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Showing papers by "Oregon Health & Science University published in 1998"


Journal ArticleDOI
TL;DR: The recent declines in morbidity and mortality due to AIDS are attributable to the use of more intensive antiretroviral therapies.
Abstract: Background and Methods National surveillance data show recent, marked reductions in morbidity and mortality associated with the acquired immunodeficiency syndrome (AIDS). To evaluate these declines, we analyzed data on 1255 patients, each of whom had at least one CD4+ count below 100 cells per cubic millimeter, who were seen at nine clinics specializing in the treatment of human immunodeficiency virus (HIV) infection in eight U.S. cities from January 1994 through June 1997. Results Mortality among the patients declined from 29.4 per 100 person-years in 1995 to 8.8 per 100 person-years in the second quarter of 1997. There were reductions in mortality regardless of sex, race, age, and risk factors for transmission of HIV. The incidence of any of three major opportunistic infections (Pneumocystis carinii pneumonia, Mycobacterium avium complex disease, and cytomegalovirus retinitis) declined from 21.9 per 100 person-years in 1994 to 3.7 per 100 person-years by mid-1997. In a failure-rate model, increases in t...

9,116 citations


Proceedings Article
26 Jan 1998
TL;DR: StackGuard is described: a simple compiler technique that virtually eliminates buffer overflow vulnerabilities with only modest performance penalties, and a set of variations on the technique that trade-off between penetration resistance and performance.
Abstract: This paper presents a systematic solution to the persistent problem of buffer overflow attacks. Buffer overflow attacks gained notoriety in 1988 as part of the Morris Worm incident on the Internet. While it is fairly simple to fix individual buffer overflow vulnerabilities, buffer overflow attacks continue to this day. Hundreds of attacks have been discovered, and while most of the obvious vulnerabilities have now been patched, more sophisticated buffer overflow attacks continue to emerge. We describe StackGuard: a simple compiler technique that virtually eliminates buffer overflow vulnerabilities with only modest performance penalties. Privileged programs that are recompiled with the StackGuard compiler extension no longer yield control to the attacker, but rather enter a fail-safe state. These programs require no source code changes at all, and are binary-compatible with existing operating systems and libraries. We describe the compiler technique (a simple patch to gcc), as well as a set of variations on the technique that trade-off between penetration resistance and performance. We present experimental results of both the penetration resistance and the performance impact of this technique.

1,536 citations


Journal ArticleDOI
TL;DR: It is concluded that CD4 and CCR5 directly or indirectly interact in a concentration-dependent manner within a pathway that is essential for infection by macrophagetropic HIV-1 and that the requirements for each are increased when the other component is present in a limiting amount.
Abstract: It has been proposed that changes in cell surface concentrations of coreceptors may control infections by human immunodeficiency virus type 1 (HIV-1), but the mechanisms of coreceptor function and the concentration dependencies of their activities are unknown. To study these issues and to generate stable clones of adherent cells able to efficiently titer diverse isolates of HIV-1, we generated two panels of HeLa-CD4/CCR5 cells in which individual clones express either large or small quantities of CD4 and distinct amounts of CCR5. The panels were made by transducing parental HeLa-CD4 cells with the retroviral vector SFF-CCR5. Derivative clones expressed a wide range of CCR5 quantities which were between 7.0 x 10(2) and 1.3 x 10(5) molecules/cell as measured by binding antibodies specific for CCR5 and the chemokine [125I]MIP1beta. CCR5 was mobile in the membranes, as indicated by antibody-induced patching. In cells with a large amount of CD4, an unexpectedly low trace of CCR5 (between 7 x 10(2) and 2.0 x 10(3) molecules/cell) was sufficient for maximal susceptibility to all tested HIV-1, including primary patient macrophagetropic and T-cell-tropic isolates. Indeed, the titers as indicated by immunoperoxidase staining of infected foci were as high as the tissue culture infectious doses measured in human peripheral blood mononuclear cells. In contrast, cells with a small amount of CD4 required a much larger quantity of CCR5 for maximal infection by macrophagetropic HIV-1 (ca. 1.0 x 10(4) to 2.0 x 10(4) molecules/cell). Cells that expressed low and high amounts of CD4 were infected with equal efficiencies when CCR5 concentrations were above threshold levels for maximal infection. Our results suggest that the concentrations of CD4 and CCR5 required for efficient infections by macrophagetropic HIV-1 are interdependent and that the requirements for each are increased when the other component is present in a limiting amount. We conclude that CD4 and CCR5 directly or indirectly interact in a concentration-dependent manner within a pathway that is essential for infection by macrophagetropic HIV-1. In addition, our results suggest that multivalent virus-receptor bonds and diffusion in the membrane contribute to HIV-1 infections.

1,222 citations


Journal ArticleDOI
TL;DR: The biophysical properties of SK channels demonstrate that kinetic differences between Apamin-sensitive and apamin-insensitive slow afterhyperpolarizations are not attributable to intrinsic gating differences between the two subtypes, and Interestingly, SK and IK channels may prove effective drug targets for diseases such as myotonic muscular dystrophy and sickle cell anemia.

996 citations


Journal ArticleDOI
TL;DR: This study explores the proposal that PTPs may be regulated by reversible reduction/oxidation involving cellular oxidants such as hydrogen peroxide (H2O2) and proposes a chemical mechanism for reversible inactivation involving a cysteine sulfenic acid intermediate.
Abstract: Protein tyrosine phosphatases (PTPs) catalyze the hydrolysis of phosphotyrosine from specific signal-transducing proteins. Although regulatory mechanisms for protein kinases have been described, no general mechanism for controlling PTPs has been demonstrated. Numerous reports have shown that cellular redox status plays an important role in tyrosine phosphorylation-dependent signal transduction pathways. This study explores the proposal that PTPs may be regulated by reversible reduction/oxidation involving cellular oxidants such as hydrogen peroxide (H2O2). Recent reports indicated that H2O2 is transiently generated during growth factor stimulation and that H2O2 production is concomitant with relevant tyrosine phosphorylation. By use of recombinant enzymes, the effects of H2O2 on three PTPs [PTP1, LAR (leukocyte antigen-related), and VHR (vaccinia H1-related)] and three distinct serine/threonine protein phosphatases (PPs: PP2Cα, calcineurin, and λ phosphatase) were determined. Hydrogen peroxide had no app...

937 citations


Journal ArticleDOI
TL;DR: Vagus nerve stimulation is an effective and safe adjunctive treatment for patients with refractory partial-onset seizures and represents the advent of a new, nonpharmacologic treatment for epilepsy.
Abstract: Objective: The purpose of this multicenter, add-on, double-blind, randomized, active-control study was to compare the efficacy and safety of presumably therapeutic (high) vagus nerve stimulation with less (low) stimulation. Background: Chronic intermittent left vagus nerve stimulation has been shown in animal models and in preliminary clinical trials to suppress the occurrence of seizures. Methods: Patients had at least six partial-onset seizures over 30 days involving complex partial or secondarily generalized seizures. Concurrent antiepileptic drugs were unaltered. After a 3-month baseline, patients were surgically implanted with stimulating leads coiled around the left vagus nerve and connected to an infraclavicular subcutaneous programmable pacemaker-like generator. After randomization, device initiation, and a 2-week ramp-up period, patients were assessed for seizure counts and safety over 3 months. The primary efficacy variable was the percentage change in total seizure frequency compared with baseline. Results: Patients receiving high stimulation (94 patients, ages 13 to 54 years) had an average 28% reduction in total seizure frequency compared with a 15% reduction in the low stimulation group (102 patients, ages 15 to 60 year; p = 0.04). The high-stimulation group also had greater improvements on global evaluation scores, as rated by a blinded interviewer and the patient. High stimulation was associated with more voice alteration and dyspnea. No changes in physiologic indicators of gastric, cardiac, or pulmonary functions occurred. Conclusions: Vagus nerve stimulation is an effective and safe adjunctive treatment for patients with refractory partial-onset seizures. It represents the advent of a new, nonpharmacologic treatment for epilepsy.

910 citations


Journal ArticleDOI
09 Apr 1998-Nature
TL;DR: It is proposed that the activation of Rap1 by C3G represents a common mechanism to induce sustained activation of the MAP kinase cascade in cells that express B-Raf.
Abstract: Activation of mitogen-activated protein (MAP) kinase (also known as extracellular-signal-regulated kinase, or ERK)1 by growth factors can trigger either cell growth or differentiation. The intracellular signals that couple growth factors to MAP kinase may determine the different effects of growth factors: for example, transient activation of MAP kinase by epidermal growth factor stimulates proliferation of PC12 cells1, whereas they differentiate in response to nerve growth factor, which acts partly by inducing a sustained activation of MAP kinase1. Here we show that activation of MAP kinase by nerve growth factor involves two distinct pathways: the initial activation of MAP kinase requires the small G protein Ras, but its activation is sustained by the small G protein Rap1. Rap1 is activated by CRK adaptor proteins and the guanine-nucleotide-exchange factor C3G, and forms a stable complex with B-Raf, an activator of MAP kinase. Rap1 is required for at least two indices of neuronal differentiation by nerve growth factor: electrical excitability and the induction of neuron-specific genes. We propose that the activation of Rap1 by C3G represents a common mechanism to induce sustained activation of the MAP kinase cascade in cells that express B-Raf.

878 citations


Journal ArticleDOI
01 Oct 1998-Neuron
TL;DR: It is reported that extracellular signal-related protein kinase (ERK) signaling is obligatory for Ca2+-stimulated transcription in PC12 cells and hippocampal neurons and suggests that the activation of CREB by ERK plays a critical role in the formation of long lasting neuronal plasticity.

878 citations


Journal ArticleDOI
01 Oct 1998-Nature
TL;DR: The mechanism of calcium gating is studied and it is found that small-conductance calcium-activated potassium channels are not gated by calcium binding directly to the channel α-subunits, instead, the functional SK channels are heteromeric complexes with calmodulin, which is constitutively associated with the α- subunits in a calcium-independent manner.
Abstract: The slow afterhyperpolarization that follows an action potential is generated by the activation of small-conductance calcium-activated potassium channels (SK channels) The slow afterhyperpolarization limits the firing frequency of repetitive action potentials (spike-frequency adaptation) and is essential for normal neurotransmission SK channels are voltage-independent and activated by submicromolar concentrations of intracellular calcium They are high-affinity calcium sensors that transduce fluctuations in intracellular calcium concentrations into changes in membrane potential Here we study the mechanism of calcium gating and find that SK channels are not gated by calcium binding directly to the channel alpha-subunits Instead, the functional SK channels are heteromeric complexes with calmodulin, which is constitutively associated with the alpha-subunits in a calcium-independent manner Our data support a model in which calcium gating of SK channels is mediated by binding of calcium to calmodulin and subsequent conformational alterations in the channel protein

852 citations


Journal ArticleDOI
TL;DR: The addition of flutamide to bilateral orchiectomy does not result in a clinically meaningful improvement in survival among patients with metastatic prostate cancer.
Abstract: Background Combined androgen blockade for the treatment of metastatic prostate cancer consists of an antiandrogen drug plus castration. In a previous trial, we found that adding the antiandrogen flutamide to leuprolide acetate (a synthetic gonadotropin-releasing hormone that results in medical ablation of testicular function) significantly improved survival as compared with that achieved with placebo plus leuprolide acetate. In the current trial, we compared flutamide plus bilateral orchiectomy with placebo plus orchiectomy. Methods We randomly assigned patients who had never received antiandrogen therapy and who had distant metastases from adenocarcinoma of the prostate to treatment with bilateral orchiectomy and either flutamide or placebo. Patients were stratified according to the extent of disease and according to performance status. Results Of the 1387 patients who were enrolled in the trial, 700 were randomly assigned to the flutamide group and 687 to the placebo group. Overall, the incidence of tox...

819 citations


Journal ArticleDOI
TL;DR: Silymarin and its active constituent, silybin, have been reported to work as antioxidants scavenging free radicals and inhibiting lipid peroxidation, and to protect against genomic injury and stabilize mast cells, chelate iron, and slow calcium metabolism.

Proceedings ArticleDOI
12 May 1998
TL;DR: A new voice conversion algorithm that modifies a source speaker's speech to sound as if produced by a target speaker is presented and is found to perform more reliably for small training sets than a previous approach.
Abstract: A new voice conversion algorithm that modifies a source speaker's speech to sound as if produced by a target speaker is presented. It is applied to a residual-excited LPC text-to-speech diphone synthesizer. Spectral parameters are mapped using a locally linear transformation based on Gaussian mixture models whose parameters are trained by joint density estimation. The LPC residuals are adjusted to match the target speakers average pitch. To study effects of the amount of training on performance, data sets of varying sizes are created by automatically selecting subsets of all available diphones by a vector quantization method. In an objective evaluation, the proposed method is found to perform more reliably for small training sets than a previous approach. In perceptual tests, it was shown that nearly optimal spectral conversion performance was achieved, even with a small amount of training data. However, speech quality improved with increases in the training set size.

Journal ArticleDOI
TL;DR: The prospective findings add uncertainty to conclusions derived mostly from cross-sectional studies that tHcy is a major, independent, causative risk factor for CHD and point more strongly to the possibility that vitamin B6 offers independent protection.
Abstract: Background—Elevated plasma total homocysteine (tHcy), low B-vitamin intake, and genetic polymorphisms related to tHcy metabolism may play roles in coronary heart disease (CHD). More prospective studies are needed. Methods and Results—We used a prospective case-cohort design to determine whether tHcy-related factors are associated with incidence of CHD over an average of 3.3 years of follow-up in a biracial sample of middle-aged men and women. Age-, race-, and field center–adjusted CHD incidence was associated positively (P<0.05) with tHcy in women but not men, and CHD was associated negatively (P<0.05) with plasma folate (women only), plasma pyridoxal 5′-phosphate (both sexes), and vitamin supplementation (women only). However, after accounting for other risk factors, only plasma pyridoxal 5′-phosphate was associated with CHD incidence; the relative risk for the highest versus lowest quintile of pyridoxal 5′-phosphate was 0.28 (95% CI=0.1 to 0.7). There was no association of CHD with the C677T mutation of...

Journal ArticleDOI
TL;DR: Cerebrospinal fluid shunt failure, predominantly from shunt obstruction and infection, remains a persistent problem in pediatric hydrocephalus.
Abstract: Objective Forty percent of standard cerebrospinal fluid shunts implanted for the treatment of pediatric hydrocephalus fail within the first year. Two new shunt valves designed to limit excess flow, particularly in upright positions, were studied to compare treatment failure rates with those for standard differential-pressure valves. Methods Three hundred-forty-four hydrocephalic children (age, birth to 18 yr) undergoing their first cerebrospinal fluid shunt insertion were randomized at 12 North American or European pediatric neurosurgical centers. Patients received one of three valves, i.e., a standard differential-pressure valve; a Delta valve (Medtronic PS Medical, Goleta, CA), which contains a siphon-control component designed to reduce siphoning in upright positions; or an Orbis-Sigma valve (Cordis, Miami, FL), with a variable-resistance, flow-limiting component. Patients were monitored for a minimum of 1 year. Endpoints were defined as shunt failure resulting from shunt obstruction, overdrainage, loculations of the cerebral ventricles, or infection. Outcome events were assessed by blinded independent case review. Results One hundred-fifty patients reached an endpoint; shunt obstruction occurred in 108 (31.4%), overdrainage in 12 (3.5%), loculated ventricles in 2 (0.6%), and infection in 28 (8.1%). Sixty-one percent were shunt failure-free at 1 year and 47% at 2 years, with a median shunt failure-free duration of 656 days. There was no difference in shunt failure-free duration among the three valves (P = 0.24). Conclusion Cerebrospinal fluid shunt failure, predominantly from shunt obstruction and infection, remains a persistent problem in pediatric hydrocephalus. Two new valve designs did not significantly affect shunt failure rates.

Journal ArticleDOI
10 Dec 1998-Nature
TL;DR: A Ca2+/calmodulin-dependent protein kinase kinase (CaM-KK) activates PKB directly, resulting in phosphorylation of BAD on serine residue 136 and the interaction of BAD with protein 14-3-3, which protects cells from apoptosis.
Abstract: The protection against apoptosis provided by growth factors in several cell lines is due to stimulation of the phosphatidylinositol-3-OH kinase (PI(3)K) pathway, which results in activation of protein kinase B (PKB; also known as c-Akt and Rac) and phosphorylation and sequestration to protein 14-3-3 of the proapoptotic Bcl-2-family member BAD. A modest increase in intracellular Ca2+ concentration also promotes survival of some cultured neurons through a pathway that requires calmodulin but is independent of PI(3)K and the MAP kinases. Here we report that Ca2+/calmodulin-dependent protein kinase kinase (CaM-KK) activates PKB directly, resulting in phosphorylation of BAD on serine residue 136 and the interaction of BAD with protein 14-3-3. Serum withdrawal induced a three- to fourfold increase in cell death of NG108 neuroblastoma cells, and this apoptosis was largely blocked by increasing the intracellular Ca2+ concentration with NMDA (N-methyl-D-aspartate) or KCl or by transfection with constitutively active CaM-KK. The effect of NMDA on cell survival was blocked by transfection with dominant-negative forms of CaM-KK or PKB. These results identify a Ca2+-triggered signalling cascade in which CaM-KK activates PKB, which in turn phosphorylates BAD and protects cells from apoptosis.

Journal ArticleDOI
TL;DR: Long-term aging in water caused a reduction in the KIc, independent of composition, but had little effect on other properties, suggesting limited degradation of composites in water.
Abstract: The purpose of this study was to evaluate the long-term effect of aging in water on the physical properties of experimental composites having systematically controlled differences in degree of conversion (DC), filler volume fraction (Vf), and percentage of silane-treated fillers. Composites were made with a 50% Bis-GMA:50% TEGDMA light-cured resin and a 1-2 microm (average size) strontium glass filler (+ 5 wt% SiO2 microfiller). For composites A-E, the DC was varied from 56-66% by changing the curing time; for D and F-I, the Vf was varied from 28-62 vol%; and for D and J-M, the percent of fillers with a silane coupling agent (gamma-MPS) was varied from 20-100%. Fracture toughness (KIc), flexure strength (FS), elastic modulus (E), and hardness (KHN) were tested after soaking in water at 37 degrees C for 1 day, 6 months, 1 year, and 2 years. The KIc was reduced 20-30% for all composites after 6 months, with minimal changes thereafter. The FS was reduced for several composites at 6 months, but only those with poor cure (A and B) were lower at 2 years than they were initially. The E was not reduced for most composites. Hardness was reduced for most composites after 6 months, but many returned to their original levels at 2 years. Long-term aging in water caused a reduction in the KIc, independent of composition, but had little effect on other properties, suggesting limited degradation of composites in water.

Journal ArticleDOI
TL;DR: Improving delivery of agents to the brain will play a major role in the therapeutic outcome of brain neoplasms and manipulation of the BBB also may be important in the treatment of central nervous system genetic disorders.
Abstract: Objective This article reviews historical aspects of the blood-brain barrier (BBB) and recent advances in mechanisms to deliver therapeutic agents across the BBB for the treatment of intracerebral tumors and other neurological diseases. Methods The development of the osmotic BBB disruption procedure as a clinically useful technique is described. Osmotic BBB disruption is contrasted with alternative methods for opening or bypassing the BBB, including pharmacological modification of the BBB with bradykinin and direct intracerebral infusion. Results Laboratory studies have played a fundamental role in advancing our understanding of the BBB and delivery of agents to brain. Preclinical animal studies will continue to serve an integral function in our efforts to improve the diagnosis and treatment of a number of neurological disorders. Techniques involving the modification of the BBB and/or blood-tumor barrier to increase delivery of therapeutic agents have been advanced to clinical trials in patients with brain tumors with very favorable results. Conclusion Improving delivery of agents to the brain will play a major role in the therapeutic outcome of brain neoplasms. As techniques for gene therapy are advanced, manipulation of the BBB also may be important in the treatment of central nervous system genetic disorders.

Journal ArticleDOI
TL;DR: Substitution of MMF for azathioprine may reduce mortality and rejection in the first year after cardiac transplantation.
Abstract: BACKGROUND After heart transplantation, 1-year and 5-year survival rates are 79% and 63%, respectively, with rejection, infection, and allograft coronary artery disease accounting for the majority of deaths. Mycophenolate mofetil (MMF), an inhibitor of the de novo pathway for purine biosynthesis, decreases rejection in animals and in human renal transplantation. METHODS In a double-blind, active-controlled trial, 28 centers randomized 650 patients undergoing their first heart transplant to receive MMF (3000 mg/day) or azathioprine (1.5-3 mg/kg/day), in addition to cyclosporine and corticosteroids. Rejection and survival data were obtained for 6 and 12 months, respectively. Because 11% of the patients withdrew before receiving study drug, data were analyzed on all randomized patients (enrolled patients) and on patients who received study medications (treated patients). RESULTS Survival and rejection were similar in enrolled patients (MMF, n=327; azathioprine, n=323). In treated patients (MMF, n=289; azathioprine, n=289), the MMF group compared with the azathioprine group was associated with significant reduction in mortality at 1 year (18 [6.2%] versus 33 deaths [11.4%]; P=0.031) and a significant reduction in the requirement for rejection treatment (65.7% versus 73.7%; P=0.026). There was a trend for fewer MMF patients to have > or = grade 3A rejection (45.0% versus 52.9%; P=0.055) or require the murine monoclonal anti-CD3 antibody or antithymocyte globulin (15.2% versus 21.1%; P=0.061). Opportunistic infections, mostly herpes simplex, were more common in the MMF group (53.3% versus 43.6%; P=0.025). CONCLUSIONS Substitution of MMF for azathioprine may reduce mortality and rejection in the first year after cardiac transplantation.

Journal ArticleDOI
29 Oct 1998-Nature
TL;DR: In this article, the authors study channel activity in cell-attached patches from hippocampal neurons and report a unique specificity of coupling between voltage-gated calcium channels and potassium channels.
Abstract: Calcium entry through voltage-gated calcium channels can activate either large- (BK) or small- (SK) conductance calcium-activated potassium channels. In hippocampal neurons, activation of BK channels underlies the falling phase of an action potential and generation of the fast afterhyperpolarization (AHP). In contrast, SK channel activation underlies generation of the slow AHP after a burst of action potentials. The source of calcium for BK channel activation is unknown, but the slow AHP is blocked by dihydropyridine antagonists, indicating that L-type calcium channels provide the calcium for activation of SK channels. It is not understood how this specialized coupling between calcium and potassium channels is achieved. Here we study channel activity in cell-attached patches from hippocampal neurons and report a unique specificity of coupling. L-type channels activate SK channels only, without activating BK channels present in the same patch. The delay between the opening of L-type channels and SK channels indicates that these channels are 50-150 nm apart. In contrast, N-type calcium channels activate BK channels only, with opening of the two channel types being nearly coincident. This temporal association indicates that N and BK channels are very close. Finally, P/Q-type calcium channels do not couple to either SK or BK channels. These data indicate an absolute segregation of coupling between channels, and illustrate the functional importance of submembrane calcium microdomains.

Journal ArticleDOI
TL;DR: The risk of late sudden death for patients surviving operation for common congenital heart defects is 25 to 100 times greater than an age-matched control population.

Journal ArticleDOI
TL;DR: There is a small but significant effect of 3- to 6-month treatment with 120 to 240 mg of G. biloba extract on objective measures of cognitive function in patients with Alzheimer disease.
Abstract: Objective To determine the effect of treatment with Ginkgo biloba extract on objective measures of cognitive function in patients with Alzheimer disease (AD) based on formal review of the current literature. Methods An attempt was made to identify all English and non–English-language articles in which G biloba extract was given to subjects with dementia or cognitive impairment. Inclusion criteria for the meta-analysis were (1) sufficiently characterized patients such that it was clearly stated there was a diagnosis of AD by either Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition , or National Institute of Neurological Disorders and Stroke–Alzheimer's Disease and Related Disorders Association criteria, or there was enough clinical detail to determine this by our review; (2) clearly stated study exclusion criteria, ie, those studies that did not have stated exclusions for depression, other neurologic disease, and central nervous system–active medications were excluded; (3) use of standardized ginkgo extract in any stated dose; (4) randomized, placebo-controlled and double-blind study design; (5) at least 1 outcome measure was an objective assessment of cognitive function; and (6) sufficient statistical information to allow for meta-analysis. Results Of more than 50 articles identified, the overwhelming majority did not meet inclusion criteria, primarily because of lack of clear diagnoses of dementia and AD. Only 4 studies met all inclusion criteria. In total there were 212 subjects in each of the placebo and ginkgo treatment groups. Overall there was a significant effect size of 0.40 ( P Conclusions Based on a quantitative analysis of the literature there is a small but significant effect of 3- to 6-month treatment with 120 to 240 mg of G biloba extract on objective measures of cognitive function in AD. The drug has not had significant adverse effects in formal clinical trials but there are 2 case reports of bleeding complications. In AD, there are limited and inconsistent data that preclude determining if there are effects on noncognitive behavioral and functional measures as well as on clinician's global rating scales. Further research in the area will need to determine if there are functional improvements and to determine the best dosage. Additional research will be needed to define which ingredients in the ginkgo extract are producing its effect in individuals with AD.

Journal ArticleDOI
TL;DR: In this paper, two missense mutations in exon 10 of the tau gene that segregate with disease, Asn279(Lys) in the Pallido-ponto-nigral degeneration (PPND) kindred and Pro301(Leu) in four other FTDP-17 kindred were found.
Abstract: Pallido-ponto-nigral degeneration (PPND) is one of the most well characterized familial neurodegenerative disorders linked to chromosome 17q21-22. These hereditary disorders are known collectively as frontotemporal dementia (FTD) and parkinsonism linked to chromosome 17 (FTDP-17). Although the clinical features and associated regional variations in the neuronal loss observed in different FTDP-17 kindreds are diverse, the diagnostic lesions of FTDP-17 brains are tau-rich filaments in the cytoplasm of specific subpopulations of neurons and glial cells. The microtubule associated protein (tau) gene is located on chromosome 17q21-22. For these reasons, we investigated the possibility that PPND and other FTDP-17 syndromes might be caused by mutations in the tau gene. Two missense mutations in exon 10 of the tau gene that segregate with disease, Asn279(Lys) in the PPND kindred and Pro301(Leu) in four other FTDP-17 kindreds, were found. A third mutation was found in the intron adjacent to the 3' splice site of exon 10 in patients from another FTDP-17 family. Transcripts that contain exon 10 encode tau isoforms with four microtubule (MT)-binding repeats (4Rtau) as opposed to tau isoforms with three MT-binding repeats (3Rtau). The insoluble tau aggregates isolated from brains of patients with each mutation were analyzed by immunoblotting using tau-specific antibodies. For each of three mutations, abnormal tau with an apparent Mr of 64 and 69 was observed. The dephosphorylated material comigrated with tau isoforms containing exon 10 having four MT-binding repeats but not with 3Rtau. Thus, the brains of patients with both the missense mutations and the splice junction mutation contain aggregates of insoluble 4Rtau in filamentous inclusions, which may lead to neurodegeneration.

Journal ArticleDOI
TL;DR: Combined analysis of CSF Abeta42 and tau levels discriminated patients with AD, including patients with mild dementia, from the NC group, supporting use of these proteins to identify AD and to distinguish early AD from aging.
Abstract: Objective To evaluate cerebrospinal fluid (CSF) levels of amyloid β protein ending at amino acid 42 (Aβ42) and tau as markers for Alzheimer disease (AD) and to determine whether clinical variables influence these levels. Design Cohort study. Setting Six academic research centers with expertise in dementia. Subjects Eighty-two patients with probable AD, including 24 with very mild dementia (Mini-Mental State Examination score >23/30) (AD group); 60 cognitively normal elderly control subjects (NC group); and 74 subjects with neurological disorders, including dementia (ND group). Main Outcome Measures Levels of Aβ42 and tau were compared among AD, NC, and ND groups. Relationships of age, sex, Mini-Mental State Examination score, and apolipoprotein E (Apo E) genotype with these levels were examined using multiple linear regression. Classification tree models were developed to optimize distinguishing AD from NC groups. Results Levels of Αβ42 were significantly lower, and levels of tau were significantly higher, in the AD group than in the NC or ND group. In the AD group, Αβ42 level was inversely associated with Apo E ϵ 4 allele dose and weakly related to Mini-Mental State Examination score; tau level was associated with male sex and 1 Apo E ϵ 4 allele. Classification tree analysis, comparing the AD and NC subjects, was 90% sensitive and 80% specific. With specificity set at greater than 90%, the tree was 77% sensitive for AD. This tree classified 26 of 74 members of the ND group as having AD. They had diagnoses difficult to distinguish from AD clinically and a high Apo E ϵ 4 allele frequency. Markers in CSF were used to correctly classify 12 of 13 patients who later underwent autopsy, including 1 with AD not diagnosed clinically. Conclusions Levels of CSF Αβ42 decrease and levels of CSF tau increase in AD. Apolipoprotein E ϵ 4 had a dose-dependent relationship with CSF levels of Αβ42, but not tau. Other covariates influenced CSF markers minimally. Combined analysis of CSF Αβ42 and tau levels discriminated patients with AD, including patients with mild dementia, from the NC group, supporting use of these proteins to identify AD and to distinguish early AD from aging. In subjects in the ND group with an AD CSF profile, autopsy follow-up will be required to decide whether CSF results are false positive, or whether AD is a primary or concomitant cause of dementia.

Journal ArticleDOI
TL;DR: It is concluded that D2R-deficient mice are not a model of Parkinson’s disease and the interaction of multiple genetic factors in the analysis of complex behaviors in gene knock-out mice is highlighted.
Abstract: Locomotor activity is a polygenic trait that varies widely among inbred strains of mice (). To characterize the role of D2 dopamine receptors in locomotion, we generated F2 hybrid (129/Sv x C57BL/6) D2 dopamine receptor (D2R)-deficient mice by gene targeting and investigated the contribution of genetic background to open-field activity and rotarod performance. Horizontal activity of D2R-/- mice was approximately half that of drug-naive, strain-matched controls but was significantly greater than haloperidol-treated controls, which were markedly hypokinetic. Wild-type 129/SvEv and C57BL/6 mice with functional D2 receptors had greater interstrain differences in spontaneous activity than those among the F2 hybrid mutants. Incipient congenic strains of D2R-deficient mice demonstrated an orderly gene dosage reduction in locomotion superimposed on both extremes of parental background locomotor activity. In contrast, F2 hybrid D2R-/- mice had impaired motor coordination on the rotarod that was corrected in the congenic C57BL/6 background. Wild-type 129/SvEv mice had the poorest rotarod ability of all groups tested, suggesting that linked substrain 129 alleles, not the absence of D2 receptors per se, were largely responsible for the reduced function of the F2 hybrid D2R-/- and D2R+/- mice. Neurochemical and pharmacological studies revealed unexpectedly normal tissue striatal monoamine levels and no evidence for supersensitive D1, D3, or D4 dopamine receptors in the D2R-/- mice. However, after acute monoamine depletion, akinetic D2R+/- mice had a significantly greater synergistic restoration of locomotion in response to SKF38393 and quinpirole compared with any group of D2R+/+ controls. We conclude that D2R-deficient mice are not a model of Parkinson's disease. Our studies highlight the interaction of multiple genetic factors in the analysis of complex behaviors in gene knock-out mice.

Journal ArticleDOI
TL;DR: By sequencing the coding regions of CRYAA, it is found that a missense mutation, R116C, is associated with ADCC in this family of congenital cataracts, and an ADCC gene in family ADCC-2 is mapped to chromosome 21q22.3 near the alpha-crystallin geneCRYAA.
Abstract: Congenital cataracts are a common major abnormality of the eye that frequently cause blindness in infants. At least a third of all cases are familial; autosomal dominant congenital cataract (ADCC) appears to be the most common familial form in the Western world. We have mapped an ADCC gene in family ADCC-2 to chromosome 21q22.3 near the alpha-crystallin gene CRYAA. By sequencing the coding regions of CRYAA, we found that a missense mutation, R116C, is associated with ADCC in this family.

Journal ArticleDOI
TL;DR: Cereal fortified with folic acid has the potential to increase plasma folic Acid levels and reduce plasma homocyst(e)ine levels, and further clinical trials are required to determine whether folicacid fortification may prevent vascular disease.
Abstract: Background The Food and Drug Administration (FDA) has recommended that cereal-grain products be fortified with folic acid to prevent congenital neural-tube defects. Since folic acid supplementation reduces levels of plasma homocyst(e)ine, or plasma total homocysteine, which are frequently elevated in arterial occlusive disease, we hypothesized that folic acid fortification might reduce plasma homocyst(e)ine levels. Methods To test this hypothesis, we assessed the effects of breakfast cereals fortified with three levels of folic acid, and also containing the recommended dietary allowances of vitamins B6 and B12, in a randomized, double-blind, placebo-controlled, crossover trial in 75 men and women with coronary artery disease. Results Plasma folic acid increased and plasma homocyst(e)ine decreased proportionately with the folic acid content of the breakfast cereal. Cereal providing 127 μg of folic acid daily, approximating the increased daily intake that may result from the FDA's enrichment policy, increas...

Journal ArticleDOI
TL;DR: The data reveal that LMP1, without the expression of other EBV genes, is oncogenic in vivo and indicate that L MP1 is a major contributing factor to the development of EBV-associated lymphomas.
Abstract: The latent membrane protein 1 (LMP1) of the Epstein–Barr virus has transforming properties in rodent fibroblasts and is expressed in most of the cancers associated with Epstein–Barr virus (EBV) infection including posttransplant lymphomas, Hodgkin’s disease, nasopharyngeal carcinoma, and AIDS-related lymphomas. In this study, three lineages of LMP1 transgenic mice were established with LMP1 expressed under the control of the Ig heavy chain promoter and enhancer. Lymphoma developed in all three lineages, and the incidence of lymphoma increased significantly with age with lymphomas developing in 42% of transgenic mice over 18 months. The expression of LMP1 was detected at high levels in the lymphoma tissues but only at trace levels in normal lymphoid tissues. Gene rearrangement of the Ig heavy chain indicated monoclonality or oligoclonality in all lymphomas, some of the lymphoid hyperplastic spleens, and some histologically normal spleens. These data reveal that LMP1, without the expression of other EBV genes, is oncogenic in vivo and indicate that LMP1 is a major contributing factor to the development of EBV-associated lymphomas.

Journal ArticleDOI
TL;DR: It is shown that in two instances, regulation of phosphatase activity employs autoinhibitory mechanisms involving either intermolecular or intramolecular interactions, whereby inhibition is mediated by sterically blocking the active-site cleft.

Journal ArticleDOI
TL;DR: It is demonstrated that the cDNA that is identified encodes the human sterol Delta7-reductase and that mutations in DHCR7 are responsible for at least some cases of SLOS.
Abstract: Summary The Smith-Lemli-Opitz syndrome (SLOS; also known as “RSH syndrome” [MIM 270400]) is an autosomal recessive multiple malformation syndrome due to a defect in cholesterol biosynthesis. Children with SLOS have elevated serum 7-dehydrocholesterol (7-DHC) levels and typically have low serum cholesterol levels. On the basis of this biochemical abnormality, it has been proposed that mutations in the human sterol D 7 -reductase (7-DHC reductase; E.C.1.3.1.21) gene cause SLOS. However, one could also propose a defect in a gene that encodes a protein necessary for either the expression or normal function of sterol D 7 -reductase. We cloned cDNA encoding a human sterol D 7 -reductase (DHCR7) on the basis of its homology with the sterol D 7 -reductase from Arabidopsis thaliana, and we confirmed the enzymatic function of the human gene product by expression in SLOS fibroblasts. SLOS fibroblasts transfected with human sterol D 7 -reductase cDNA showed a significant reduction in 7-DHC levels, compared with those in SLOS fibroblasts transfected with the vector alone. Using radiation-hybrid mapping, we show that the DHCR7 gene is encoded at chromosome 11q12-13. To establish that defects in this gene cause SLOS, we sequenced cDNA clones from SLOS patients. In three unrelated patients we have identified four different mutant alleles. Our results demonstrate both that the cDNA that we have identified encodes the human sterol D 7 -reductase and that

Journal ArticleDOI
24 Jul 1998-Cell
TL;DR: The role of one member of a novel gene family, PACS-1, in the localization of trans-Golgi network (TGN) membrane proteins and a mechanism by which membrane proteins in mammalian cells are localized to the TGN are reported.