Showing papers by "University of California, San Francisco published in 1999"
TL;DR: This report hopes this report will generate further thought about ways to improve the quality of reports of meta-analyses of RCTs and that interested readers, reviewers, researchers, and editors will use the QUOROM statement and generate ideas for its improvement.
4,767 citations
TL;DR: How the new classification for periodontal diseases and conditions presented in this volume differs from the classification system developed at the 1989 World Workshop in Clinical Periodontics is summarized.
Abstract: Classification systems are necessary in order to provide a framework in which to scientifically study the etiology, pathogenesis, and treatment of diseases in an orderly fashion. In addition, such systems give clinicians a way to organize the health care needs of their patients. The last time scientists and clinicians in the field of periodontology and related areas agreed upon a classi- fication system for periodontal diseases was in 1989 at the World Workshop in Clinical Periodontics.1 Subsequently, a simpler classification was agreed upon at the 1st European Workshop in Periodontology.2 These classification systems have been widely used by clinicians and research scientists throughout the world. Unfortunately, the 1989 classification had many shortcomings including: 1) considerable overlap in disease categories, 2) absence of a gingival disease component, 3) inappropriate emphasis on age of onset of disease and rates of progression, and 4) inadequate or unclear classification criteria. The 1993 Europea...
4,653 citations
TL;DR: General principles that govern the structure and behaviour of modules may be discovered with help from synthetic sciences such as engineering and computer science, from stronger interactions between experiment and theory in cell biology, and from an appreciation of evolutionary constraints.
Abstract: Cellular functions, such as signal transmission, are carried out by 'modules' made up of many species of interacting molecules Understanding how modules work has depended on combining phenomenological analysis with molecular studies General principles that govern the structure and behaviour of modules may be discovered with help from synthetic sciences such as engineering and computer science, from stronger interactions between experiment and theory in cell biology, and from an appreciation of evolutionary constraints
3,604 citations
TL;DR: It is shown that β-catenin activates transcription from the cyclin D1 promoter, and that sequences within the promoter that are related to consensus TCF/LEF-binding sites are necessary for activation.
Abstract: Mutations in the adenomatous polyposis coli (APC) tumour-suppressor gene occur in most human colon cancers. Loss of functional APC protein results in the accumulation of beta-catenin. Mutant forms of beta-catenin have been discovered in colon cancers that retain wild-type APC genes, and also in melanomas, medulloblastomas, prostate cancer and gastric and hepatocellular carcinomas. The accumulation of beta-catenin activates genes that are responsive to transcription factors of the TCF/LEF family, with which beta-catenin interacts. Here we show that beta-catenin activates transcription from the cyclin D1 promoter, and that sequences within the promoter that are related to consensus TCF/LEF-binding sites are necessary for activation. The oncoprotein p21ras further activates transcription of the cyclin D1 gene, through sites within the promoter that bind the transcriptional regulators Ets or CREB. Cells expressing mutant beta-catenin produce high levels of cyclin D1 messenger RNA and protein constitutively. Furthermore, expression of a dominant-negative form of TCF in colon-cancer cells strongly inhibits expression of cyclin D1 without affecting expression of cyclin D2, cyclin E, or cyclin-dependent kinases 2, 4 or 6. This dominant-negative TCF causes cells to arrest in the G1 phase of the cell cycle; this phenotype can be rescued by expression of cyclin D1 under the cytomegalovirus promoter. Abnormal levels of beta-catenin may therefore contribute to neoplastic transformation by causing accumulation of cyclin D1.
3,500 citations
TL;DR: In stable patients undergoing nonurgent major noncardiac surgery, this index can identify patients at higher risk for complications and may be useful for identification of candidates for further risk stratification with noninvasive technologies or other management strategies.
Abstract: Background Cardiac complications are important causes of morbidity after noncardiac surgery. The purpose of this prospective cohort study was to develop and validate an index for risk of cardiac complications. Methods and results We studied 4315 patients aged > or = 50 years undergoing elective major noncardiac procedures in a tertiary-care teaching hospital. The main outcome measures were major cardiac complications. Major cardiac complications occurred in 56 (2%) of 2893 patients assigned to the derivation cohort. Six independent predictors of complications were identified and included in a Revised Cardiac Risk Index: high-risk type of surgery, history of ischemic heart disease, history of congestive heart failure, history of cerebrovascular disease, preoperative treatment with insulin, and preoperative serum creatinine >2.0 mg/dL. Rates of major cardiac complication with 0, 1, 2, or > or = 3 of these factors were 0.5%, 1.3%, 4%, and 9%, respectively, in the derivation cohort and 0.4%, 0.9%, 7%, and 11%, respectively, among 1422 patients in the validation cohort. Receiver operating characteristic curve analysis in the validation cohort indicated that the diagnostic performance of the Revised Cardiac Risk Index was superior to other published risk-prediction indexes. Conclusions In stable patients undergoing nonurgent major noncardiac surgery, this index can identify patients at higher risk for complications. This index may be useful for identification of candidates for further risk stratification with noninvasive technologies or other management strategies, as well as low-risk patients in whom additional evaluation is unlikely to be helpful.
3,183 citations
TL;DR: Despite an increased frequency of early symptomatic intracranial hemorrhage, treatment with IA r-proUK within 6 hours of the onset of acute ischemic stroke caused by MCA occlusion significantly improved clinical outcome at 90 days.
Abstract: ContextIntravenous tissue-type plasminogen activator can be beneficial to some
patients when given within 3 hours of stroke onset, but many patients present
later after stroke onset and alternative treatments are needed.ObjectiveTo determine the clinical efficacy and safety of intra-arterial (IA)
recombinant prourokinase (r-proUK) in patients with acute stroke of less than
6 hours' duration caused by middle cerebral artery (MCA) occlusion.DesignPROACT II (Prolyse in Acute Cerebral Thromboembolism II), a randomized,
controlled, multicenter, open-label clinical trial with blinded follow-up
conducted between February 1996 and August 1998.SettingFifty-four centers in the United States and Canada.PatientsA total of 180 patients with acute ischemic stroke of less than 6 hours'
duration caused by angiographically proven occlusion of the MCA and without
hemorrhage or major early infarction signs on computed tomographic scan.InterventionPatients were randomized to receive 9 mg of IA r-proUK plus heparin
(n = 121) or heparin only (n = 59).Main Outcome MeasuresThe primary outcome, analyzed by intention-to-treat, was based on the
proportion of patients with slight or no neurological disability at 90 days
as defined by a modified Rankin score of 2 or less. Secondary outcomes included
MCA recanalization, the frequency of intracranial hemorrhage with neurological
deterioration, and mortality.ResultsFor the primary analysis, 40% of r-proUK patients and 25% of control
patients had a modified Rankin score of 2 or less (P
= .04). Mortality was 25% for the r-proUK group and 27% for the control group.
The recanalization rate was 66% for the r-proUK group and 18% for the control
group (P<.001). Intracranial hemorrhage with neurological
deterioration within 24 hours occurred in 10% of r-proUK patients and 2% of
control patients (P = .06).ConclusionDespite an increased frequency of early symptomatic intracranial hemorrhage,
treatment with IA r-proUK within 6 hours of the onset of acute ischemic stroke
caused by MCA occlusion significantly improved clinical outcome at 90 days.
3,014 citations
TL;DR: A simple model is described that unifies much of the data that previously were viewed as contradictory about the molecular mechanisms of this long-lasting increase in synaptic strength in the hippocampus.
Abstract: Long-term potentiation of synaptic transmission in the hippocampus is the leading experimental model for the synaptic changes that may underlie learning and memory. This review presents a current understanding of the molecular mechanisms of this long-lasting increase in synaptic strength and describes a simple model that unifies much of the data that previously were viewed as contradictory.
2,769 citations
TL;DR: Risedronate, a potent bisphosphonate, has been shown to be effective in the treatment of Paget disease of bone and other metabolic bone diseases, but, to the knowledge, it has not been evaluated in this article.
Abstract: Context Risedronate, a potent bisphosphonate, has been shown to be effective in the treatment of Paget disease of bone and other metabolic bone diseases but, to our knowledge, it has not been evaluated in the treatment of established postmenopausal osteoporosis.
2,345 citations
TL;DR: It is shown that the vasodilator response to anandamide in isolated arteries is capsaicin-sensitive and accompanied by release of calcitonin-gene-related peptide (CGRP), which indicates that the vanilloid receptor may be another molecular target for endogenousAnandamide, besides cannabinoid receptors, in the nervous and cardiovascular systems.
Abstract: The endogenous cannabinoid receptor agonist anandamide is a powerful vasodilator of isolated vascular preparations, but its mechanism of action is unclear. Here we show that the vasodilator response to anandamide in isolated arteries is capsaicin-sensitive and accompanied by release of calcitonin-gene-related peptide (CGRP). The selective CGRP-receptor antagonist 8-37 CGRP, but not the cannabinoid CB1 receptor blocker SR141716A, inhibited the vasodilator effect of anandamide. Other endogenous (2-arachidonylglycerol, palmitylethanolamide) and synthetic (HU 210, WIN 55,212-2, CP 55,940) CB1 and CB2 receptor agonists could not mimic the action of anandamide. The selective 'vanilloid receptor' antagonist capsazepine inhibited anandamide-induced vasodilation and release of CGRP. In patch-clamp experiments on cells expressing the cloned vanilloid receptor (VR1), anandamide induced a capsazepine-sensitive current in whole cells and isolated membrane patches. Our results indicate that anandamide induces vasodilation by activating vanilloid receptors on perivascular sensory nerves and causing release of CGRP. The vanilloid receptor may thus be another molecular target for endogenous anandamide, besides cannabinoid receptors, in the nervous and cardiovascular systems.
2,113 citations
TL;DR: It is shown that VEGF-mediated capillary invasion is an essential signal that regulates growth plate morphogenesis and triggers cartilage remodeling and VEGf is anessential coordinator of chondrocyte death, chondROclast function, extracellular matrix remodeling, angiogenesis and bone formation in the growth plate.
Abstract: Hypertrophic chondrocytes in the epiphyseal growth plate express the angiogenic protein vascular endothelial growth factor (VEGF). To determine the role of VEGF in endochondral bone formation, we inactivated this factor through the systemic administration of a soluble receptor chimeric protein (Flt-(1-3)-IgG) to 24-day-old mice. Blood vessel invasion was almost completely suppressed, concomitant with impaired trabecular bone formation and expansion of hypertrophic chondrocyte zone. Recruitment and/or differentiation of chondroclasts, which express gelatinase B/matrix metalloproteinase-9, and resorption of terminal chondrocytes decreased. Although proliferation, differentiation and maturation of chondrocytes were apparently normal, resorption was inhibited. Cessation of the anti-VEGF treatment was followed by capillary invasion, restoration of bone growth, resorption of the hypertrophic cartilage and normalization of the growth plate architecture. These findings indicate that VEGF-mediated capillary invasion is an essential signal that regulates growth plate morphogenesis and triggers cartilage remodeling. Thus, VEGF is an essential coordinator of chondrocyte death, chondroclast function, extracellular matrix remodeling, angiogenesis and bone formation in the growth plate.
2,003 citations
TL;DR: In this article, Latency-Aged Peptide (LAP) was shown to be a ligand for the integrin alpha v beta 6 and that alpha-v beta 6-expressing cells induce spatially restricted activation of TGF beta 1.
TL;DR: Treatment with myeloablative therapy and autologous bone marrow transplantation improved event-free survival among children with high-risk neuroblastoma, and treatment with 13-cis-retinoic acid was beneficial for patients without progressive disease when it was administered after chemotherapy or transplantation.
Abstract: Background Children with high-risk neuroblastoma have a poor outcome. In this study, we assessed whether myeloablative therapy in conjunction with transplantation of autologous bone marrow improved event-free survival as compared with chemotherapy alone, and whether subsequent treatment with 13-cis-retinoic acid (isotretinoin) further improves event-free survival. Methods All patients were treated with the same initial regimen of chemotherapy, and those without disease progression were then randomly assigned to receive continued treatment with myeloablative chemotherapy, total-body irradiation, and transplantation of autologous bone marrow purged of neuroblastoma cells or to receive three cycles of intensive chemotherapy alone. All patients who completed cytotoxic therapy without disease progression were then randomly assigned to receive no further therapy or treatment with 13-cis-retinoic acid for six months. Results The mean (±SE) event-free survival rate three years after the first randomization was si...
TL;DR: In this paper, a review of the literature on the prevalence of mental health problems among women with a history of intimate partner violence is presented, with a focus on depression and posttraumatic stress disorder (PTSD).
Abstract: This article reviews literature on the prevalence of mental health problems among women with a history of intimate partner violence. The weighted mean prevalence of mental health problems among battered women was 47.6% in 18 studies of depression, 17.9% in 13 studies of suicidality, 63.8% in 11 studies of posttraumatic stress disorder (PTSD), 18.5% in 10 studies of alcohol abuse, and 8.9% in four studies of drug abuse. These were typically inconsistent across studies. Weighted mean odds ratios representing associations of these problems with violence ranged from 3.55 to 5.62, and were typically consistent across studies. Variability was accounted for by differences in sampling frames. Dose-response relationships of violence to depression and PTSD were observed. Although research has not addressed many criteria for causal inferences, the existing research is consistent with the hypothesis that intimate partner violence increases risk for mental health problems. The appropriate way to conceptualize these problems deserves careful attention.
TL;DR: The Multiple Outcomes of Raloxifene Evaluation (MORE) as discussed by the authors was a multicenter, randomized, double-blind trial, in which women taking raloxion hydrochloride or placebo were followed up for a median of 40 months at 180 clinical centers composed of community settings and medical practices in 25 countries, mainly in the United States and Europe.
Abstract: ContextRaloxifene hydrochloride is a selective estrogen
receptor modulator that has antiestrogenic effects on breast and
endometrial tissue and estrogenic effects on bone, lipid metabolism,
and blood clotting.ObjectiveTo determine whether women taking raloxifene have a
lower risk of invasive breast cancer.Design and SettingThe Multiple Outcomes of Raloxifene Evaluation
(MORE), a multicenter, randomized, double-blind trial, in which women
taking raloxifene or placebo were followed up for a median of 40 months
(SD, 3 years), from 1994 through 1998, at 180 clinical centers composed
of community settings and medical practices in 25 countries, mainly in
the United States and Europe.ParticipantsA total of 7705 postmenopausal women, younger than 81
(mean age, 66.5) years, with osteoporosis, defined by the presence of
vertebral fractures or a femoral neck or spine T-score of at least 2.5
SDs below the mean for young healthy women. Almost all participants
(96%) were white. Women who had a history of breast cancer or who were
taking estrogen were excluded.InterventionRaloxifene, 60 mg, 2 tablets daily; or raloxifene, 60
mg, 1 tablet daily and 1 placebo tablet; or 2 placebo tablets.Main Outcome MeasuresNew cases of breast cancer, confirmed by
histopathology. Transvaginal ultrasonography was used to assess the
endometrial effects of raloxifene in 1781 women. Deep vein thrombosis
or pulmonary embolism were determined by chart review.ResultsThirteen cases of breast cancer were confirmed among the
5129 women assigned to raloxifene vs 27 among the 2576 women assigned
to placebo (relative risk [RR], 0.24; 95% confidence interval
[CI], 0.13-0.44; P<.001). To prevent 1 case of breast
cancer, 126 women would need to be treated. Raloxifene decreased the
risk of estrogen receptor–positive breast cancer by 90% (RR, 0.10;
95% CI, 0.04-0.24), but not estrogen receptor–negative invasive
breast cancer (RR, 0.88; 95% CI, 0.26-3.0). Raloxifene increased the
risk of venous thromboembolic disease (RR, 3.1; 95% CI, 1.5-6.2), but
did not increase the risk of endometrial cancer (RR, 0.8; 95% CI,
0.2-2.7).ConclusionAmong postmenopausal women with osteoporosis, the
risk of invasive breast cancer was decreased by 76% during 3 years of
treatment with raloxifene.
TL;DR: This paper examines the data regarding the SES‐health gradient, addressing causal direction, generalizability across populations and diseases, and associations with health for different indicators of SES.
Abstract: In the past 15 years, we have seen a marked increase in research on socioeconomic status (SES) and health. Research in the first part of this era examined the nature of the relationship of SES and health, revealing a graded association; SES is important to health not only for those in poverty, but at all levels of SES. On average, the more advantaged individuals are, the better their health. In this paper we examine the data regarding the SES-health gradient, addressing causal direction, generalizability across populations and diseases, and associations with health for different indicators of SES. In the most recent era, researchers are increasingly exploring the mechanisms by which SES exerts an influence on health. There are multiple pathways by which SES determines health; a comprehensive analysis must include macroeconomic contexts and social factors as well as more immediate social environments, individual psychological and behavioral factors, and biological predispositions and processes.
TL;DR: It is proposed that responses to noxious heat involve these related, but distinct, ion-channel subtypes that together detect a range of stimulus intensities.
Abstract: Pain-producing heat is detected by several classes of nociceptive sensory neuron that differ in their thermal response thresholds. The cloned capsaicin receptor, also known as the vanilloid receptor subtype 1 (VR1), is a heat-gated ion channel that has been proposed to mediate responses of small-diameter sensory neurons to moderate (43 degrees C) thermal stimuli. VR1 is also activated by protons, indicating that it may participate in the detection of noxious thermal and chemical stimuli in vivo. Here we identify a structurally related receptor, VRL-1, that does not respond to capsaicin, acid or moderate heat. Instead, VRL-1 is activated by high temperatures, with a threshold of approximately 52 degrees C. Within sensory ganglia, VRL-1 is most prominently expressed by a subset of medium- to large-diameter neurons, making it a candidate receptor for transducing high-threshold heat responses in this class of cells. VRL-1 transcripts are not restricted to the sensory nervous system, indicating that this channel may be activated by stimuli other than heat. We propose that responses to noxious heat involve these related, but distinct, ion-channel subtypes that together detect a range of stimulus intensities.
TL;DR: Angiopoietin-1 may be useful for reducing microvascular leakage in diseases in which the leakage results from chronic inflammation or elevated V EGF and, in combination with VEGF, for promoting growth of nonleaky vessels.
Abstract: Angiopoietin-1 (Ang1) and vascular endothelial growth factor (VEGF) are endothelial cell-specific growth factors. Direct comparison of transgenic mice overexpressing these factors in the skin revealed that the VEGF-induced blood vessels were leaky, whereas those induced by Ang1 were nonleaky. Moreover, vessels in Ang1-overexpressing mice were resistant to leaks caused by inflammatory agents. Coexpression of Ang1 and VEGF had an additive effect on angiogenesis but resulted in leakage-resistant vessels typical of Ang1. Ang1 therefore may be useful for reducing microvascular leakage in diseases in which the leakage results from chronic inflammation or elevated VEGF and, in combination with VEGF, for promoting growth of nonleaky vessels.
TL;DR: Hyperfractionation and accelerated fractionation with concomitant boost are more efficacious than standard fractionation for locally advanced head and neck cancer.
Abstract: Purpose: The optimal fractionation schedule for radiotherapy of head and neck cancer has been controversial. The objective of this randomized trial was to test the efficacy of hyperfractionation and two types of accelerated fractionation individually against standard fractionation. Methods and Materials: Patients with locally advanced head and neck cancer were randomly assigned to receive radiotherapy delivered with: 1) standard fractionation at 2 Gy/fraction/day, 5 days/week, to 70 Gy/35 fractions/7 weeks; 2) hyperfractionation at 1.2 Gy/fraction, twice daily, 5 days/week to 81.6 Gy/68 fractions/7 weeks; 3) accelerated fractionation with split at 1.6 Gy/fraction, twice daily, 5 days/week, to 67.2 Gy/42 fractions/6 weeks including a 2-week rest after 38.4 Gy; or 4) accelerated fractionation with concomitant boost at 1.8 Gy/fraction/day, 5 days/week and 1.5 Gy/fraction/day to a boost field as a second daily treatment for the last 12 treatment days to 72 Gy/42 fractions/6 weeks. Of the 1113 patients entered, 1073 patients were analyzable for outcome. The median follow-up was 23 months for all analyzable patients and 41.2 months for patients alive. Results: Patients treated with hyperfractionation and accelerated fractionation with concomitant boost had significantly better local-regional control (p = 0.045 and p = 0.050 respectively) than those treated with standard fractionation. There was also a trend toward improved disease-free survival (p = 0.067 and p = 0.054 respectively) although the difference in overall survival was not significant. Patients treated with accelerated fractionation with split had similar outcome to those treated with standard fractionation. All three altered fractionation groups had significantly greater acute side effects compared to standard fractionation. However, there was no significant increase of late effects. Conclusions: Hyperfractionation and accelerated fractionation with concomitant boost are more efficacious than standard fractionation for locally advanced head and neck cancer. Acute but not late effects are also increased.
TL;DR: It is shown that PIK3CA is frequently increased in copy number in ovarian cancers, that the increased copy number is associated with increased Pik3CA transcription, p110α protein expression and PI3-kinase activity and that treatment with the PI3 -kinase inhibitor LY294002 decreases proliferation and increases apoptosis.
Abstract: Ovarian cancer is the leading cause of death from gynecological malignancy and the fourth leading cause of cancer death among American women, yet little is known about its molecular aetiology. Studies using comparative genomic hybridization (CGH) have revealed several regions of recurrent, abnormal, DNA sequence copy number that may encode genes involved in the genesis or progression of the disease. One region at 3q26 found to be increased in copy number in approximately 40% of ovarian and others cancers contains PIK3CA, which encodes the p110alpha catalytic subunit of phosphatidylinositol 3-kinase (PI3-kinase). The association between PIK3CA copy number and PI3-kinase activity makes PIK3CA a candidate oncogene because a broad range of cancer-related functions have been associated with PI3-kinase mediated signalling. These include proliferation, glucose transport and catabolism, cell adhesion, apoptosis, RAS signalling and oncogenic transformation. In addition, downstream effectors of PI3-kinase, AKT1 and AKT2, have been found to be amplified or activated in human tumours, including ovarian cancer. We show here that PIK3CA is frequently increased in copy number in ovarian cancers, that the increased copy number is associated with increased PIK3CA transcription, p110alpha protein expression and PI3-kinase activity and that treatment with the PI3-kinase inhibitor LY294002 decreases proliferation and increases apoptosis. Our observations suggest PIK3CA is an oncogene that has an important role in ovarian cancer.
TL;DR: The characterization of three mammalian Slit homologs are described and it is shown that the Drosophila Slit protein and at least one of the mammals Slit proteins, Slit2, are proteolytically processed and show specific, high-affinity binding to Robo proteins.
TL;DR: It is shown that overexpression of FAD(717V-->F)-mutant human APP in neurons of transgenic mice decreases the density of presynaptic terminals and neurons well before these mice develop amyloid plaques, suggesting a neurotoxic effect of Abeta that is independent of plaque formation.
Abstract: Autosomal dominant forms of familial Alzheimer’s disease (FAD) are associated with increased production of the amyloid β peptide, Aβ42, which is derived from the amyloid protein precursor (APP). In FAD, as well as in sporadic forms of the illness, Aβ peptides accumulate abnormally in the brain in the form of amyloid plaques. Here, we show that overexpression of FAD(717V→F)-mutant human APP in neurons of transgenic mice decreases the density of presynaptic terminals and neurons well before these mice develop amyloid plaques. Electrophysiological recordings from the hippocampus revealed prominent deficits in synaptic transmission, which also preceded amyloid deposition by several months. Although in young mice, functional and structural neuronal deficits were of similar magnitude, functional deficits became predominant with advancing age. Increased Aβ production in the context of decreased overall APP expression, achieved by addition of the Swedish FAD mutation to the APP transgene in a second line of mice, further increased synaptic transmission deficits in young APP mice without plaques. These results suggest a neurotoxic effect of Aβ that is independent of plaque formation.
TL;DR: It is concluded that plexins are receptors for multiple (and perhaps all) classes of semaphorins, either alone or in combination with neuropilins, and trigger a novel signal transduction pathway controlling cell repulsion.
TL;DR: These findings indicate that patients with heart failure should not generally be maintained on very low doses of an ACE inhibitor (unless these are the only doses that can be tolerated) and suggest that the difference in efficacy between intermediate and high doses of a ACE inhibitor is likely to be very small.
Abstract: Background—Angiotensin-converting enzyme (ACE) inhibitors are generally prescribed by physicians in doses lower than the large doses that have been shown to reduce morbidity and mortality in patients with heart failure. It is unclear, however, if low doses and high doses of ACE inhibitors have similar benefits. Methods and Results—We randomly assigned 3164 patients with New York Heart Association class II to IV heart failure and an ejection fraction #30% to double-blind treatment with either low doses (2.5 to 5.0 mg daily, n51596) or high doses (32.5 to 35 mg daily, n51568) of the ACE inhibitor, lisinopril, for 39 to 58 months, while background therapy for heart failure was continued. When compared with the low-dose group, patients in the high-dose group had a nonsignificant 8% lower risk of death (P50.128) but a significant 12% lower risk of death or hospitalization for any reason (P50.002) and 24% fewer hospitalizations for heart failure (P50.002). Dizziness and renal insufficiency was observed more frequently in the high-dose group, but the 2 groups were similar in the number of patients requiring discontinuation of the study medication. Conclusions—These findings indicate that patients with heart failure should not generally be maintained on very low doses of an ACE inhibitor (unless these are the only doses that can be tolerated) and suggest that the difference in efficacy between intermediate and high doses of an ACE inhibitor (if any) is likely to be very small. (Circulation. 1999;100:2312-2318.)
TL;DR: This work explores the advantage of using accurate mass measurement (and thus constraint on the possible elemental composition of components in a protein digest) in strategies for searching protein, gene, and EST databases that employ mass values alone, fragment-ion tagging derived from MS/MS spectra, and de novo interpretation of MS/ MS spectra.
Abstract: We describe the impact of advances in mass measurement accuracy, ±10 ppm (internally calibrated), on protein identification experiments. This capability was brought about by delayed extraction techniques used in conjunction with matrix-assisted laser desorption ionization (MALDI) on a reflectron time-of-flight (TOF) mass spectrometer. This work explores the advantage of using accurate mass measurement (and thus constraint on the possible elemental composition of components in a protein digest) in strategies for searching protein, gene, and EST databases that employ (a) mass values alone, (b) fragment-ion tagging derived from MS/MS spectra, and (c) de novo interpretation of MS/MS spectra. Significant improvement in the discriminating power of database searches has been found using only molecular weight values (i.e., measured mass) of >10 peptide masses. When MALDI-TOF instruments are able to achieve the ±0.5−5 ppm mass accuracy necessary to distinguish peptide elemental compositions, it is possible to matc...
TL;DR: This paper explores and compares techniques for automatically recognizing facial actions in sequences of images and provides converging evidence for the importance of using local filters, high spatial frequencies, and statistical independence for classifying facial actions.
Abstract: The facial action coding system (FAGS) is an objective method for quantifying facial movement in terms of component actions. This paper explores and compares techniques for automatically recognizing facial actions in sequences of images. These techniques include: analysis of facial motion through estimation of optical flow; holistic spatial analysis, such as principal component analysis, independent component analysis, local feature analysis, and linear discriminant analysis; and methods based on the outputs of local filters, such as Gabor wavelet representations and local principal components. Performance of these systems is compared to naive and expert human subjects. Best performances were obtained using the Gabor wavelet representation and the independent component representation, both of which achieved 96 percent accuracy for classifying 12 facial actions of the upper and lower face. The results provide converging evidence for the importance of using local filters, high spatial frequencies, and statistical independence for classifying facial actions.
01 Feb 1999
TL;DR: This article provides a framework for analyzing invisible work in CSCW systems and sample across a variety of kinds of work to enrich the understanding of how invisibility and visibility operate.
Abstract: No work is inherently either visible or invisible. We always ’’see‘‘ work through a selection of indicators: straining muscles, finished artifacts, a changed state of affairs. The indicators change with context, and that context becomes a negotiation about the relationship between visible and invisible work. With shifts in industrial practice these negotiations require longer chains of inference and representation, and may become solely abstract.
This article provides a framework for analyzing invisible work in CSCW systems. We sample across a variety of kinds of work to enrich the understanding of how invisibility and visibility operate. Processes examined include creating a ’’non-person‘‘ in domestic work; disembedding background work; and going backstage. Understanding these processes may inform the design of CSCW systems and the development of related social theory.
TL;DR: It is suggested that the abnormalities in plt mice are due to a genetic defect in the expression of SLC and that SLC mediates the entry of naive T cells and antigen-stimulated DCs into the T cell zones of secondary lymphoid organs.
Abstract: Secondary lymphoid organ chemokine (SLC) is expressed in high endothelial venules and in T cell zones of spleen and lymph nodes (LNs) and strongly attracts naive T cells. In mice homozygous for the paucity of lymph node T cell (plt) mutation, naive T cells fail to home to LNs or the lymphoid regions of spleen. Here we demonstrate that expression of SLC is undetectable in plt mice. In addition to the defect in T cell homing, we demonstrate that dendritic cells (DCs) fail to accumulate in spleen and LN T cell zones of plt mice. DC migration to LNs after contact sensitization is also substantially reduced. The physiologic significance of these abnormalities in plt mice is indicated by a markedly increased sensitivity to infection with murine hepatitis virus. The plt mutation maps to the SLC locus; however, the sequence of SLC introns and exons in plt mice is normal. These findings suggest that the abnormalities in plt mice are due to a genetic defect in the expression of SLC and that SLC mediates the entry of naive T cells and antigen-stimulated DCs into the T cell zones of secondary lymphoid organs.
TL;DR: It is concluded that exposure of a three amino acid motif (RKR) can explain how assembly of an ion channel complex is coupled to intracellular trafficking.
TL;DR: Current understanding of the roles played by chemokines in the functional biology of secondary lymphoid organs will be reviewed and a central role for the chemokine family of molecules has been uncovered.
Abstract: As few as one in 100,000 B and T lymphocytes are specific for a single protein antigen, such as tetanus toxin, yet these cells must come together if an antibody response is to occur. Bringing antigen-presenting cells and rare antigen-specific B and T lymphocytes into physical contact is a principal function of secondary lymphoid organs. In the last few years, details have begun to emerge on the cues that guide cell movements inside lymphoid organs, and a central role for the chemokine family of molecules has been uncovered. Here, current understanding of the roles played by chemokines in the functional biology of secondary lymphoid organs will be reviewed.
TL;DR: It is suggested that the hephaestin protein is a multi–copper ferroxidase necessary for iron egress from intestinal enterocytes into the circulation and that it is an important link between copper and iron metabolism in mammals.
Abstract: Iron is essential for many cellular functions; consequently, disturbances of iron homeostasis, leading to either iron deficiency or iron overload, can have significant clinical consequences. Despite the clinical prevalence of these disorders, the mechanism by which dietary iron is absorbed into the body is poorly understood. We have identified a key component in intestinal iron transport by study of the sex-linked anaemia (sla) mouse, which has a block in intestinal iron transport. Mice carrying the sla mutation develop moderate to severe microcytic hypochromic anaemia. Although these mice take up iron from the intestinal lumen into mature epithelial cells normally, the subsequent exit of iron into the circulation is diminished. As a result, iron accumulates in enterocytes and is lost during turnover of the intestinal epithelium. Biochemical studies have failed to identify the underlying difference between sla and normal mice, therefore, we used a genetic approach to identify the gene mutant in sla mice. We describe here a novel gene, Heph, encoding a transmembrane-bound ceruloplasmin homologue that is mutant in the sla mouse and highly expressed in intestine. We suggest that the hephaestin protein is a multicopper ferroxidase necessary for iron egress from intestinal enterocytes into the circulation and that it is an important link between copper and iron metabolism in mammals.