taurodehydrocholate does not cause enhancement of PC translocation in Mdr2-SVs; third, enzyme marker studies indicate that TC behaves as a potent lipid solubilizer directly extracting PC molecules out of the bilayer without causing leakage. This results in the formation of intravesicular aggregates or mixed micelles, and provokes the apparent stimulation of Mdr2 activity. These data demonstrate a unique relationship between Mdr2, PC, and TC in the process of bile formation and secretion.

4-Chloro-7-nitrobenzofurazan↗

Exo-endocytotic recycling of synaptic vesicles in developing processes of cultured hippocampal neurons.

In mature neurons synaptic vesicles (SVs) undergo cycles of exo-endocytosis at synapses. It is currently unknown whether SV exocytosis and recycling occurs also in developing axons prior to synapse formation. To address this question, we have developed an immunocytochemical assay to reveal SV exo-endocytosis in hippocampal neurons developing in culture. In this assay antibodies directed against the lumenal domain of synaptotagmin I (Syt I), an intrinsic membrane protein of SVs, are used to reveal exposure of SV membranes at the cell surface. Addition of antibodies to the culture medium of living neurons for 1 hr at 37 degrees C resulted in their rapid and specific internalization by all neuronal processes and, particularly, by axons. Double immunofluorescence and electron microscopy immunocytochemistry indicated that the antibodies were retained within SVs in cell processes and underwent cycles of exo-endocytosis in parallel with SV membranes. In contrast, another endocytotic marker, wheat germ agglutinin, was rapidly cleared from the processes and transported to the cell body. Antibody-labeled SVs were still present in axons several days after antibody loading and became clustered at presynaptic sites in parallel with synaptogenesis. These results demonstrate that SVs undergo multiple cycles of exo-endocytosis in developing neuronal processes irrespective of the presence of synaptic contacts.

Calcium-Binding Proteins↗

Synaptophysin I controls the targeting of VAMP2/synaptobrevin II to synaptic vesicles.

Synaptic vesicle (SV) proteins are synthesized at the level of the cell body and transported down the axon in membrane precursors of SVs. To investigate the mechanisms underlying sorting of proteins to SVs, fluorescent chimeras of vesicle-associated membrane protein (VAMP) 2, its highly homologous isoform VAMP1 and synaptotagmin I (SytI) were expressed in hippocampal neurons in culture. Interestingly, the proteins displayed a diffuse component of distribution along the axon. In addition, VAMP2 was found to travel in vesicles that constitutively fuse with the plasma membrane. Coexpression of VAMP2 with synaptophysin I (SypI), a major resident of SVs, restored the correct sorting of VAMP2 to SVs. The effect of SypI on VAMP2 sorting was dose dependent, being reversed by increasing VAMP2 expression levels, and highly specific, because the sorting of the SV proteins VAMP1 and SytI was not affected by SypI. The cytoplasmic domain of VAMP2 was found to be necessary for both the formation of VAMP2-SypI hetero-dimers and for VAMP2 sorting to SVs. These data support a role for SypI in directing the correct sorting of VAMP2 in neurons and demonstrate that a direct interaction between the two proteins is required for SypI in order to exert its effect.

Animals↗

SynFlow: an interactive online genome structural variant viewer.

MOTIVATION: Structural variations (SVs), including inversions, translocations (TRAs), duplications, and large insertions or deletions, are key drivers of genome evolution and phenotypic diversity. With the increasing number of high-quality, chromosome-scale genome assemblies, the ability to detect and interpret SVs has become a crucial aspect of modern genomics. While SV detection has advanced, most visualization methods produce static plots that fall short when researchers, particularly in comparative genomics, need to interactively explore large datasets, zoom into specific genomic regions, or dynamically filter structural events in real time. RESULTS: To address this gap, we introduce SynFlow, a lightweight, web-based interactive application specifically designed for exploring and visualizing SVs identified by SyRI. We demonstrate that SynFlow can reproduce complex static synteny plots published in literature, but transforms them into dynamic, shareable visualizations that support real-time filtering, reordering, and deep exploration of specific SVs, including TRAs. SynFlow is available as a web server and offers multiple entry points: browsing precomputed datasets (e.g. banana and grapevine genomes), uploading user-provided SyRI outputs, or running an integrated workflow to produce and visualize SVs on the fly. AVAILABILITY AND IMPLEMENTATION: https://synflow.southgreen.fr; source code https://github.com/SouthGreenPlatform/synflow; preprocessing Snakemake workflow https://gitlab.cirad.fr/agap/cluster/snakemake/synflow.

Software↗

Rat brain synaptic vesicles are devoid of Mg2+-ATPase activity and contain beta-amyloid precursor protein.

Rat brain synaptic vesicles (SVs) isolated by gel filtration on Sephacryl S-500 had little Mg2+(H+)-ATPase activity, though it was identified by Western blots with antibodies against the H+-ATPase A-subunit and other vesicle proteins. In contrast, tyrosine hydroxylase and dopa decarboxylase activities in the SVs were substantial, suggesting that the absence of Mg2+(H+)-ATPase activity was not due to inactivation during isolation but rather to the nature of the SVs. The vesicle component reactive to H+-ATPase antibody was also identified in the synaptosomal cytosol, so the antibody for the A-subunit seemed unnecessary to detect H+-ATPase. The SVs contained beta-amyloid precursor protein of approximately 100 kDa. Based on these observations, SVs without Mg2+(H+)-ATPase seemed to play a role(s) in the delivery of cytoplasmic and plasma membrane proteins to nerve terminals as well as in neurotransmission.

Amyloid beta-Protein Precursor↗

Panorama of Chromosomal Instability in Lung Cancer.

Lung cancer is a highly heterogeneous disease primarily driven by tobacco smoking. About 20% of lung cancers occur among patients who have never smoked (LCINS) with differences in patient ancestry, sex, tumor histology, and clinical features. Our understanding of chromosomal instability in lung cancer, especially LCINS, is still limited. Here, we perform a comprehensive study of 182,429 somatic structural variations (SVs) detected in 1,209 whole-genome sequenced lung cancers, of which 864 LCINS. SVs are more abundant in tumors from patients who have smoked (LCSS); however, they are more complex and play more important roles in tumorigenesis in LCINS. EGFR mutations and KRAS mutations profoundly and independently shape the SV landscape. EGFR-mutant tumors have higher SV burden and more cancer-driving SVs. In contrast, KRAS mutations are associated with lower SV burden and less driver SVs. We decompose 16 SV signatures for both complex and simple SVs that likely represent divergent molecular mechanisms. The SV breakpoints have distinct distributions across the genome depending on the signatures due to mutagenic mechanisms and positive selection. Many established cancer-driving genes are recurrently rearranged by multiple SV signatures suggesting functional convergence of these genome instability mechanisms.

Journal Article↗

Expression of growth hormone-releasing hormone receptor splicing variants in human primary adrenocortical tumours.

OBJECTIVE: Several splice variants (SVs) of GHRH receptor (GHRH-R) have been identified in various human cancers through which GHRH antagonists may exert their IGF-II-mediated antiproliferative action. Because the overexpression of the IGF-II gene is a frequent feature of adrenal carcinoma, we searched for the presence of GHRH-R SVs in these tumours. METHODS AND RESULTS: The expression of GHRH-R SVs was assessed by nested PCR in 45 human adrenocortical tumours. We have amplified 720-, 566- and 335-bp PCR products only in carcinomas. Their sequence revealed three open reading frames, corresponding to SV1, SV2 and SV4 of GHRH-R. SV2 was detected in five of 24 cancers examined, whereas the incidence of SV1 and SV4 was lower. Their simultaneous expression was observed in one carcinoma. No PCR products for SV3 or wild-type GHRH-R were found in carcinomas; mRNA for wild-type GHRH-R or SVs of GHRH-R were not observed either in adenomas or in normal adrenal or in NCI-H295R cells. Interestingly, all carcinomas which expressed SVs were also positive for the presence of GHRH mRNA. CONCLUSION: This is the first time that the expression of splice variants of GHRH-R has been demonstrated in human adrenal carcinoma. This study raises the possibility that splice variants might play a role in adrenal carcinogenesis and might offer the possibility for new therapeutic strategies at least in a subgroup of adrenal carcinomas.

Adenoma↗

Lumbar CSF shunting preferentially drains the cerebral subarachnoid over the ventricular spaces: implications for the treatment of slit ventricle syndrome.

Based on a proposed pathophysiology of slit ventricle syndrome (SVS), we have hypothesized that lumboperitoneal shunting exerts effects in SVS patients by increasing the buffering capacity for raised intracranial pressure (ICP) via an increase in cerebrospinal fluid drainage from the cerebral subarachnoid space (SAS). We describe 3 SVS patients with patent lumbar subarachnoid drainage but under-functioning ventriculoperitoneal shunts (VPS) who presented with ventriculomegaly (not SVS), and persistence of shunt malfunction like symptoms. Revision of the VPS resulted in complete resolution of symptoms despite a finding of low pressure in the ventricular space. This supports the hypothesis that lumboperitoneal shunting preferentially drains the SAS over the intraventricular space and in these cases allows the 'SVS' ventricles to enlarge by creating a pressure gradient from ventricles to SAS through the cortical mantle.

Cerebral Ventricles↗

Slit-ventricle syndrome: review of 15 cases.

The slit-ventricle syndrome (SVS) has been the subject of diverse opinions and recommendations during the past 2 decades. In an effort to define the clinical features of SVS and to make recommendations concerning management we have reviewed 15 cases treated by a fairly uniform technique during the past 5 years. The syndrome consists of: (1) intermittent, but self-limiting episodes resembling shunt malfunction, usually lasting a few days, (2) nonfilling of the pumping device after compression, and (3) a slit-like ventricular system on CT scan. In all but 2 patients the initial shunt was performed in infancy. The mean interval from the initial shunt to treatment of SVS was 6 years. The age range at onset of SVS varied from 2 to 17 years with a mean of 7 years. All patients in this series were relieved of symptoms by placement of an antisiphon device and, in most patients, upgrading the valve resistance. Analysis of this series has led to the following conclusions: (1) SVS is a characteristic clinical entity, usually distinguishable from persistent shunt malfunction and from low-pressure headache, (2) the pathogenesis is intermittent obstruction of the ventricular catheter, (3) there is no good evidence that changes of brain compliance or La Place principles apply, and (4) placement of antisiphon device and upgrading valve resistance are effective treatments.

Brain Diseases↗

Unveiling the Genetic Landscape of Coronary Artery Disease Through Common and Rare Structural Variants.

BACKGROUND: Genome-wide association studies have identified several hundred susceptibility single nucleotide variants for coronary artery disease (CAD). Despite single nucleotide variant-based genome-wide association studies improving our understanding of the genetics of CAD, the contribution of structural variants (SVs) to the risk of CAD remains largely unclear. METHOD AND RESULTS: We leveraged SVs detected from high-coverage whole genome sequencing data in a diverse group of participants from the National Heart Lung and Blood Institute's Trans-Omics for Precision Medicine program. Single variant tests were performed on 58 706 SVs in a study sample of 11 556 CAD cases and 42 907 controls. Additionally, aggregate tests using sliding windows were performed to examine rare SVs. One genome-wide significant association was identified for a common biallelic intergenic duplication on chromosome 6q21 (P=1.54E-09, odds ratio=1.34). The sliding window-based aggregate tests found 1 region on chromosome 17q25.3, overlapping USP36, to be significantly associated with coronary artery disease (P=1.03E-10). USP36 is highly expressed in arterial and adipose tissues while broadly affecting several cardiometabolic traits. CONCLUSIONS: Our results suggest that SVs, both common and rare, may influence the risk of coronary artery disease.

Humans↗

Inhibitory effect of all-trans retinoic acid on androgen-induced growth of mouse seminal vesicles in vivo and its mechanism.

We examined the effect of all-trans retinoic acid (ATRA) on the androgen-induced growth of mouse seminal vesicles (SVs) in vivo and its mechanisms. Testosterone propionate (TP) alone or with ATRA was injected daily into adult castrated BALB/c mice. Injections of ATRA significantly inhibited the TP-induced growth of SVs in terms of wet weight and DNA synthesis by a pair of SVs evaluated by [3H]thymidine uptake. The bromodeoxyuridine labelling index showed that ATRA inhibited the proliferation of both epithelial and stromal cells. Immunoreactivity for retinoic acid receptor-alpha was found in the basal epithelial cells. Injections of ATRA affected neither 5alpha-reductase activity nor the expression of mRNAs for TGF-beta1, 2 and 3 and TGF-beta receptor 1 and 2 in the SVs. However, androgen receptor (AR) binding assays and Western blotting revealed a decrease in AR without a change in ligand-binding affinity. The present study showed that retinoid inhibited the androgen-induced growth of mouse SVs in vivo, and suggests that a decrease in AR is one of its mechanisms.

Animals↗

Augmentation of endothelial function by endothelin antagonism in human saphenous vein conduits.

OBJECT: Cerebral revascularization with saphenous vein (SV) conduits is used in the management of hard-to-treat lesions that require deliberate arterial occlusion and in selected patients with occlusive vascular disease. Endothelial dysfunction is thought to contribute to acute perioperative vasospasm and chronic graft atherosclerosis. In the present study the authors examined the contribution of the potent vasoconstrictor endothelin-1 (ET-1) to endothelial dysfunction in human SVs. METHODS: The effects of an ET(A/B) receptor antagonist (bosentan), an ET(A) receptor antagonist (BQ-123), and an ET(B) receptor antagonist (BQ-788) on in vitro endothelium-dependent and -independent responses were studied in human SVs. Vascular segments were obtained in 34 patients who had undergone revascularization procedures, and isometric dose-response curves (DRCs) were constructed using the isolated tissue bath procedure as follows: 1) cumulative DRCs to norepinephrine; and 2) DRCs to acetylcholine (ACh) and sodium nitroprusside in the absence and presence of bosentan, BQ-123, or BQ-788. Maximal vasodilatory responses and sensitivity were compared between groups. In the presence of bosentan (Experiment 1) and BQ-123 or BQ-788 (Experiment 2), ACh responses were significantly augmented (percent maximum relaxation values: 7+/-2 [control] compared with 17+/-3 [bosentan], p < 0.002 [Experiment 1]; and 12+/-2 [control] compared with 29+/-2 [BQ-123] and 25+/-2 [BQ-788], p < 0.003 and p < 0.002, respectively [Experiment 2]). The sensitivity of SVs to ACh was unaffected by treatment. These beneficial effects were specific for the endothelium. CONCLUSIONS: Blockade of ET receptors significantly improves endothelial function in SVs. Furthermore, these effects appear to be independently and maximally mediated by antagonism of either ET(A) or ET(B) receptors. Interventions aimed at improving endothelial function may serve to counter perioperative vasospasm and impede atherosclerosis in SVs used for revascularization procedures.

Aged↗

Accuracy of 3-dimensional color Doppler-derived flow volumes with increasing image depth.

OBJECTIVES: We and others have reported on the use of digital color Doppler sonography from real-time 3-dimensional (3D) echocardiography and its use in accurately calculating cardiac flow volumes, namely stroke volume (SV) and, hence, cardiac output. However, in some patients, image depth is higher than average, and this may affect the accuracy of volume calculation. We sought to investigate the impact of image depth and the accompanying change in signal strength, spatial resolution, and pulse repetition frequency on the accuracy of SV calculation from 3D color Doppler data in an in vitro model. METHODS: A tube model of the left ventricular outflow tract was constructed from plastic tubing and connected to a pulsatile pump. The volume flowing through the tube was imaged using a 3D echocardiography system. Stroke volumes from the pump were computed from the DICOM data using commercially available software and compared with a reference standard of timed volumes with the use of a graduated measuring cylinder over a range of depth settings and SVs. RESULTS: There was good correlation between the 3D-derived SVs and the reference cylinder measures over all depths from 4 to 16 cm at 1-cm increments with a tube diameter of 17 mm, a pump rate of 60 beats/min, and SVs ranging from 20 to 70 mL. The average r(2) value for the 13 different depths was 0.976. However, the accuracy of the 3D method of volume calculation appeared to fall at depths greater than 13 cm, especially at higher SVs. CONCLUSIONS: Stroke volume calculation from real-time 3D color Doppler data in this in vitro study shows that at depths greater than approximately 13 cm, accuracy decreases, especially at higher SVs. This may be due to decreased resolution and the reduced frame rate at these depths. At shallower depths, volume calculation form the 3D Doppler data appears very accurate.

Analysis of Variance↗