Showing papers by "Dartmouth College published in 1994"

Verification, Validation, and Confirmation of Numerical Models in the Earth Sciences

Abstract: Verification and validation of numerical models of natural systems is impossible. This is because natural systems are never closed and because model results are always nonunique. Models can be confirmed by the demonstration of agreement between observation and prediction, but confirmation is inherently partial. Complete confirmation is logically precluded by the fallacy of affirming the consequent and by incomplete access to natural phenomena. Models can only be evaluated in relative terms, and their predictive value is always open to question. The primary value of models is heuristic.

Instrumental Variables Regression with Weak Instruments

Abstract: This paper develops asymptotic distribution theory for instrumental variable regression when the partial correlation between the instruments and a single included endogenous variable is weak, here modeled as local to zero. Asymptotic representations are provided for various instrumental variable statistics, including the two-stage least squares (TSLS) and limited information maximum- likelihood (LIML) estimators and their t-statistics. The asymptotic distributions are found to provide good approximations to sampling distributions with just 20 observations per instrument. Even in large samples, TSLS can be badly biased, but LIML is, in many cases, approximately median unbiased. The theory suggests concrete quantitative guidelines for applied work. These guidelines help to interpret Angrist and Krueger's (1991) estimates of the returns to education: whereas TSLS estimates with many instruments approach the OLS estimate of 6%, the more reliable LIML and TSLS estimates with fewer instruments fall between 8% and 10%, with a typical confidence interval of (6%, 14%).

CEO Duality as a Double-Edged Sword: How Boards of Directors Balance Entrenchment Avoidance and Unity of Command

Abstract: When a firm's chief executive officer is also the chairperson of its board, directors have opposing objectives. According to organization theory, such CEO duality establishes strong, unambiguous le...

Simulation of nonideal gases and liquid-gas phase transitions by the lattice Boltzmann equation.

Abstract: We describe in detail a recently proposed lattice-Boltzmann model [X. Shan and H. Chen, Phys. Rev. E 47, 1815 (1993)] for simulating flows with multiple phases and components. In particular, the focus is on the modeling of one-component fluid systems which obey nonideal gas equations of state and can undergo a liquid-gas-type phase transition. The model is shown to be momentum conserving. From the microscopic mechanical stability condition, the densities in bulk liquid and gas phases are obtained as functions of a temperaturelike parameter. Comparisons with the thermodynamic theory of phase transitions show that the lattice-Boltzmann-equation model can be made to correspond exactly to an isothermal process. The density profile in the liquid-gas interface is also obtained as a function of the temperaturelike parameter and is shown to be isotropic. The surface tension, which can be changed independently, is calculated. The analytical conclusions are verified by numerical simulations.

Neuropsychological Deficits in Neuroleptic Naive Patients With First-Episode Schizophrenia

Abstract: Background: Medication and chronicity have complicated past attempts to characterize the neuropsychological performance of patients with schizophrenia. There have been inconsistencies regarding the pattern, selectivity, and sources of observed deficits. Our objective was to comprehensively examine neuropsychological function in patients with schizophrenia who had never been exposed to neuroleptic medication, and who were experiencing their first episode (FE) of psychosis. Methods: Subjects were consecutive recruitments that included 37 patients with FE schizophrenia who were never exposed to neuroleptics. These subjects were compared with 65 unmedicated, previously treated (PT) patients and 131 healthy controls. Results: The patient groups had nearly identical profiles showing generalized impairment, particularly in verbal memory and learning, attention-vigilance, and speeded visual-motor processing and attention. Verbal memory and learning accounted for most of the variance between patients and controls and removing this effect substantially attenuated all other differences. By contrast, both the FE group and PT group continued to show highly significant deficits in verbal memory and learning after controlling for attention, abstraction, and all other functions. Some functions not typically implicated in schizophrenia (spatial cognition, fine motor speed, and visual memory) were more impaired in the PT group than in the FE group. Conclusions: Verbal memory, as a primary neuropsychological deficit present early in the course of schizophrenia, implicates the left temporal-hippocampal system. Neuropsychological evaluations before treatment permit differentiation of primary deficits from changes secondary to medication or chronicity. This is essential for developing a neurobehavioral perspective on schizophrenia.

Interpreting Tests of the Convergence Hypothesis

Abstract: This paper provides a framework for understanding the cross- section and time series approaches which have been used to test the convergence hypothesis First, we present two definitions of convergence which capture the implications of the neoclassical growth model for the relationship between current and future cross-country output differences Second, we identify how the cross-section and time series approaches relate to these definitions Cross-section tests are shown to be associated with a weaker notion of convergence than time series tests Third, we show how these alternative approaches make different assumptions on whether the data are well characterized by a limiting distribution As a result, the choice of an appropriate testing framework is shown to depend on both the specific null and alternative hypotheses under consideration as well as on the initial conditions characterizing the data being studied

Wavelet transform domain filters: a spatially selective noise filtration technique

Abstract: Wavelet transforms are multiresolution decompositions that can be used to analyze signals and images They describe a signal by the power at each scale and position Edges can be located very effectively in the wavelet transform domain A spatially selective noise filtration technique based on the direct spatial correlation of the wavelet transform at several adjacent scales is introduced A high correlation is used to infer that there is a significant feature at the position that should be passed through the filter The authors have tested the technique on simulated signals, phantom images, and real MR images It is found that the technique can reduce noise contents in signals and images by more than 80% while maintaining at least 80% of the value of the gradient at most edges The authors did not observe any Gibbs' ringing or significant resolution loss on the filtered images Artifacts that arose from the filtration are very small and local The noise filtration technique is quite robust There are many possible extensions of the technique The authors see its applications in spatially dependent noise filtration, edge detection and enhancement, image restoration, and motion artifact removal They have compared the performance of the technique to that of the Weiner filter and found it to be superior >

Guidelines for Meta-analyses Evaluating Diagnostic Tests

Abstract: Objectives: To introduce guidelines for the conduct, reporting, and critical appraisal of meta-analyses evaluating diagnostic tests and to apply these guidelines to recently published meta-analyses...

Iron: Nutritious, Noxious, and Not Readily Available.

Abstract: Fe(I1) and Fe(II1) are relatively small ions with a marked propensity to form six-coordinate complexes with ligands containing O, N, and S. This property, combined with the remarkable range of redox potentials covered by ironcontaining enzymes, accounts for the role of iron in such fundamental reactions as ribonucleotide and dinitrogen reduction as well as in the energy-yielding electron transfer reactions of respiration and photosynthesis. At the same time, the chemical properties of iron place limitations on the cellular accumulation of this element. First, Fe(I1) and Fe(II1) can act catalytically to generate hydroxyl radicals that are the most potent oxidizing agents known (Table I). Because of the potential of iron for wreaking cellular havoc, organisms generally regulate its uptake; as well, they store iron in the form of ferritin, a multimeric protein consisting of a 24-subunit shell that can house up to 4500 atoms of iron in its central cavity (Theil, 1987). Iron stored in this manner is nontoxic and is readily available to the cell. The second limit to iron acquisition is the fact that iron is found in nature mostly as a constituent of insoluble oxyhydroxide polymers of the general composition FeOOH (Table I). These Fe(II1) oxides (e.g. goethite, hematite) are produced by the weathering of rock. Because Fe(II1) oxides are quite stable and not very soluble at neutra1 pH, free Fe(II1) in an aerobic, aqueous environment is limited to an equilibrium concentration of approximately 10-17 M, a value far below that required for the optimal growth of plants or microbes (Table I). Thus, the problem that soil-based organisms have with iron is not one of abundance, since iron ranks fourth among a11 elements on the surface of the earth, but rather one of availability in aerobic environments at biological pH. Iron deficiency can be particularly pronounced in plants grown on calcareous soils, which cover approximately onethird of the earth's surface. Iron deficiency is usually recognized by chlorotic or yellowed interveinal areas in new leaves and, if severe, can lead to reduction in crop yields and even complete crop failure. Chemically speaking, organisms have three means at their disposal to dissolve Fe(II1) oxides: protonation, chelation, and reduction. To compete successfully for iron, organisms have thus evolved specific mechanisms to acquire iron that are based on these chemical processes. In many organisms, in-

A Clinical Trial of Antioxidant Vitamins to Prevent Colorectal Adenoma

Abstract: Background People who consume a diet high in vegetables and fruits have a lower risk of cancer of the large bowel. Antioxidant vitamins, which are present in vegetables and fruits, have been associated with a diminished risk of cancers at various anatomical sites. We conducted a randomized, controlled clinical trial to test the efficacy of beta carotene and vitamins C and E in preventing colorectal adenoma, a precursor of invasive cancer. Methods We randomly assigned 864 patients, using a two-by-two factorial design, to four treatment groups, which received placebo, beta carotene (25 mg daily), vitamin C (1 g daily) and vitamin E (400 mg daily), or beta carotene plus vitamins C and E. In order to identify new adenomas, we performed complete colonoscopic examinations in the patients one year and four years after they entered the study. The primary end points for analyses were new adenomas identified after the first of these two follow-up examinations. Results Patients adhered well to the prescribed regimen...

Microbial Iron Transport

Abstract: Iron, an essential nutrient, is not readily available in aquatic or terrestrial environments or in animal hosts. Therefore, microbes have developed various strategies for acquiring iron while at the same time protecting themselves from iron's potential toxic effects. The major strategies used by bacteria and fungi to acquire iron include production and utilization of siderophores (ferric specific chelators); utilization of host iron compounds such as heme, transferrin, and lactoferrin; and reduction of Fe(III) to Fe(II) with subsequent transport of Fe(II). Selected examples are discussed with attention to which strategies work best in which environments. The similarities and differences among the different systems with respect to iron binding compounds, receptors, and regulation are also presented.

Negative Feedback Defining a Circadian Clock: Autoregulation of the Clock Gene Frequency

Abstract: The frequency (frq) locus of Neurospora crassa was originally identified in searches for loci encoding components of the circadian clock. The frq gene is now shown to encode a central component in a molecular feedback loop in which the product of frq negatively regulated its own transcript, which resulted in a daily oscillation in the amount of frq transcript. Rhythmic messenger RNA expression was essential for overt rhythmicity in the organism and no amount of constitutive expression rescued normal rhythmicity in frq loss-of-function mutants. Step reductions in the amount of FRQ-encoding transcript set the clock to a specific and predicted phase. These results establish frq as encoding a central component in a circadian oscillator.

Outcomes after Displaced Fractures of the Femoral Neck. A Meta-Analysis of One Hundred and Six Published Reports.

Abstract: Methods of meta-analysis, a technique for the combination of data from multiple sources, were applied to analyze 106 reports of the treatment of displaced fractures of the femoral neck. Two years or less after primary internal fixation of a displaced fracture of the femoral neck, a non-union had developed in 33 per cent of the patients and avascular necrosis, in 16 per cent. The rate of performance of a second operation within two years ranged from 20 to 36 per cent after internal fixation and from 6 to 18 per cent after hemiarthroplasty (relative risk, 2.6; 95 per cent confidence interval, 1.4 to 4.6). Conversion to an arthroplasty was the most common reoperation after internal fixation and accounted for about two-thirds of these procedures. The remaining one-third of the reoperations were for removal of the implant or revision of the internal fixation. For the patients who had had a hemiarthroplasty, the most common reoperations were conversion to a total hip replacement, removal or revision of the prosthesis, and debridement of the wound. Although we observed an increase in the rate of mortality at thirty days after primary hemiarthroplasty compared with that after primary internal fixation, the difference was not significant (p = 0.22) and did not persist beyond three months. The absolute difference in perioperative mortality between the two groups was small. An anterior operative approach for arthroplasty consistently was associated with a lower rate of mortality at two months than was a posterior approach. Some reports showed promising results after total hip replacement for displaced fractures of the femoral neck; however, randomized clinical trials are still needed to establish the value of this treatment.

The epidemiology of diagnosed pulmonary embolism and deep venous thrombosis in the elderly

Abstract: Background: There are no studies that define the basic epidemiology of pulmonary embolism (PE) and deep venous thrombosis (DVT) in the elderly. This project was undertaken to provide that information. Methods: We obtained all Medicare claims during the period 1986 through 1989 from a random 5% sample of US Medicare enrollees. By selecting codes used for diagnoses and treatment, we identified 7174 cases of PE and 8923 cases of DVT. These cohorts were analyzed to provide incidence by age, race, sex, and geographic location; frequency of invasive treatment; frequency of PE after treatment for DVT; frequency of recurrence of PE; and survival after diagnosis. Results: Annual incidence rates per 1000 at age 65 to 69 years for PE and DVT were 1.3 and 1.8, respectively. Both rates increased steadily with age to 2.8 and 3.1 by age 85 to 89 years. For PE, women had lower rates than men (adjusted relative risk, 0.86; 95% confidence interval, 0.82 to 0.90), and blacks had higher rates than whites (adjusted relative risk, 1.25; 95% confidence interval, 1.15 to 1.36). For DVT, the associations with gender and race were weaker and in the opposite direction. Pulmonary embolectomy was done in 0.2% of cases of PE; interruption of the vena cava was done in 4.4% of cases of PE and in 2% of cases of DVT. Thrombectomy was done in 0.3% of all cases. Pulmonary embolism occurred in 1.7% of patients with DVT within 1 year of hospital discharge for initial treatment. The 1-year recurrence rate for PE was 8.0%. In-hospital mortality associated with PE and DVT was 21% and 3%, respectively. One-year mortality was 39% and 21%. respectively. Conclusions: Pulmonary embolism and DVT are common problems in the elderly. Both increase with age, but the effects of race and sex are small. Current treatment patterns appear to be effective in preventing both PE after DVT and recurrence of PE. Both are associated with substantial 1-year mortality, suggesting the need to understand the role of associated conditions as well as the indications for prophylaxis and the methods of treatment. (Arch Intern Med. 1994;154:861-866)

Energy Transduction by Cytochrome Complexes in Mitochondrial and Bacterial Respiration: The Enzymology of Coupling Electron Transfer Reactions to Transmembrane Proton Translocation

Abstract: INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 676 THE PROTONMOTIVE ENZYME COMPLEXES OF RESPIRATION ..... . . . 676 A COMPARISON OF MITOCHONDRIAL AND BACTERIAL RESPIRATORY SYSTEMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 677 PROTON TRANSLOCATION SCHEMES . . . . . . . . . . . . . . . . . . . . . . . . . . 679 Cytochrome bd: Formation of a Proton Gradient by Substrate Protons without a Transmembrane Channel . . . . . . . . . . . . . . . . . . . . . . . . . . 679 Cytochrome bo: Proton Translocation by Substrate Protons Plus a Transmembrane Channel 680 Cytochrome c Oxidase: A Proton Pump . . . . . . . . . . . . . . . . . . . . . . . . . . 681 Cytochrome bCI Complex: Proton Translocation by Substrate Protons . . . . . . . 681

Lactation and a reduced risk of premenopausal breast cancer

Abstract: Background The evidence of an association of lactation with a reduction in the risk of breast cancer among women has been limited and inconsistent. The effect of lactation appears to be confined to premenopausal women with a history of long lactation, but most studies of this relation have been limited in statistical power. We conducted a multicenter, population-based, case-control study with a sample large enough for us to describe more precisely the association between lactation and the risk of breast cancer. Methods Patients less than 75 years old who had breast cancer were identified from statewide tumor registries in Wisconsin, Massachusetts, Maine, and New Hampshire. Controls were randomly selected from lists of licensed drivers if the case subjects were less than 65 years old, and from lists of Medicare beneficiaries if they were 65 through 74 years old. Information on lactation, reproductive history, and family and medical history was obtained by means of telephone interviews. After the exclusion ...

gp39-CD40 interactions are essential for germinal center formation and the development of B cell memory.

Abstract: gp39, the ligand for CD40 expressed on activated CD4+ T helper cells, is required for the generation of antibody responses to T-dependent (TD) antigens. Treatment of mice with anti-gp39 in vivo inhibits both primary and secondary antibody formation to TD, but not T-independent antigens. However, the role of this receptor-ligand pair in the development of germinal centers and the generation of B cell memory is as yet undefined. Using an antibody to gp39, this study examines the in vivo requirement for gp39-CD40 interactions in the induction of germinal center formation, as well as in the generation of B cell memory. Animals were immunized, treated in vivo with anti-gp39, and evaluated using immunohistochemical staining for the presence of splenic germinal centers 9-11 d after immunization. The results demonstrate that the formation of germinal centers was completely inhibited as a result of treatment with anti-gp39. Moreover, adoptive transfer experiments demonstrate that the generation of antigen-specific memory B cells is also inhibited as a consequence of blocking gp39-CD40 interactions. Taken together, the data demonstrate that gp39-CD40 interactions are critical not only for the generation of antibody responses, but also in the development of B cell memory. Chemicals/CAS: Antigens, CD; Antigens, CD40; Antigens, Differentiation, B-Lymphocyte; CD40 Ligand, 147205-72-9; Membrane Glycoproteins

The Impact of Serious Illness on Patients' Families

Abstract: Objective. —To examine the impact of illness on the families of seriously ill adults and to determine the correlates of adverse economic impact. Design. —Data were collected during the Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatment (SUPPORT), a prospective cohort study of outcomes, preferences, and decision making in seriously ill hospitalized adults and their families. Setting. —Five tertiary care hospitals in the United States. Participants. —The 2661 seriously ill patients in nine diagnostic categories who survived their index hospitalization and were discharged home were eligible for this analysis. Surrogate and/or patient interviews about the impact of illness on the family were obtained for 2129 (80%) of these patients (mean age, 62 years; 43% women; 6-month survival, 75%). Outcome Measures. —Surrogates and patients were surveyed to determine the frequency of adverse caregiving and economic burdens. Multivariable analyses were performed to determine correlates of loss of family savings. Results. —One third (34%) of patients required considerable caregiving assistance from a family member. In 20% of cases, a family member had to quit work or make another major life change to provide care for the patient. Loss of most or all of the family savings was reported by 31% of families, whereas 29% reported loss of the major source of income. Patient factors independently associated with loss of the family's savings on multivariable analysis included poor functional status (odds ratio [OR], 1.40; 95% confidence interval [CI], 1.10 to 1.78 for patients needing assistance with three or more activities of daily living), lower family income (OR, 1.74; 95% CI, 1.37 to 2.21 for those with annual incomes below $25 000), and young age (OR, 2.85; 95% CI, 2.13 to 3.82 for those younger than 45 years compared with those 65 years or older). Conclusions. —Many families of seriously ill patients experience severe caregiving and financial burdens. Families of younger, poorer, and more functionally dependent patients are most likely to report loss of most or all of the family's savings. (JAMA. 1994;272:1839-1844)

Sequential strategy to identify a susceptibility gene for schizophrenia: Report of potential linkage on chromosome 22q12‐q13.1: Part 1

Abstract: We describe four infants with a novel subtype of an isolated deficiency of one of the peroxisomal beta-oxidation enzymes with detectable enzyme protein. The patients showed characteristic clinical and biochemical abnormalities, including hypotonia, psychomotor retardation, hepatomegaly, typical facial appearance, accumulation of very-long-chain fatty acids, and decreased lignoceric acid oxidation. However, beta-oxidation enzyme proteins were detected by immunoblot analyses, and large peroxisomes were identified by immunofluorescence staining. In order to identify the underlying defect in these patients, complementation analysis was introduced using fibroblasts from these patients and patients with an established deficiency of either acyl-CoA oxidase or bifunctional enzyme, as identified by immunoblotting. In the complementing combinations, fused cells showed increased lignoceric acid oxidation, resistance against 1-pyrene dodecanoic acid/UV selection, and normalization of the size and the distribution of peroxisomes. The results indicate that two patients with a more severe clinical course were suffering from bifunctional enzyme deficiency and that the other two infants, who were siblings and had a less severe clinical presentation, were the first patients with acyl-CoA oxidase deficiency with detectable enzyme protein.

Aminoguanidine, an inhibitor of inducible nitric oxide synthase, ameliorates experimental autoimmune encephalomyelitis in SJL mice.

Abstract: Previous work from our laboratory localized nitric oxide to the affected spinal cords of mice with experimental autoimmune encephalomyelitis, a prime model for the human disease multiple sclerosis. The present study shows that activated lymphocytes sensitized to the central nervous system encephalitogen, myelin basic protein, can induce nitric oxide production by a murine macrophage cell line. Induction was inhibited by amino-guanidine, a preferential inhibitor of the inducible nitric oxide synthase isoform, and by NG-monomethyl-L-arginine. Aminoguanidine, when administered to mice sensitized to develop experimental autoimmune encephalomyelitis, inhibited disease expression in a dose-related manner. At 400 mg aminoguanidine/kg per day, disease onset was delayed and the mean maximum clinical score was 0.9 +/- 1.2 in aminoguanidine versus 3.9 +/- 0.9 in placebo-treated mice. Histologic scoring of the spinal cords for inflammation, demyelination, and axonal necrosis revealed significantly less pathology in the aminoguanidine-treated group. The present study implicates excessive nitric oxide production in the pathogenesis of murine inflammatory central nervous system demyelination, and perhaps in the human disease multiple sclerosis.

A Tale of Two Cities: Distinctiveness Theory and Advertising Effectiveness:

Abstract: The authors conducted an empirical study to test McGuire's (1984) distinctiveness theory within an advertising context. First, following the distinctiveness theory postulate, they found that member...

Economies of Integration Versus Bureaucracy Costs: Does Vertical Integration Improve Performance?

Abstract: This study tested links between vertical integration, cost structure, and performance at the line-of-business level of analysis. Major findings were (1) Vertical integration results in economies ev...

Choosing and leaving science in highly selective institutions

Abstract: This study sought to discover some of the causes of initial interset in and atrition from the natural sciences and engineering among the students (N=5320) who entered four highly selective institutions in 1988, with particular attention to possible special causes for the disproportionate attrition of women from science. Though a smaller proportion of women (35 percent) than men (49 percent) were initially interested in science, gender added little to the prediction of such initial choice when preadmission measures of developed abilities were taken into account in regression analysis. Of the group of 2,276 students initially interested in science, 40 percent did not finally concentrate in science, and smaller proportions of women (48 percent) than of men (66 percent) persisted. The most significant cognitive, factor predicting these losses was low grades earned in science courses taken during the first two years of study. With grades held equal, gender was not a significant predictor of persistence in engineering and biology; gender added strongly to grades, however, as a factor associated with unusually large losses of women from a category that included the physical sciences and mathematics. Responses to a questionnaire administered in the fall of 1991 showed that science majors regarded their instruction as too competitive, with too few opportunities to ask questions, taught by professors who were relatively unresponsive, not dedicated, and not motivating. Students who defected from science did so largely because of the attraction of other fields, but many shared the criticism of overcompetitiveness and inferior instruction, along with the view that the work was too difficult. Several items were about elements of classroom instruction and atmosphere thought to be especially difficult for women (i.e., the chilly climate), but except for perceived competitiveness, women did not rate their classroom experiences as being more unpleasant than did men.

The Protonmotive Q Cycle in Mitochondria and Bacteria

Abstract: The cytochrome bc1 complex is an oligomeric electron transfer enzyme located in the inner membrane of mitochondria and the plasma membrane of bacteria. The cytochrome bc1 complex participates in respiration in eukaryotic cells and also participates in respiration, cyclic photosynthetic electron transfer, denitrification, and nitrogen fixation in a phylogenetically diverse collection of bacteria. In all of these organisms, the cytochrome bc1 complex transfers electrons from ubiquinol to cytochrome c and links this electron transfer to translocation of protons across the membrane in which it resides, thus converting the available free energy of the oxidation-reduction reaction into an electrochemical proton gradient. The mechanism by which the cytochrome bc1 complex achieves this energy transduction is the protonmotive Q cycle. The Q cycle mechanism has been documented by extensive experimentation, and recent investigations have focused on structural features of the three redox subunits of the bc1 c...