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PubMed2025

Structural variation detection and association analysis of whole-genome-sequence data from 16,543 Alzheimer's disease sequencing project subjects.

INTRODUCTION: The role of structural variations (SVs) in Alzheimer's disease (AD) remains understudied. METHODS: We analyzed whole-genome sequencing data from the Alzheimer's Disease Sequencing Project (N = 16,543) and identified 400,234 (168,223 high-quality) SVs. Laboratory validation yielded a sensitivity of 82% (85% for high-quality). RESULTS: We found a burden of singletons (odds ratio [OR] = 1.07, p = 0.0017) and homozygous deletions (OR = 1.14, p < 0.0001) in cases. On AD genes, we observed the ultra-rare SVs associated with the disease, including protein-altering SVs in ABCA7, APP, PLCG2, and SORL1. Twenty-one SVs are in linkage disequilibrium (LD) with known AD-risk variants, exemplified by a 5k deletion in LD (R2 = 0.99) with rs143080277 in NCK2. We identified a rare deletion near RNA5SP293 associated with AD (OR = 1.99, p = 1.3 × 10-5), which was replicated using an independent dataset. DISCUSSION: This study highlights the pivotal role of SVs in AD genetics. HIGHLIGHTS: Observed a significant burden of singletons and homozygous deletions in Alzheimer's disease (AD) patients. Identified rare protein-altering structural variations (SVs) in ABCA7, APP, PLCG2, and SORL1. Established linkages between SVs and AD risk-associated single nucleotide variants (SNVs). Discovered a novel deletion near RNA5SP293 linked to AD, replicated independently. Uncovered over-representation of SVs in neuronal function pathways.

Humans↗

PubMed1999

Identification of low density lipoprotein receptor-related protein-2/megalin as an endocytic receptor for seminal vesicle secretory protein II.

The low density lipoprotein receptor-related protein-2/megalin (LRP-2) is an endocytic receptor that is expressed on the apical surfaces of epithelial cells lining specific regions of the male and female reproductive tracts. In the present study, immunohistochemical staining revealed that LRP-2 is also expressed by epithelial cells lining the ductal region and the ampulla of the rat seminal vesicle. To identify LRP-2 ligands in the seminal vesicle, we probed seminal vesicle fluid with 125I-labeled LRP-2 in a gel-blot overlay assay. A 100-kDa protein (under non-reducing conditions) was found to bind the radiolabeled receptor. The protein was isolated and subjected to protease digestion, and the proteolytic fragments were subjected to mass spectroscopic sequence analysis. As a result, the 100-kDa protein was identified as the seminal vesicle secretory protein II (SVS-II), a major constituent of the seminal coagulum. Using purified preparations of SVS-II and LRP-2, solid-phase binding assays were used to show that the SVS-II bound to the receptor with high affinity (Kd = 5.6 nM). The binding of SVS-II to LRP-2 was inhibited using a known antagonist of LRP-2 function, the 39-kDa receptor-associated protein RAP. Using a series of recombinant subfragments of SVS-II, the LRP-2 binding site was mapped to a stretch of repeated 13-residue modules located in the central portion of the SVS-II polypeptide. To evaluate the ability of LRP-2 to mediate 125I-SVS-II endocytosis and lysosomal degradation, ligand clearance assays were performed using differentiated mouse F9 cells, which express high levels of LRP-2. Radiolabeled SVS-II was internalized and degraded by the cells, and both processes were inhibited by antibodies to LRP-2 or by RAP. The results indicate that LRP-2 binds SVS-II and can mediate its endocytosis leading to lysosomal degradation.

Amino Acid Sequence↗

PubMed2026

The value of structural variants to conservation genomics in the pangenome era.

Structural variants (SVs) comprise an axis of genetic diversity with strong consequences for phenotype and fitness, making them a potentially important target for conservation genomics. Here, we review how and why SVs can play a role in conservation genomics; the different types of SVs and how they can affect phenotype; and how pangenomes and long-read sequencing are illuminating their evolution in populations, including small populations and those of conservation concern. SVs comprise multinucleotide mutations including insertions, deletions, transpositions, inversions, and other multinucleotide mutations, often overlapping genes and other functional genome regions. As a result, SVs often play important roles in phenotypic evolution and local adaptation and can contribute substantially to genetic load in inbred populations. However, our understanding of the factors influencing SV diversity in populations is still in its infancy and is complicated by the vast range of sizes, effects, and mechanisms of formation of these mutations. We argue that SVs are an important axis of genetic diversity which should be characterized alongside more traditional metrics of genetic diversity in conservation contexts. There are a number of analytical challenges to detecting and studying SVs, but analyses aimed at understanding the role of SVs in inbreeding load and population health are rapidly becoming realizable goals, accelerated by new technologies and analytical approaches. New tools, including population-scale long-read sequencing and pangenome approaches, are beginning to make SVs accessible in ways which can be readily applied in conservation settings.

Genomic Structural Variation↗

PubMed1994

Inhibitory effects of transforming growth factor-beta 1 on androgen-induced development of neonatal mouse seminal vesicles in vitro.

The effects of transforming growth factor-beta 1 (TGF beta 1) on the development of seminal vesicles (SVs) of neonatal mice were investigated in vitro. SVs from 0-day-old male mice were cultured for 2-8 days in serum-free, chemically defined medium with or without 5 alpha-dihydrotestosterone (DHT) at 10(-8) M in the presence or absence of TGF beta 1. Before culture, SVs from 0-day-old mice had no epithelial branches. SVs cultured in medium with DHT formed numerous epithelial branches after day 2 of culture, whereas epithelial branching did not occur in SVs cultured without DHT. The addition of TGF beta 1 (10 ng/ml) to DHT-containing medium almost completely inhibited the formation of epithelial branches. However, the removal of TGF beta 1 from DHT-containing medium on day 2 or 4 of culture initiated the formation of epithelial branches. TGF beta 1 (10 ng/ml) decreased [3H]thymidine labeling indices of both epithelium and mesenchyme of SVs cultured in medium with DHT during 8 days of culture, an effect that was reversed after the removal of TGF beta 1 from the medium on day 2 or 4 of culture. In contrast, TGF beta 1 (10 ng/ml) did not affect the labeling indices of either epithelium or mesenchyme of SVs cultured in medium without DHT. TGF beta 1 (10 ng/ml) also suppressed the normal increase in protein and DNA contents of SVs cultured in medium with DHT, whereas it did not reduce protein or DNA contents of SVs cultured in medium without DHT. The present study indicates that androgen-dependent growth of the SV can be reversibly inhibited by TGF beta 1, whereas androgen-independent growth of the SV is insensitive to TGF beta 1.

Androgens↗

PubMed1990

Structural characterization of the rat seminal vesicle secretion II protein and gene.

The gene encoding rat seminal vesicle secretion II (SVS II) protein has been cloned from a rat genomic DNA library using a cDNA probe generated from rat dorsal prostate androgen-dependent mRNA. The cloned 7.3-kilobase pair genomic fragment contains approximately 5000 base pairs (bp) of the 5'-flanking region and the entire coding region of the SVS II protein within two exons. A sequence of 4156 bp of the rat SVS II gene has been determined, including 2037 bp of the 5'-flanking region, exon 1 (95 bp), intron 1 (236 bp), exon 2 (1171 bp), and 614 bp of the 3'-flanking region. The 5'-flanking region contains three conserved elements found in other seminal vesicle secretion genes (SVS IV-VI proteins) within 250 bp of the transcription start site as well as a glucocorticoid response element at position -314 in the SVS II gene. The first exon encodes a 22-amino acid leader peptide plus the first 2 amino acids of the secreted protein. The second exon encodes the remaining amino acids in the SVS II protein sequence. The mature protein contains 392 residues and has an Mr of 43,116. Concomitant with the gene analysis, the rat SVS II protein was purified to homogeneity, and 333 residues (85%) of the amino acid sequence were determined by automated Edman degradation. The DNA-deduced sequence and that determined by direct analysis of the protein are in complete agreement. The blocked NH2-terminal amino acid was identified as pyroglutamic acid by mass spectrometry and aminopeptidase digestion. A 13-residue structure with the consensus sequence GSQLKSFGQVKSS is repeated 13 times within the SVS II protein and appears to be involved in the formation of the rat copulatory plug via a transglutaminase reaction cross-linking glutamine and lysine residues. Overall, the SVS II protein sequence exhibits little structural relatedness to any other known protein sequence; however, some similarity can be found between the 13-residue repeat and another repeating structure and apparent transglutaminase substrate in the guinea pig seminal vesicle clotting protein.

Amino Acid Sequence↗

PubMed1995

Inhibitory effects of suramin on androgen-dependent and -independent growth of neonatal mouse seminal vesicles in vitro.

The effects of suramin on the growth of seminal vesicles (SVs) of neonatal mice were investigated in vitro. SVs from 0-day-old male mice were cultured in serum-free chemically defined medium supplemented with 5 alpha-dihydrotestosterone (DHT, 10(-8) M) and insulin (10 micrograms/ml), alone and in combination. Prior to culture, SVs from 0-day-old mice had no epithelial branches. SVs cultured in medium with DHT formed numerous epithelial branches, while epithelial branching did not occur in SVs cultured without DHT. The addition of suramin (0.2 mM) to medium containing DHT inhibited the formation of epithelial branches almost completely. Removal of suramin from the medium on days 2, 4, and 6 of culture initiated the formation of epithelial branches. Suramin (0.2 mM) reversibly decreased 3H-thymidine-labeling indices (3H-LI) of both epithelium and mesenchyme of SVs cultured in medium with DHT plus insulin or DHT alone during 8 days of culture. Suramin also decreased 3H-LI of both epithelium and mesenchyme of SVs cultured in medium with insulin alone. The present study indicates that suramin reversibly inhibits not only androgen-dependent but also androgen-independent growth and ductal branching morphogenesis of neonatal mouse SVs.

Androgens↗

PubMed2006

A comparison of the changes in generic quality of life after superficial venous surgery with those after laparoscopic cholecystectomy.

BACKGROUND: Superficial venous surgery (SVS) results in a significant improvement in generic health-related quality of life (HRQL). However, it is unclear how this improvement compares with that observed after other commonly performed general and vascular operations. The aim of this study was to compare the changes in generic HRQL observed before and after SVS for CEAP clinical grade 2 to 4 venous disease with those observed before and after elective laparoscopic cholecystectomy (ELC) for biliary colic. METHODS: The Short Form 12 questionnaire was mailed to patients before and 3, 6, and 12 months after SVS (n = 143) and ELC (n = 60). The responses were used to calculate physical (PCS) and mental (MCS) component summary scores at each time point. A higher score indicates a better HRQL. RESULTS: Before surgery and 3 and 12 months after surgery, patients in the ELC group had a significantly lower PCS than those in the SVS group (40.2 vs 49.5, 48.9 vs 53.1, and 45.4 vs 53.8; P < .001, P = .033, and P < .001, respectively; Mann-Whitney U test). However, the change in PCS observed over the first 12 postoperative months was not significantly different between the SVS and ELC groups. Patients in the ELC group had a significantly lower MCS than those in the SVS group before surgery (45.9 vs 50.8; P = .002; Mann-Whitney U test), but not after surgery. There was no difference between the two groups in terms of postoperative change in MCS. CONCLUSIONS: SVS is associated with a statistically significant and clinically meaningful improvement in generic HRQL that is similar to that observed after ELC. These novel data lend further support to the clinical benefit of SVS and will help health care purchasers make decisions regarding the prioritization of vascular and general surgical services.

Adult↗

PubMed1982

Effect of castration on the synthesis of seminal vesicle secretory protein IV in the rat.

The effects of castration on the synthesis (accumulation) of a major seminal vesicle secretory protein (SVS IV) were examined in young adult rats. In vitro incorporation of labeled amino acids into SVS IV by minced tissue was monitored by immunological methods. Castration resulted in a large decrease in the differential synthesis of SVS IV. A significant decrease in the relative incorporation of isotope into SVS IV was evident within 3 days of castration, and by 4 weeks relative incorporation dropped some 30-fold. These changes took place in the presence of a large generalized decline in protein synthesis so that incorporation into SVS IV on an organ basis decreased by over 200-fold. SVS IV messenger RNA levels were estimated by RNA excess solution hybridization using a cloned cDNA probe. Relative message levels declined after castration in harmony with the declines in SVS IV synthesis. SVS IV mRNA was decreased by a relative factor of approximately 20 and an absolute factor of approximately 200 in long-term (40-day) castrates. Accordingly, the seminal vesicle conforms to the general pattern of steroid regulated systems in which hormone withdrawal leads to differential decreases in the steady-state pool size for specific mRNAs. The seminal vesicle is unusual, however, in that a prolonged period is required for maximum differential effects to occur.

Animals↗

PubMed1995

The t-SNAREs syntaxin 1 and SNAP-25 are present on organelles that participate in synaptic vesicle recycling.

Syntaxin 1 and synaptosome-associated protein of 25 kD (SNAP-25) are neuronal plasmalemma proteins that appear to be essential for exocytosis of synaptic vesicles (SVs). Both proteins form a complex with synaptobrevin, an intrinsic membrane protein of SVs. This binding is thought to be responsible for vesicle docking and apparently precedes membrane fusion. According to the current concept, syntaxin 1 and SNAP-25 are members of larger protein families, collectively designated as target-SNAP receptors (t-SNAREs), whose specific localization to subcellular membranes define where transport vesicles bind and fuse. Here we demonstrate that major pools of syntaxin 1 and SNAP-25 recycle with SVs. Both proteins cofractionate with SVs and clathrin-coated vesicles upon subcellular fractionation. Using recombinant proteins as standards for quantitation, we found that syntaxin 1 and SNAP-25 each comprise approximately 3% of the total protein in highly purified SVs. Thus, both proteins are significant components of SVs although less abundant than synaptobrevin (8.7% of the total protein). Immunoisolation of vesicles using synaptophysin and syntaxin specific antibodies revealed that most SVs contain syntaxin 1. The widespread distribution of both syntaxin 1 and SNAP-25 on SVs was further confirmed by immunogold electron microscopy. Botulinum neurotoxin C1, a toxin that blocks exocytosis by proteolyzing syntaxin 1, preferentially cleaves vesicular syntaxin 1. We conclude that t-SNAREs participate in SV recycling in what may be functionally distinct forms.

Animals↗

PubMed2005

Significance of susceptibility vessel sign on T2*-weighted gradient echo imaging for identification of stroke subtypes.

BACKGROUND AND PURPOSE: In contrast to platelet-rich white thrombi, red thrombi in the heart are rich in fibrin and trapped erythrocytes. The magnetic susceptibility effect of deoxygenated hemoglobin in red thrombi may result in hypointense signals on T2*-weighted gradient echo imaging (GRE). We tested the hypothesis that a GRE susceptibility vessel sign (SVS) is specific for cardioembolic stroke. METHODS: This retrospective study examined data from acute ischemic stroke patients who underwent diffusion-weighted imaging, GRE and magnetic resonance angiography (MRA) within 24 hours of stroke onset and who had symptomatic occlusion of large intracranial arteries in the circle of Willis. Hypointense signals within vascular cisterns on GRE corresponding to symptomatic vascular occlusion were termed "GRE SVS." Recanalization was assessed on follow-up MRA performed within 7 days of onset. The relationships between GRE SVS and stroke subtypes and subsequent recanalization were explored. RESULTS: Of the 95 patients who met the inclusion criteria, GRE SVS was observed in 45 (47.4%). GRE SVS was more commonly associated with cardioembolic stroke patients (31 of 40, 77.5%) than with other stroke subtypes (14 of 55, 25.5%; P<0.001). In 66 patients who underwent follow-up MRA, GRE SVS was associated with subsequent recanalization (P<0.001). Multivariate analysis showed that GRE SVS was an independent predictor of cardioembolic stroke and subsequent recanalization (odds ratio, 10.75 and 4.26; 95% CI, 3.68 to 31.47 and 1.12 to 16.30). CONCLUSIONS: GRE SVS may predict cardioembolic stroke and subsequent recanalization. Identifying clot composition may be important in choosing the optimal treatment based on clot characteristics.

Adult↗

PubMed2004

Synaptic vesicles: test for a role in presynaptic calcium regulation.

Membrane-bound organelles such as mitochondria and the endoplasmic reticulum play an important role in neuronal Ca(2+) homeostasis. Synaptic vesicles (SVs), the organelles responsible for exocytosis of neurotransmitters, occupy more of the volume of presynaptic nerve terminals than any other organelle and, under some conditions, can accumulate Ca(2+). They are also closely associated with voltage-gated Ca(2+) channels (VGCCs) that trigger transmitter release by admitting Ca(2+) into the nerve terminal in response to action potentials (APs). We tested the hypothesis that SVs can modulate Ca(2+) signals in the presynaptic terminal. This has been a difficult question to address because neither pharmacological nor genetic approaches to block Ca(2+) permeation of the SV membrane have been available. To investigate the possible role of SVs in Ca(2+) regulation, we used imaging techniques to compare Ca(2+) dynamics in motor nerve terminals before and after depletion of SVs. We used the temperature-sensitive Drosophila dynamin mutant shibire, in which SVs can be eliminated by stimulation. There was no difference in the amplitude or time course of Ca(2+) responses during high-frequency trains of APs, or single APs, in individual presynaptic boutons before and after depletion of SVs. SVs have a limited role, if any, in the rapid sequestration of Ca(2+) within the neuronal cytosol or the synaptic microdomain. We also conclude that SVs are not important for regulation of synaptic VGCCs.

Action Potentials↗

PubMed2004

Parathyroid hormone venous sampling before reoperative surgery in renal hyperparathyroidism: comparison with noninvasive localization procedures and review of the literature.

OBJECTIVES: To analyze the predictive values of selective venous sampling (SVS) in our own experience and in a systematic meta-analysis of the international literature and to compare them with the results of noninvasive localization studies before reoperative parathyroid surgery. DATA SOURCES: Twenty-one consecutive patients with persistent or recurrent renal hyperparathyroidism underwent preoperative SVS and noninvasive imaging. These data were added to a systematic review of the literature on localization studies before reoperative surgery. The literature search included localization studies, recurrent hyperparathyroidism, and reoperation. STUDY SELECTION Prospective and retrospective studies that provided at least the true-positive rate of 1 procedure were included. Data from initial surgery, hyperfunctioning autografts, and case reports were excluded. DATA EXTRACTION: Thirty-one publications reported on SVS (n = 22), technetium Tc 99m sestamibi scintigraphy (n = 17), thallium-technetium scintigraphy (n = 11), ultrasonography (n = 18), magnetic resonance imaging (n = 12), and computed tomography (n = 13). The overall analysis was performed by dividing the overall number of true- and false-positive results by the total number of patients. DATA SYNTHESIS: Localization by SVS was correct in 20 of 21 patients. In 1 patient with 2 localizations, only 1 was predicted correctly. Therefore, the sensitivity of SVS was at least 90%, with no false-positive results. Overall true- and false-positive rates, respectively, in 31 studies were 71% and 9% for SVS, 69% and 7% for technetium Tc 99m sestamibi scintigraphy, 54% and 16% for magnetic resonance imaging, 55% and 15% for thallium-technetium scintigraphy, 50% and 18% for ultrasonography, and 45% and 14% for computed tomography. CONCLUSIONS: With its high sensitivity, SVS is the gold standard in patients with persistent or recurrent renal hyperparathyroidism and negative results of noninvasive localization procedures. The noninvasive procedure of choice is now technetium Tc 99m sestamibi scintigraphy, with high sensitivity and a low rate of false-positive results.

Adolescent↗

PubMed2005

Effect of superficial venous surgery on venous function in chronic venous insufficiency.

Patients with chronic venous insufficiency often have combined superficial and deep venous incompetence. The aims of this study were to determine the effects of superficial venous surgery (SVS) on deep venous haemodynamics and on ambulatory venous pressure (AVP) and to determine if the AVP tourniquet test can predict the effect of SVS. Of 119 legs, 42 legs (32 subjects) with chronic venous insufficiency, healed ulceration, or active ulceration and with combined superficial and deep incompetence underwent preoperative duplex imaging and AVP measurement followed by appropriate SVS. Four months later, all underwent postoperative duplex imaging and AVP measurement. The pressure relief index (PRI) was calculated from the AVP measurement as an overall assessment of venous function. Seventeen of 119 (14%) showed no tourniquet improvement in PRI and were therefore excluded from SVS. Of those suitable for SVS, median (range) age was 56 (32-78) years. Twenty-two limbs underwent long saphenous surgery, four limbs short saphenous surgery, and 16 limbs both, based on duplex findings. Segmental deep incompetence resolved in 11/21 (52%) limbs after surgery compared to 6/21 (29%) with multisegment incompetence. Median (range) PRI improved from 319 (4-1,600) preoperatively to 1,300 (360-2,670) postoperatively (p < 0.001, Wilcoxon). PRI with thigh tourniquet correlated with postoperative PRI (r = +0.828, p = 0.01, Spearman), as did calf tourniquet (r = +0.996, p = 0.004) and both tourniquets (r = 0.535, p = 0.046). The majority of patients with combined superficial and deep incompetence can be selected for SVS on the basis of AVP measurement with tourniquets. SVS can improve segmental deep incompetence and PRI in those properly selected.

Adult↗

PubMed2007

Oculomotor plasticity: are mechanisms of adaptation for reactive and voluntary saccades separate?

Saccadic eye movements are permanently controlled and their accuracy maintained by adaptive mechanisms that compensate for physiological or pathological perturbations. In contrast to the adaptation of reactive saccades (RS) which are automatically triggered by the sudden appearance of a single target, little is known about the adaptation of voluntary saccades which allow us to intentionally scan our environment in nearly all our daily activities. In this study, we addressed this issue in human subjects by determining the properties of adaptation of scanning voluntary saccades (SVS) and comparing these features to those of RS. We also tested the reciprocal transfers of adaptation between the two saccade types. Our results revealed that SVS and RS adaptations disclosed similar adaptation fields, time course and recovery levels, with only a slightly lower after-effect for SVS. Moreover, RS and SVS main sequences both remained unaffected after adaptation. Finally and quite unexpectedly, the pattern of adaptation transfers was asymmetrical, with a much stronger transfer from SVS to RS (79%) than in the reverse direction (22%). These data demonstrate that adaptations of RS and SVS share several behavioural properties but at the same time rely on partially distinct processes. Based on these findings, it is proposed that adaptations of RS and SVS may involve a neural network including both a common site and two separate sites specifically recruited for each saccade type.

Adaptation, Ocular↗

PubMed2006

Localization of hyperfunctioning parathyroid glands by selective venous sampling in reoperation for primary or secondary hyperparathyroidism.

BACKGROUND: Localization of hyperfunctioning parathyroid glands in patients with previous cervical operations is not always successful with noninvasive methods such as ultrasound, sestamibi scan, or magnetic resonance imaging. The aim of our study was to evaluate the results of selective venous sampling (SVS) of intact parathyroid hormone (PTH) in patients undergoing surgery for primary (75%) or secondary (25%) hyperparathyroidism (HPT). METHODS: Between January 2000 and January 2006, SVS for PTH was performed in 51 consecutive patients with persistent or recurrent HPT or patients with previous cervical explorations. The results of SVS were compared with those of noninvasive localization studies. RESULTS: Successful surgical treatment was achieved in 47 of 51 patients (92%). SVS had a sensitivity of 83.3% for the correct localization of a parathyroid adenoma (79.5%) or hyperplastic parathyroid glands (91.6%). False-positive or indeterminate results of SVS were found in 6% and 2%, respectively, of the patients. Ultrasound detected enlarged parathyroid glands with a sensitivity of 33.3%, and sestamibi scan with a sensitivity of 57.1%. CONCLUSIONS: Compared with noninvasive localization studies, SVS for PTH yielded the best results for recurrent or persistent HPT and for patients with previous neck explorations. SVS is strongly recommended in reoperative surgery for HPT with indeterminate results of noninvasive methods.

Adult↗

PubMed2001

Effects of ketamine in normal and schizophrenic volunteers.

This study evaluates the effects of ketamine on healthy and schizophrenic volunteers (SVs) in an effort to define the detailed behavioral effects of the drug in a psychosis model. We compared the effects of ketamine on normal and SVs to establish the comparability of their responses and the extent to which normal subjects might be used experimentally as a model. Eighteen normal volunteers (NVs) and 17 SVs participated in ketamine interviews. Some (n = 7 NVs; n = 9 SVs) had four sessions with a 0.1-0.5 mg/kg of ketamine and a placebo; others (n = 11 NVs; n = 8 SVs) had two sessions with one dose of ketamine (0.3 mg/kg) and a placebo. Experienced research clinicians used the BPRS to assess any change in mental status over time and documented the specifics in a timely way. In both volunteer groups, ketamine induced a dose-related, short (<30 min) increase in psychotic symptoms. The scores of NVs increased on both the Brief Psychiatric Rating Scale (BPRS) psychosis subscale (p =.0001) and the BPRS withdrawal subscale (p =.0001), whereas SVs experienced an increase only in positive symptoms (p =.0001). Seventy percent of the patients reported an increase (i.e., exacerbation) of previously experienced positive symptoms. Normal and schizophrenic groups differed only on the BPRS withdrawal score. The magnitude of ketamine-induced changes in positive symptoms was similar, although the psychosis baseline differed, and the dose-response profiles over time were superimposable across the two populations. The similarity between ketamine-induced symptoms in SVs and their own positive symptoms suggests that ketamine provides a unique model of psychosis in human volunteers. The data suggest that the phencyclidine (PCP) model of schizophrenia maybe a more valid human psychosis/schizophrenia drug model than the amphetamine model, with a broader range of psychotic symptoms. This study indicates that NVs could be used for many informative experimental psychosis studies involving ketamine interviews.

Adult↗

PubMed2006

MADD/DENN splice variant of the IG20 gene is necessary and sufficient for cancer cell survival.

The IG20 gene is overexpressed in human tumors and cancer cell lines, and encodes at least four splice variants (SVs) namely, IG20pa, MADD, IG20-SV2 and DENN-SV. Earlier, gain-of-function studies showed that IG20-SVs can exhibit diverse functions and play a critical role in cell proliferation and apoptosis. Expression of exogenous IG20pa or DENN-SV rendered cells either susceptible or resistant to induced apoptosis, respectively, whereas MADD and IG20-SV2 had no apparent effect. In order to understand the contrasting effects of the IG20-SVs in a physiologically more relevant system, we expressed exon-specific small hairpin RNAs (shRNAs) to selectively knockdown specific IG20-SVs. Consistent with an earlier study, knockdown of all IG20-SVs resulted in spontaneous apoptosis of HeLa and PA-1 cells. In addition, we unambiguously demonstrated that knockdown of MADD can render cells susceptible to spontaneous apoptosis but had no discernible effect on cell proliferation, colony size or cell cycle progression. Moreover, expression of MADD alone, and not DENN-SV, in the absence of endogenous IG20-SVs was sufficient to prevent spontaneous apoptosis. Our results show the utility of shRNAs for selective knockdown of particular IG20-SVs and their potential therapeutic value in cancer. Further, they demonstrate that MADD alone is sufficient and necessary for cancer cell survival.

Alternative Splicing↗

PubMed2002

Accuracy of selective venous sampling for intact parathyroid hormone in difficult patients with recurrent or persistent hyperparathyroidism.

BACKGROUND: Preoperative noninvasive localization studies of the neck and mediastinum are beneficial before reoperation. However, the role of selective venous sampling (SVS) for parathyroid hormone (PTH) in reoperative parathyroid surgery has never been clearly defined. The purpose of this study was to evaluate the accuracy of SVS when applied selectively to the subset of patients with indeterminate noninvasive localization studies. METHODS: Between January 1990 and December 2001, 64 of 235 (27%) patients with persistent or recurrent hyperparathyroidism were considered candidates for SVS in addition to noninvasive localization studies. Accuracy of SVS for PTH was retrospectively evaluated. RESULTS: Successful surgical treatment was achieved in 86% of these patients. SVS for PTH yielded true-positive results in 75% of patients and was not useful for the surgeon in 17% (completely false-positive in 12% and indeterminate in 5%). In 2% of patients, SVS identified successfully 1 gland but failed to locate another abnormal gland. In 6% of patients, the location of the abnormal parathyroid tissue remained unknown, and the patients have persistent hyperparathyroidism. CONCLUSIONS: We showed that SVS is clinically useful in patients with persistent or recurrent hyperparathyroidism when the noninvasive localization studies do not clearly localize the abnormal parathyroid glands.

Adolescent↗