Showing papers by "Harvard University published in 2004"

Bioconductor: open software development for computational biology and bioinformatics

Abstract: The Bioconductor project is an initiative for the collaborative creation of extensible software for computational biology and bioinformatics. The goals of the project include: fostering collaborative development and widespread use of innovative software, reducing barriers to entry into interdisciplinary scientific research, and promoting the achievement of remote reproducibility of research results. We describe details of our aims and methods, identify current challenges, compare Bioconductor to other open bioinformatics projects, and provide working examples.

Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib

Abstract: BACKGROUND Most patients with non-small-cell lung cancer have no response to the tyrosine kinase inhibitor gefitinib, which targets the epidermal growth factor receptor (EGFR). However, about 10 percent of patients have a rapid and often dramatic clinical response. The molecular mechanisms underlying sensitivity to gefitinib are unknown. METHODS We searched for mutations in the EGFR gene in primary tumors from patients with non-small-cell lung cancer who had a response to gefitinib, those who did not have a response, and those who had not been exposed to gefitinib. The functional consequences of identified mutations were evaluated after the mutant proteins were expressed in cultured cells. RESULTS Somatic mutations were identified in the tyrosine kinase domain of the EGFR gene in eight of nine patients with gefitinib-responsive lung cancer, as compared with none of the seven patients with no response (P<0.001). Mutations were either small, in-frame deletions or amino acid substitutions clustered around the ATP-binding pocket of the tyrosine kinase domain. Similar mutations were detected in tumors from 2 of 25 patients with primary non-small-cell lung cancer who had not been exposed to gefitinib (8 percent). All mutations were heterozygous, and identical mutations were observed in multiple patients, suggesting an additive specific gain of function. In vitro, EGFR mutants demonstrated enhanced tyrosine kinase activity in response to epidermal growth factor and increased sensitivity to inhibition by gefitinib. CONCLUSIONS A subgroup of patients with non-small-cell lung cancer have specific mutations in the EGFR gene, which correlate with clinical responsiveness to the tyrosine kinase inhibitor gefitinib. These mutations lead to increased growth factor signaling and confer susceptibility to the inhibitor. Screening for such mutations in lung cancers may identify patients who will have a response to gefitinib.

EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy.

Abstract: Receptor tyrosine kinase genes were sequenced in nonsmall cell lung cancer (NSCLC) and matched normal tissue. Somatic mutations of the epidermal growth factor receptor gene EGFR were found in 15 of 58 unselected tumors from Japan and 1 of 61 from the United States. Treatment with the EGFR kinase inhibitor gefitinib (Iressa) causes tumor regression in some patients with NSCLC, more frequently in Japan. EGFR mutations were found in additional lung cancer samples from U.S. patients who responded to gefitinib therapy and in a lung adenocarcinoma cell line that was hypersensitive to growth inhibition by gefitinib, but not in gefitinibinsensitive tumors or cell lines. These results suggest that EGFR mutations may predict sensitivity to gefitinib. Protein kinase activation by somatic mutation or

Bariatric surgery: a systematic review and meta-analysis.

Abstract: ContextAbout 5% of the US population is morbidly obese. This disease remains largely refractory to diet and drug therapy, but generally responds well to bariatric surgery.ObjectiveTo determine the impact of bariatric surgery on weight loss, operative mortality outcome, and 4 obesity comorbidities (diabetes, hyperlipidemia, hypertension, and obstructive sleep apnea).Data Sources and Study SelectionElectronic literature search of MEDLINE, Current Contents, and the Cochrane Library databases plus manual reference checks of all articles on bariatric surgery published in the English language between 1990 and 2003. Two levels of screening were used on 2738 citations.Data ExtractionA total of 136 fully extracted studies, which included 91 overlapping patient populations (kin studies), were included for a total of 22 094 patients. Nineteen percent of the patients were men and 72.6% were women, with a mean age of 39 years (range, 16-64 years). Sex was not reported for 1537 patients (8%). The baseline mean body mass index for 16 944 patients was 46.9 (range, 32.3-68.8).Data SynthesisA random effects model was used in the meta-analysis. The mean (95% confidence interval) percentage of excess weight loss was 61.2% (58.1%-64.4%) for all patients; 47.5% (40.7%-54.2%) for patients who underwent gastric banding; 61.6% (56.7%-66.5%), gastric bypass; 68.2% (61.5%-74.8%), gastroplasty; and 70.1% (66.3%-73.9%), biliopancreatic diversion or duodenal switch. Operative mortality (≤30 days) in the extracted studies was 0.1% for the purely restrictive procedures, 0.5% for gastric bypass, and 1.1% for biliopancreatic diversion or duodenal switch. Diabetes was completely resolved in 76.8% of patients and resolved or improved in 86.0%. Hyperlipidemia improved in 70% or more of patients. Hypertension was resolved in 61.7% of patients and resolved or improved in 78.5%. Obstructive sleep apnea was resolved in 85.7% of patients and was resolved or improved in 83.6% of patients.ConclusionsEffective weight loss was achieved in morbidly obese patients after undergoing bariatric surgery. A substantial majority of patients with diabetes, hyperlipidemia, hypertension, and obstructive sleep apnea experienced complete resolution or improvement.

Type Ia supernova discoveries at z > 1 from the Hubble Space Telescope: Evidence for past deceleration and constraints on dark energy evolution

Abstract: We have discovered 16 Type Ia supernovae (SNe Ia) with the Hubble Space Telescope (HST) and have used them to provide the first conclusive evidence for cosmic deceleration that preceded the current epoch of cosmic acceleration. These objects, discovered during the course of the GOODS ACS Treasury program, include 6 of the 7 highest redshift SNe Ia known, all at z > 1.25, and populate the Hubble diagram in unexplored territory. The luminosity distances to these objects and to 170 previously reported SNe Ia have been determined using empirical relations between light-curve shape and luminosity. A purely kinematic interpretation of the SN Ia sample provides evidence at the greater than 99% confidence level for a transition from deceleration to acceleration or, similarly, strong evidence for a cosmic jerk. Using a simple model of the expansion history, the transition between the two epochs is constrained to be at z = 0.46 ± 0.13. The data are consistent with the cosmic concordance model of ΩM ≈ 0.3, ΩΛ ≈ 0.7 (χ = 1.06) and are inconsistent with a simple model of evolution or dust as an alternative to dark energy. For a flat universe with a cosmological constant, we measure ΩM = 0.29 ± (equivalently, ΩΛ = 0.71). When combined with external flat-universe constraints, including the cosmic microwave background and large-scale structure, we find w = -1.02 ± (and w < -0.76 at the 95% confidence level) for an assumed static equation of state of dark energy, P = wρc2. Joint constraints on both the recent equation of state of dark energy, w0, and its time evolution, dw/dz, are a factor of ~8 more precise than the first estimates and twice as precise as those without the SNe Ia discovered with HST. Our constraints are consistent with the static nature of and value of w expected for a cosmological constant (i.e., w0 = -1.0, dw/dz = 0) and are inconsistent with very rapid evolution of dark energy. We address consequences of evolving dark energy for the fate of the universe.

The World Mental Health (WMH) Survey Initiative Version of the World Health Organization (WHO) Composite International Diagnostic Interview (CIDI).

Abstract: This paper presents an overview of the World Mental Health (WMH) Survey Initiative version of the World Health Organization (WHO) Composite International Diagnostic Interview (CIDI) and a discussion of the methodological research on which the development of the instrument was based. The WMH-CIDI includes a screening module and 40 sections that focus on diagnoses (22 sections), functioning (four sections), treatment (two sections), risk factors (four sections), socio-demographic correlates (seven sections), and methodological factors (two sections). Innovations compared to earlier versions of the CIDI include expansion of the diagnostic sections, a focus on 12-month as well as lifetime disorders in the same interview, detailed assessment of clinical severity, and inclusion of information on treatment, risk factors, and consequences. A computer-assisted version of the interview is available along with a direct data entry software system that can be used to keypunch responses to the paper-and-pencil version of the interview. Computer programs that generate diagnoses are also available based on both ICD-10 and DSM-IV criteria. Elaborate CD-ROM-based training materials are available to teach interviewers how to administer the interview as well as to teach supervisors how to monitor the quality of data collection.

Automatically Parcellating the Human Cerebral Cortex

Abstract: We present a technique for automatically assigning a neuroanatomical label to each location on a cortical surface model based on probabilistic information estimated from a manually labeled training set. This procedure incorporates both geometric information derived from the cortical model, and neuroanatomical convention, as found in the training set. The result is a complete labeling of cortical sulci and gyri. Examples are given from two different training sets generated using different neuroanatomical conventions, illustrating the flexibility of the algorithm. The technique is shown to be comparable in accuracy to manual labeling.

Export Versus FDI with Heterogeneous Firms

Abstract: Multinational sales have grown at high rates over the last two decades, outpacing the remarkable expansion of trade in manufactures. Consequently, the trade literature has sought to incorporate the mode of foreign market access into the “new” trade theory. This literature recognizes that Ž rms can serve foreign buyers through a variety of channels: they can export their products to foreign customers, serve them through foreign subsidiaries, or license foreign Ž rms to produce their products. Our work focuses on the Ž rm’s choice between exports and “horizontal” foreign direct investment (FDI). Horizontal FDI refers to an investment in a foreign production facility that is designed to serve customers in the foreign market. Firms invest abroad when the gains from avoiding trade costs outweigh the costs of maintaining capacity in multiple markets. This is known as the proximity-concentration tradeoff. We introduce heterogeneous Ž rms into a simple multicountry, multisector model, in which Ž rms face a proximity-concentration trade-off. Every Ž rm decides whether to serve a foreign market, and whether to do so through exports or local subsidiary sales. These modes of market access have different relative costs: exporting involves lower Ž xed costs while FDI involves lower variable costs. Our model highlights the important role of within-sector Ž rm productivity differences in explaining the structure of international trade and investment. First, only the most productive Ž rms engage in foreign activities. This result mirrors other Ž ndings on Ž rm heterogeneity and trade; in particular, the results reported in Melitz (2003). Second, of those Ž rms that serve foreign markets, only the most productive engage in FDI. Third, FDI sales relative to exports are larger in sectors with more Ž rm heterogeneity. Using U.S. exports and afŽ liate sales data that cover 52 manufacturing sectors and 38 countries, we show that cross-sectoral differences in Ž rm heterogeneity predict the composition of trade and investment in the manner suggested by our model. We construct several measures of Ž rm heterogeneity, using different data sources, and show that our results are robust across all these measures. In addition, we conŽ rm the predictions of the proximityconcentration trade-off. That is, Ž rms tend to substitute FDI sales for exports when transport * Helpman: Department of Economics, Harvard University, Cambridge, MA 02138, Tel Aviv University, and CIAR (e-mail: ehelpman@harvard.edu); Melitz: Department of Economics, Harvard University, Cambridge, MA 02138, National Bureau of Economic Research, and Centre for Economic Policy Research (e-mail: mmelitz@ harvard.edu); Yeaple: Department of Economics, University of Pennsylvania, 3718 Locust Walk, Philadelphia, PA 19104, and National Bureau of Economic Research (e-mail: snyeapl2@ssc.upenn.edu). The statistical analysis of Ž rmlevel data on U.S. Multinational Corporations reported in this study was conducted at the International Investment Division, U.S. Bureau of Economic Analysis, under an arrangement that maintained legal conŽ dentiality requirements. Views expressed are those of the authors and do not necessarily re ect those of the Bureau of Economic Analysis. Elhanan Helpman thanks the NSF for Ž nancial support. We also thank Daron Acemoglu, Roberto Rigobon, Yona Rubinstein, and Dani Tsiddon for comments on an earlier draft, and Man-Keung Tang for excellent research assistance. 1 See Wilfred J. Ethier (1986), Ignatius Horstmann and James R. Markusen (1987), and Ethier and Markusen (1996) for models that incorporate the licensing alternative. We therefore exclude “vertical” motives for FDI that involve fragmentation of production across countries. See Helpman (1984, 1985), Markusen (2002, Ch. 9), and Gordon H. Hanson et al. (2002) for treatments of this form of FDI. 3 See, for example, Horstmann and Markusen (1992), S. Lael Brainard (1993), and Markusen and Anthony J. Venables (2000). 4 See also Andrew B. Bernard et al. (2003) for an alternative theoretical model and Yeaple (2003a) for a model based on worker-skill heterogeneity. James R. Tybout (2003) surveys the recent micro-level evidence on trade that has motivated these theoretical models. 5 This result is loosely connected to the documented empirical pattern that foreign-owned afŽ liates are more productive than domestically owned producers. See Mark E. Doms and J. Bradford Jensen (1998) for the United States and Sourafel Girma et al. (2002) for the United Kingdom.

Economic Costs of Diabetes in the U.S. in 2002

Abstract: Diabetes is the fifth leading cause of death by disease in the U.S. Diabetes also contributes to higher rates of morbidity-people with diabetes are at higher risk for heart disease, blindness, kidney failure, extremity amputations, and other chronic conditions. This study estimates the direct medical and indirect productivity-related costs attributable to diabetes and calculates the total and per capita medical expenditures for people with and without diabetes. Direct medical and indirect expenditures attributable to diabetes in 2002 were estimated at 132 billion US dollars. Direct medical expenditures alone totaled 91.8 billion US dollars and comprised 23.2 billion US dollars for diabetes care, 24.6 billion US dollars for chronic complications attributable to diabetes, and 44.1 billion US dollars for excess prevalence of general medical conditions. Inpatient days (43.9%), nursing home care (15.1%), and office visits (10.9%) constituted the major expenditure groups by service settings. In addition, 51.8% of direct medical expenditures were incurred by people >65 years old. The estimated 132 billion US dollars cost likely underestimates the true burden of diabetes because it omits intangibles, such as pain and suffering, care provided by nonpaid caregivers.

Institutions Rule: The Primacy of Institutions over Geography and Integration in Economic Development

Abstract: We estimate the respective contributions of institutions, geography, and trade in determining income levels around the world, using recently developed instrumental variables for institutions and trade. Our results indicate that the quality of institutions “trumps” everything else. Once institutions are controlled for, conventional measures of geography have at best weak direct effects on incomes, although they have a strong indirect effect by influencing the quality of institutions. Similarly, once institutions are controlled for, trade is almost always insignificant, and often enters the income equation with the “wrong” (i.e., negative) sign. We relate our results to recent literature, and where differences exist, trace their origins to choices on samples, specification, and instrumentation.

Applied Longitudinal Analysis

Abstract: Preface.Acknowledgments.PART I: INTRODUCTION TO LONGITUDINAL AND CLUSTERED DATA.1. Longitudinal and Clustered Data.2. Longitudinal Data: Basic Concepts.PART II: LINEAR MODELS FOR LONGITUDINAL CONTINUOUS DATA.3. Overview of Linear Models for Longitudinal Data.4. Estimation and Statistical Inference.5. Modelling the Mean: Analyzing Response Profiles.6. Modelling the Mean: Parametric Curves.7. Modelling the Covariance.8. Linear Mixed Effects Models.9. Residual Analyses and Diagnostics.PART III: GENERALIZED LINEAR MODELS FOR LONGITUDINAL DATA.10. Review of Generalized Linear Models.11. Marginal Models: Generalized Estimating Equations (GEE).12. Generalized Linear Mixed Effects Models.13. Contrasting Marginal and Mixed Effects Models.PART IV: ADVANCED TOPICS FOR LONGITUDINAL AND CLUSTERED DATA.14. Missing Data and Dropout.15. Some Aspects of the Design of Longitudinal Studies.16. Repeated Measures and Related Designs.17. Multilevel Models.Appendix A: Gentle Introduction to Vectors and Matrices.Appendix B: Properties of Expectations and Variances.Appendix C: Critical Points for a 50:50 Mixture of Chi-Squared Distributions.References.Index.

Human MicroRNA Targets

Abstract: MicroRNAs (miRNAs) interact with target mRNAs at specific sites to induce cleavage of the message or inhibit translation. The specific function of most mammalian miRNAs is unknown. We have predicted target sites on the 3′ untranslated regions of human gene transcripts for all currently known 218 mammalian miRNAs to facilitate focused experiments. We report about 2,000 human genes with miRNA target sites conserved in mammals and about 250 human genes conserved as targets between mammals and fish. The prediction algorithm optimizes sequence complementarity using position-specific rules and relies on strict requirements of interspecies conservation. Experimental support for the validity of the method comes from known targets and from strong enrichment of predicted targets in mRNAs associated with the fragile X mental retardation protein in mammals. This is consistent with the hypothesis that miRNAs act as sequence-specific adaptors in the interaction of ribonuclear particles with translationally regulated messages. Overrepresented groups of targets include mRNAs coding for transcription factors, components of the miRNA machinery, and other proteins involved in translational regulation, as well as components of the ubiquitin machinery, representing novel feedback loops in gene regulation. Detailed information about target genes, target processes, and open-source software for target prediction (miRanda) is available at http://www.microrna.org. Our analysis suggests that miRNA genes, which are about 1% of all human genes, regulate protein production for 10% or more of all human genes.

The Infrared Array Camera (IRAC) for the Spitzer Space Telescope

Abstract: The Infrared Array Camera (IRAC) is one of three focal plane instruments on the Spitzer Space Telescope. IRAC is a four-channel camera that obtains simultaneous broadband images at 3.6, 4.5, 5.8, and 8.0 � m. Two nearly adjacent 5A2 ; 5A2 fields of view in the focal plane are viewed by the four channels in pairs (3.6 and 5.8 � m; 4.5 and 8 � m). All four detector arrays in the camera are 256 ; 256 pixels in size, with the two shorter wavelength channels using InSb and the two longer wavelength channels using Si:As IBC detectors. IRAC is a powerful survey instrument because of its high sensitivity, large field of view, and four-color imaging. This paper summarizes the in-flight scientific, technical, and operational performance of IRAC.

Endoplasmic Reticulum Stress Links Obesity, Insulin Action, and Type 2 Diabetes

Abstract: Obesity contributes to the development of type 2 diabetes, but the underlying mechanisms are poorly understood. Using cell culture and mouse models, we show that obesity causes endoplasmic reticulum (ER) stress. This stress in turn leads to suppression of insulin receptor signaling through hyperactivation of c-Jun N-terminal kinase (JNK) and subsequent serine phosphorylation of insulin receptor substrate-1 (IRS-1). Mice deficient in X-box-binding protein-1 (XBP-1), a transcription factor that modulates the ER stress response, develop insulin resistance. These findings demonstrate that ER stress is a central feature of peripheral insulin resistance and type 2 diabetes at the molecular, cellular, and organismal levels. Pharmacologic manipulation of this pathway may offer novel opportunities for treating these common diseases.

Neurodegenerative diseases and oxidative stress.

Abstract: Oxidative stress has been implicated in the progression of Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Oxygen is vital for life but is also potentially dangerous, and a complex system of checks and balances exists for utilizing this essential element. Oxidative stress is the result of an imbalance in pro-oxidant/antioxidant homeostasis that leads to the generation of toxic reactive oxygen species. The systems in place to cope with the biochemistry of oxygen are complex, and many questions about the mechanisms of oxygen regulation remain unanswered. However, this same complexity provides a number of therapeutic targets, and different strategies, including novel metal-protein attenuating compounds, aimed at a variety of targets have shown promise in clinical studies.

How Do Family Ownership, Control, and Management Affect Firm Value?

Abstract: Using proxy data on all Fortune 500 firms during 1994-2000, we establish that, in order to understand whether and when family firms are more or less valuable than nonfamily firms, one must distinguish among three fundamental elements in the definition of family firms: ownership, control, and management. Specifically, we find that family ownership creates value only when the founder serves as the CEO of the family firm or as its Chairman with a hired CEO. Control mechanisms including dual share classes, pyramids, and voting agreements reduce the founder's premium. When descendants serve as CEOs, firm value is destroyed. Our findings further suggest that the classic owner-manager conflict in nonfamily firms is more costly than the conflict between family and nonfamily shareholders in founder-CEO firms. However, the conflict between family and nonfamily shareholders in descendant-CEO firms is more costly than the owner-manager conflict in nonfamily firms.

The Spitzer Space Telescope mission

Abstract: The Spitzer Space Telescope, NASA's Great Observatory for infrared astronomy, was launched 2003 August 25 and is returning excellent scientific data from its Earth-trailing solar orbit. Spitzer combines the intrinsic sensitivity achievable with a cryogenic telescope in space with the great imaging and spectroscopic power of modern detector arrays to provide the user community with huge gains in capability for exploration of the cosmos in the infrared. The observatory systems are largely performing as expected, and the projected cryogenic lifetime is in excess of 5 years. This paper summarizes the on-orbit scientific, technical, and operational performance of Spitzer. Subsequent papers in this special issue describe the Spitzer instruments in detail and highlight many of the exciting scientific results obtained during the first 6 months of the Spitzer mission.

Circulating Angiogenic Factors and the Risk of Preeclampsia

Abstract: Background The cause of preeclampsia remains unclear. Limited data suggest that excess circulating soluble fms-like tyrosine kinase 1 (sFlt-1), which binds placental growth factor (PlGF) and vascul...

Stress-Dependent Regulation of FOXO Transcription Factors by the SIRT1 Deacetylase

Abstract: The Sir2 deacetylase modulates organismal life-span in various species. However, the molecular mechanisms by which Sir2 increases longevity are largely unknown. We show that in mammalian cells, the Sir2 homolog SIRT1 appears to control the cellular response to stress by regulating the FOXO family of Forkhead transcription factors, a family of proteins that function as sensors of the insulin signaling pathway and as regulators of organismal longevity. SIRT1 and the FOXO transcription factor FOXO3 formed a complex in cells in response to oxidative stress, and SIRT1 deacetylated FOXO3 in vitro and within cells. SIRT1 had a dual effect on FOXO3 function: SIRT1 increased FOXO3's ability to induce cell cycle arrest and resistance to oxidative stress but inhibited FOXO3's ability to induce cell death. Thus, one way in which members of the Sir2 family of proteins may increase organismal longevity is by tipping FOXO-dependent responses away from apoptosis and toward stress resistance.

Detection of large-scale variation in the human genome.

Abstract: We identified 255 loci across the human genome that contain genomic imbalances among unrelated individuals. Twenty-four variants are present in > 10% of the individuals that we examined. Half of these regions overlap with genes, and many coincide with segmental duplications or gaps in the human genome assembly. This previously unappreciated heterogeneity may underlie certain human phenotypic variation and susceptibility to disease and argues for a more dynamic human genome structure.

Revised Bethesda Guidelines for Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome) and Microsatellite Instability

Abstract: Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is a common autosomal dominant syndrome characterized by early age at onset, neoplastic lesions, and microsatellite instability (MSI). Because cancers with MSI account for approximately 15% of all colorectal cancers and because of the need for a better understanding of the clinical and histologic manifestations of HNPCC, the National Cancer Institute hosted an international workshop on HNPCC in 1996, which led to the development of the Bethesda Guidelines for the identification of individuals with HNPCC who should be tested for MSI. To consider revision and improvement of the Bethesda Guidelines, another HNPCC workshop was held at the National Cancer Institute in Bethesda, MD, in 2002. In this commentary, we summarize the Workshop presentations on HNPCC and MSI testing; present the issues relating to the performance, sensitivity, and specificity of the Bethesda Guidelines; outline the revised Bethesda Guidelines for identifying individuals at risk for HNPCC; and recommend criteria for MSI testing.

Investor Sentiment and the Cross-Section of Stock Returns

Abstract: We examine how investor sentiment affects the cross-section of stock returns. Theory predicts that a broad wave of sentiment will disproportionately affect stocks whose valuations are highly subjective and are difficult to arbitrage. We test this prediction by studying how the cross-section of subsequent stock returns varies with proxies for beginning-of-period investor sentiment. When sentiment is low, subsequent returns are relatively high on smaller stocks, high volatility stocks, unprofitable stocks, non-dividend-paying stocks, extreme-growth stocks, and distressed stocks, consistent with an initial underpricing of these stocks. When sentiment is high, on the other hand, these patterns attenuate or fully reverse. The results are consistent with predictions and appear unlikely to reflect an alternative explanation based on compensation for systematic risk.

Activating Mutations of NOTCH1 in Human T Cell Acute Lymphoblastic Leukemia

Abstract: Very rare cases of human T cell acute lymphoblastic leukemia (T-ALL) harbor chromosomal translocations that involve NOTCH1, a gene encoding a transmembrane receptor that regulates normal T cell development. Here, we report that more than 50% of human T-ALLs, including tumors from all major molecular oncogenic subtypes, have activating mutations that involve the extracellular heterodimerization domain and/or the C-terminal PEST domain of NOTCH1. These findings greatly expand the role of activated NOTCH1 in the molecular pathogenesis of human T-ALL and provide a strong rationale for targeted therapies that interfere with NOTCH signaling.

A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease

Abstract: Background Restenosis after coronary stenting necessitates repeated percutaneous or surgical revascularization procedures. The delivery of paclitaxel to the site of vascular injury may reduce the incidence of neointimal hyperplasia and restenosis. Methods At 73 U.S. centers, we enrolled 1314 patients who were receiving a stent in a single, previously untreated coronary-artery stenosis (vessel diameter, 2.5 to 3.75 mm; lesion length, 10 to 28 mm) in a prospective, randomized, double-blind study. A total of 652 patients were randomly assigned to receive a bare-metal stent, and 662 to receive an identical-appearing, slow-release, polymer-based, paclitaxel-eluting stent. Angiographic follow-up was prespecified at nine months in 732 patients. Results In terms of base-line characteristics, the two groups were well matched. Diabetes mellitus was present in 24.2 percent of patients; the mean reference-vessel diameter was 2.75 mm, and the mean lesion length was 13.4 mm. A mean of 1.08 stents (length, 21.8 mm) were...

Sacred and Secular: Religion and Politics Worldwide

Abstract: Part I. Understanding Secularization: 1. The secularization debate 2. Measuring secularization 3. Comparing secularization worldwide Part II. Case Studies of Religion and Politics: 4. The puzzle of secularization in the United States and Western Europe 5. A religious revival in post-communist Europe? 6. Religion and politics in the Muslim world Part III. The Consequences of Secularization: 7. Religion, the Protestant ethic, and moral values 8. Religious organizations and social capital 9. Religious parties and electoral behavior Part IV. Conclusions: 10. Secularization and its consequences 11. Re-examining the theory of existential security 12. Re-examining evidence for the security thesis.

Protected Carotid-Artery Stenting versus Endarterectomy in High-Risk Patients

Abstract: background Carotid endarterectomy is more effective than medical management in the prevention of stroke in patients with severe symptomatic or asymptomatic atherosclerotic carotidartery stenosis. Stenting with the use of an emboli-protection device is a less invasive revascularization strategy than endarterectomy in carotid-artery disease. methods We conducted a randomized trial comparing carotid-artery stenting with the use of an emboli-protection device to endarterectomy in 334 patients with coexisting conditions that potentially increased the risk posed by endarterectomy and who had either a symptomatic carotid-artery stenosis of at least 50 percent of the luminal diameter or an asymptomatic stenosis of at least 80 percent. The primary end point of the study was the cumulative incidence of a major cardiovascular event at 1 year — a composite of death, stroke, or myocardial infarction within 30 days after the intervention or death or ipsilateral stroke between 31 days and 1 year. The study was designed to test the hypothesis that the less invasive strategy, stenting, was not inferior to endarterectomy. results The primary end point occurred in 20 patients randomly assigned to undergo carotidartery stenting with an emboli-protection device (cumulative incidence, 12.2 percent) and in 32 patients randomly assigned to undergo endarterectomy (cumulative incidence, 20.1 percent; absolute difference, i7.9 percentage points; 95 percent confidence interval, i16.4 to 0.7 percentage points; P=0.004 for noninferiority, and P=0.053 for superiority). At one year, carotid revascularization was repeated in fewer patients who had received stents than in those who had undergone endarterectomy (cumulative incidence, 0.6 percent vs. 4.3 percent; P=0.04). conclusions Among patients with severe carotid-artery stenosis and coexisting conditions, carotid stenting with the use of an emboli-protection device is not inferior to carotid endarterectomy.

Do Institutions Cause Growth

Abstract: We revisit the debate over whether political institutions cause economic growth, or whether, alternatively, growth and human capital accumulation lead to institutional improvement. We find that most indicators of institutional quality used to establish the proposition that institutions cause growth are constructed to be conceptually unsuitable for that purpose. We also find that some of the instrumental variable techniques used in the literature are flawed. Basic OLS results, as well as a variety of additional evidence, suggest that (a) human capital is a more basic source of growth than are the institutions, (b) poor countries get out of poverty through good policies, often pursued by dictators, and (c) subsequently improve their political institutions.