Showing papers by "Indiana University published in 1998"
TL;DR: Highly luminescent semiconductor quantum dots (zinc sulfide-capped cadmium selenide) have been covalently coupled to biomolecules for use in ultrasensitive biological detection and these nanometer-sized conjugates are water-soluble and biocompatible.
Abstract: Highly luminescent semiconductor quantum dots (zinc sulfide-capped cadmium selenide) have been covalently coupled to biomolecules for use in ultrasensitive biological detection. In comparison with organic dyes such as rhodamine, this class of luminescent labels is 20 times as bright, 100 times as stable against photobleaching, and one-third as wide in spectral linewidth. These nanometer-sized conjugates are water-soluble and biocompatible. Quantum dots that were labeled with the protein transferrin underwent receptor-mediated endocytosis in cultured HeLa cells, and those dots that were labeled with immunomolecules recognized specific antibodies or antigens.
7,393 citations
Book•
28 Sep 1998TL;DR: The authors combine theory and practice to make sophisticated methods of analysis accessible to researchers and practitioners working with widely different types of data and software in areas such as applied statistics, econometrics, marketing, operations research, actuarial studies, demography, biostatistics and quantitative social sciences.
Abstract: Students in both social and natural sciences often seek regression methods to explain the frequency of events, such as visits to a doctor, auto accidents, or new patents awarded. This book, now in its second edition, provides the most comprehensive and up-to-date account of models and methods to interpret such data. The authors combine theory and practice to make sophisticated methods of analysis accessible to researchers and practitioners working with widely different types of data and software in areas such as applied statistics, econometrics, marketing, operations research, actuarial studies, demography, biostatistics and quantitative social sciences. The new material includes new theoretical topics, an updated and expanded treatment of cross-section models, coverage of bootstrap-based and simulation-based inference, expanded treatment of time series, multivariate and panel data, expanded treatment of endogenous regressors, coverage of quantile count regression, and a new chapter on Bayesian methods.
4,849 citations
TL;DR: In this paper, the economics of small business finance in private equity and debt markets are examined. But the authors focus on the macroeconomic environment and do not consider the impact of the macro economic environment on small business.
Abstract: This article examines the economics of financing small business in private equity and debt markets. Firms are viewed through a financial growth cycle paradigm in which different capital structures are optimal at different points in the cycle. We show the sources of small business finance, and how capital structure varies with firm size and age. The interconnectedness of small firm finance is discussed along with the impact of the macroeconomic environment. We also analyze a number of research and policy issues, review the literature, and suggest topics for future research.
2,778 citations
[...]
TL;DR: Total mortality, rather than classifications of cardiac and arrhythmic mortality, should be used as primary objectives for many outcome studies.
Abstract: Sudden cardiac death describes the unexpected natural death from a cardiac cause within a short time period, generally ≤ 1 h from the onset of symptoms, in a person without any prior condition that would appear fatal [1, 2]. Such a rapid death is often attributed to a cardiac arrhythmia, but with the advent of monitoring capabilities from implantable cardioverter-defibrillators (ICDs), it is now well recognized that classifications based on clinical circumstances can be misleading and often impossible, because 40% of sudden deaths can be unwitnessed [3]. Only an ECG or a ventricular electrogram recorded from an implanted device at the time of death can provide definitive information about an arrhythmia. Prodromal symptoms are often nonspecific, and even those taken to indicate ischemia (chest pain), a tachyarrhythmia (palpitations), or congestive heart failure symptoms (dyspnea) can only be considered suggestive. For these reasons, total mortality, rather than classifications of cardiac and arrhythmic mortality, should be used as primary objectives for many outcome studies.
2,590 citations
TL;DR: Monoclonal antibody assessment of cancellous cellular marrow grafts demonstrated cells that were capable of responding to the growth factors by bearing cell membrane receptors and evidenced a radiographic maturation rate 1.62 to 2.16 times that of grafts without platelet-rich plasma.
Abstract: Platelet-rich plasma is an autologous source of platelet-derived growth factor and transforming growth factor beta that is obtained by sequestering and concentrating platelets by gradient density centrifugation. This technique produced a concentration of human platelets of 338% and identified platelet-derived growth factor and transforming growth factor beta within them. Monoclonal antibody assessment of cancellous cellular marrow grafts demonstrated cells that were capable of responding to the growth factors by bearing cell membrane receptors. The additional amounts of these growth factors obtained by adding platelet-rich plasma to grafts evidenced a radiographic maturation rate 1.62 to 2.16 times that of grafts without platelet-rich plasma. As assessed by histomorphometry, there was also a greater bone density in grafts in which platelet-rich plasma was added (74.0% +/- 11%) than in grafts in which platelet-rich plasma was not added (55.1% +/- 8%; p = 0.005).
2,587 citations
TL;DR: The authors provide meta-analyses of 54 empirical studies of board composition (159 samples, n = 40,160) and 31 empirical studies on board leadership structure and their relationship to firm financial performance.
Abstract: Careful review of extant research addressing the relationships between board composition, board leadership structure, and firm financial performance demonstrates little consistency in results. In general, neither board composition nor board leadership structure has been consistently linked to firm financial performance. In response to these findings, we provide metaanalyses of 54 empirical studies of board composition (159 samples, n = 40,160) and 31 empirical studies of board leadership structure (69 samples, n= 12,915) and their relationships to firm financial performance. These—and moderator analyses relying on firm size, the nature of the financial performance indicator, and various operationalizations of board composition— provide little evidence of systematic governance structure/financial performance relationships. © 1998 John Wiley & Sons, Ltd.
2,289 citations
TL;DR: In this paper, the authors discuss two major empirical findings that begin to show how individuals achieve results that are better than rational by building conditions where reciprocity, reputation, and trust can help to overcome the strong temptations of short-run self-interest.
Abstract: Extensive empirical evidence and theoretical developments in multiple disciplines stimulate a need to expand the range of rational choice models to be used as a foundation for the study of social dilemmas and collective action. After an introduction to the problem of overcoming social dilemmas through collective action, the remainder of this article is divided into six sections. The first briefly reviews the theoretical predictions of currently accepted rational choice theory related to social dilemmas. The second section summarizes the challenges to the sole reliance on a complete model of rationality presented by extensive experimental research. In the third section, I discuss two major empirical findings that begin to show how individuals achieve results that are “better than rational” by building conditions where reciprocity, reputation, and trust can help to overcome the strong temptations of short-run self-interest. The fourth section raises the possibility of developing second-generation models of rationality, the fifth section develops an initial theoretical scenario, and the final section concludes by examining the implications of placing reciprocity, reputation, and trust at the core of an empirically tested, behavioral theory of collective action.
2,265 citations
TL;DR: In this article, a general Lorentz-violating extension of the minimal quantum field theory is presented, which can be viewed as the low-energy limit of a physically relevant fundamental theory with Lorenerz-covariant dynamics in which spontaneous LorentZ violation occurs.
Abstract: In the context of conventional quantum field theory, we present a general Lorentz-violating extension of the minimal $\mathrm{SU}(3)\ifmmode\times\else\texttimes\fi{}\mathrm{SU}(2)\ifmmode\times\else\texttimes\fi{}\mathrm{U}(1)$ standard model including $\mathrm{CPT}$-even and $\mathrm{CPT}$-odd terms. It can be viewed as the low-energy limit of a physically relevant fundamental theory with Lorentz-covariant dynamics in which spontaneous Lorentz violation occurs. The extension has gauge invariance, energy-momentum conservation, and covariance under observer rotations and boosts, while covariance under particle rotations and boosts is broken. The quantized theory is Hermitian and power-counting renormalizable, and other desirable features such as microcausality, positivity of the energy, and the usual anomaly cancellation are expected. Spontaneous symmetry breaking to the electromagnetic U(1) is maintained, although the Higgs expectation is shifted by a small amount relative to its usual value and the ${Z}^{0}$ field acquires a small expectation. A general Lorentz-breaking extension of quantum electrodynamics is extracted from the theory, and some experimental tests are considered. In particular, we study modifications to photon behavior. One possible effect is vacuum birefringence, which could be bounded from cosmological observations by experiments using existing techniques. Radiative corrections to the photon propagator are examined. They are compatible with spontaneous Lorentz and $\mathrm{CPT}$ violation in the fermion sector at levels suggested by Planck-scale physics and accessible to other terrestrial laboratory experiments.
1,968 citations
Book•
[...]
01 Jan 1998
TL;DR: For example, it has become increasingly clear over the past two decades that knowledge from one organism, even one so simple as a worm, can provide tremendous power when connected with knowledge from other organisms.
Abstract: Why should one study a worm? This simple creature is one of several “model” organisms that together have provided tremendous insight into how all organisms are put together. It has become increasingly clear over the past two decades that knowledge from one organism, even one so simple as a worm, can provide tremendous power when connected with knowledge from other organisms. And because of the experimental accessibility of nematodes, knowledge about worms can come more quickly and cheaply than knowledge about higher organisms.
1,138 citations
TL;DR: Results show that SNPs in the mu opioid receptor gene can alter binding and signal transduction in the resulting receptor and may have implications for normal physiology, therapeutics, and vulnerability to develop or protection from diverse diseases including the addictive diseases.
Abstract: Opioid drugs play important roles in the clinical management of pain, as well as in the development and treatment of drug abuse. The mu opioid receptor is the primary site of action for the most commonly used opioids, including morphine, heroin, fentanyl, and methadone. By sequencing DNA from 113 former heroin addicts in methadone maintenance and 39 individuals with no history of drug or alcohol abuse or dependence, we have identified five different single-nucleotide polymorphisms (SNPs) in the coding region of the mu opioid receptor gene. The most prevalent SNP is a nucleotide substitution at position 118 (A118G), predicting an amino acid change at a putative N-glycosylation site. This SNP displays an allelic frequency of approximately 10% in our study population. Significant differences in allele distribution were observed among ethnic groups studied. The variant receptor resulting from the A118G SNP did not show altered binding affinities for most opioid peptides and alkaloids tested. However, the A118G variant receptor binds β-endorphin, an endogenous opioid that activates the mu opioid receptor, approximately three times more tightly than the most common allelic form of the receptor. Furthermore, β-endorphin is approximately three times more potent at the A118G variant receptor than at the most common allelic form in agonist-induced activation of G protein-coupled potassium channels. These results show that SNPs in the mu opioid receptor gene can alter binding and signal transduction in the resulting receptor and may have implications for normal physiology, therapeutics, and vulnerability to develop or protection from diverse diseases including the addictive diseases.
1,048 citations
TL;DR: The updated data on BMD for the total femur ROI of NHW have been selected as the reference database for femur standardization efforts by the International Committee on Standards in Bone Measurements.
Abstract: This paper describes data on bone mineral levels in the proximal femur of US adults based on the nationally representative sample examined during both phases of the third National Health and Nutrition Examination Survey (NHANES III, 1988–94), and updates data previously presented from phase 1 only. The data were collected from 14646 men and women aged 20 years and older using dual-energy X-ray absorptiometry, and included bone mineral density (BMD), bone mineral content (BMC) and area of bone scanned in four selected regions of interest (ROI) in the proximal femur: femur neck, trochanter, intertrochanter and total. These variables are provided separately by age and sex for non-Hispanic whites (NHW), non-Hispanic blacks (NHB) and Mexican Americans (MA). NHW in the southern United States had slightly lower BMD levels than NHW in other US regions, but these differences were not sufficiently large to prevent pooling of the data. The updated data provide valuable reference data on femur bone mineral levels of noninstitutionalized adults. The updated data on BMD for the total femur ROI of NHW have been selected as the reference database for femur standardization efforts by the International Committee on Standards in Bone Measurements.
TL;DR: KCNQ2, KCNQ3 and undiscovered genes of the same family of K+ channels are strong candidates for other IGEs, and a missense mutation in the critical pore region in perfect co-segregation with the BFNC phenotype is found.
Abstract: Epileptic disorders affect about 20-40 million people worldwide, and 40% of these are idiopathic generalized epilepsies (IGEs; ref. 1). Most of the IGEs that are inherited are complex, multigenic diseases. To address basic mechanisms for epilepsies, we have focused on one well-defined class of IGEs with an autosomal-dominant mode of inheritance: the benign familial neonatal convulsions (BFNC; refs 2,3). Genetic heterogeneity of BFNC has been observed. Two loci, EBN1 and EBN2, have been mapped by linkage analysis to chromosome 20q13 (refs 5,6) and chromosome 8q24 (refs 7,8), respectively. By positional cloning, we recently identified the gene for EBN1 as KCNQ2 (ref. 9). This gene, a voltage-gated potassium channel, based on homology, is a member of the KQT-like family. Here we describe an additional member, KCNQ3. We mapped this new gene to chromosome 8, between markers D8S256 and D8S284 on a radiation hybrid map. We screened KCNQ3 for mutations in the large BFNC family previously linked to chromosome 8q24 in the same marker interval. We found a missense mutation in the critical pore region in perfect co-segregation with the BFNC phenotype. The same conserved amino acid is also mutated in KVLQT1 (KCNQ1) in an LQT patient. KCNQ2, KCNQ3 and undiscovered genes of the same family of K+ channels are strong candidates for other IGEs.
TL;DR: The differential environmental fates and toxicities of various hexachlorocyclohexane (HCH) isomers including lindane and isomers in the technical mixture will be the focus of this review.
Abstract: The differential environmental fates and toxicities of the various hexachlorocyclohexane (HCH) isomers including lindane and isomers in the technical mixture will be the focus of this review. HCHs are one of the most widely used and most readily detected organochlorine pesticides in environmental samples. The relatively high volatility of HCH has led to global transport, even into formerly pristine locations such as the Arctic. Certain HCHs cause central nervous system, reproductive, and endocrine damage. Because γ-HCH is rapidly metabolized, the β-HCH isomer is consistently found in higher concentrations in human fat, blood, and breast milk. In contrast, α- and γ-HCH are the most prevalent isomers in soil, water, and air samples. The ratio of the α- to γ-isomers can be used to track global transport of HCHs. A new area of HCH research focuses on the selective degradation of the two α-HCH enantiomers in various environmental matrices. These HCH issues and recommendations for future HCH research are presen...
TL;DR: Using recombinant PEK produced inEscherichia coli or Sf-9 insect cells, it is demonstrated that PEK is autophosphorylated on both serine and threonine residues and that the recombinant enzyme can specifically phosphorylate eIF-2α on serine-51.
Abstract: In response to various environmental stresses, eukaryotic cells down-regulate protein synthesis by phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF-2alpha). In mammals, the phosphorylation was shown to be carried out by eIF-2alpha kinases PKR and HRI. We report the identification and characterization of a cDNA from rat pancreatic islet cells that encodes a new related kinase, which we term pancreatic eIF-2alpha kinase, or PEK. In addition to a catalytic domain with sequence and structural features conserved among eIF-2alpha kinases, PEK contains a distinctive amino-terminal region 550 residues in length. Using recombinant PEK produced in Escherichia coli or Sf-9 insect cells, we demonstrate that PEK is autophosphorylated on both serine and threonine residues and that the recombinant enzyme can specifically phosphorylate eIF-2alpha on serine-51. Northern blot analyses indicate that PEK mRNA is expressed in all tissues examined, with highest levels in pancreas cells. Consistent with our mRNA assays, PEK activity was predominantly detected in pancreas and pancreatic islet cells. The regulatory role of PEK in protein synthesis was demonstrated both in vitro and in vivo. The addition of recombinant PEK to reticulocyte lysates caused a dose-dependent inhibition of translation. In the Saccharomyces model system, PEK functionally substituted for the endogenous yeast eIF-2alpha kinase, GCN2, by a process requiring the serine-51 phosphorylation site in eIF-2alpha. We also identified PEK homologs from both Caenorhabditis elegans and the puffer fish Fugu rubripes, suggesting that this eIF-2alpha kinase plays an important role in translational control from nematodes to mammals.
TL;DR: The addition of flutamide to bilateral orchiectomy does not result in a clinically meaningful improvement in survival among patients with metastatic prostate cancer.
Abstract: Background Combined androgen blockade for the treatment of metastatic prostate cancer consists of an antiandrogen drug plus castration. In a previous trial, we found that adding the antiandrogen flutamide to leuprolide acetate (a synthetic gonadotropin-releasing hormone that results in medical ablation of testicular function) significantly improved survival as compared with that achieved with placebo plus leuprolide acetate. In the current trial, we compared flutamide plus bilateral orchiectomy with placebo plus orchiectomy. Methods We randomly assigned patients who had never received antiandrogen therapy and who had distant metastases from adenocarcinoma of the prostate to treatment with bilateral orchiectomy and either flutamide or placebo. Patients were stratified according to the extent of disease and according to performance status. Results Of the 1387 patients who were enrolled in the trial, 700 were randomly assigned to the flutamide group and 687 to the placebo group. Overall, the incidence of tox...
TL;DR: The findings in terms of the need for specialization of ACT or ICM teams to address social and vocational functioning and substance abuse are discussed, including evaluating implementation fidelity, exploring patient predictors of improvement, and evaluating the role of the helping alliance in mediating outcome.
Abstract: We describe different models of community care for persons with severe mental illness and review the research literature on case management, including the results of 75 studies. Most research has been conducted on the assertive community treatment (ACT) or intensive case management (ICM) models. Controlled research on ACT and ICM indicates that these models reduce time in the hospital and improve housing stability, especially among patients who are high service users. ACT and ICM appear to have moderate effects on improving symptomatology and quality of life. Most studies suggest little effect of ACT and ICM on social functioning, arrests and time spent in jail, or vocational functioning. Studies on reducing or withdrawing ACT or ICM services suggest some deterioration in gains. Research on other models of community care is inconclusive. We discuss the implications of the findings in terms of the need for specialization of ACT or ICM teams to address social and vocational functioning and substance abuse. We suggest directions for future research on models of community care, including evaluating implementation fidelity, exploring patient predictors of improvement, and evaluating the role of the helping alliance in mediating outcome.
Posted Content•
TL;DR: In this article, the authors integrate the notion of extra-role performance with the current understanding of the relationships among salesperson job attitudes (job satisfaction and organizational commitment), role perceptions (ambiguity and conflict), in-and extra role behavior, and turnover.
Abstract: The purpose of this study is to integrate the notion of extra-role performance with the current understanding of the relationships among salesperson job attitudes (job satisfaction and organizational commitment), role perceptions (ambiguity and conflict), in- and extra-role behavior, and turnover The authors develop and test a theoretical model that specifies the relationships between in- and extra-role performance and salesperson job satisfaction, organizational commitment, role perceptions, and turnover using cross-sectional data from a large sample (N = 672) of commission sales personnel The results generally indicate that performance and job attitudes mediate the relationships between role perceptions and turnover However, the most notable aspect of the findings is that they are consistent with the hypothesis that in- and extra-role performance are intertwined, with in-role performance serving as an antecedent ot job satisfaction and organizational commitment, and extra-role performance as a consequence of these two variables The authors discuss the implications of these findings for sales research
Book•
01 Jan 1998TL;DR: This is the definitive reference on the radiance lighting simulation and rendering system.
Abstract: Radiance is a collection of approximately 50 programs that do everything from object modeling to point calculation, rendering, image processing and display. This is the definitive reference on the radiance lighting simulation and rendering system.
TL;DR: The existence of IGEs alters the genotype-phenotype relationship, changing the evolutionary process in some dramatic and non-intuitive ways.
Abstract: Indirect genetic effects (IGEs) are environmental influences on the phenotype of one individual that are due to the expression of genes in a different, conspecific, individual. Historically, work has focused on the influence of parents on offspring but recent advances have extended this perspective to interactions among other relatives and even unrelated individuals. IGEs lead to complicated pathways of inheritance, where environmental sources of variation can be transmitted across generations and therefore contribute to evolutionary change. The existence of IGEs alters the genotype-phenotype relationship, changing the evolutionary process in some dramatic and non-intuitive ways.
TL;DR: There was suggestive evidence for a protective locus on chromosome 4 near the alcohol dehydrogenase genes, for which protective effects have been reported in Asian populations.
Abstract: Alcohol dependence is a leading cause of morbidity and premature death. Several lines of evidence suggest a substantial genetic component to the risk for alcoholism: sibs of alcoholic probands have a 3-8 fold increased risk of also developing alcoholism, and twin heritability estimates of 50-60% are reported by contemporary studies of twins. We report on the results of a six-center collaborative study to identify susceptibility loci for alcohol dependence. A genome-wide screen examined 291 markers in 987 individuals from 105 families. Two-point and multipoint nonparametric linkage analyses were performed to detect susceptibility loci for alcohol dependence. Multipoint methods provided the strongest suggestions of linkage with susceptibility loci for alcohol dependence on chromosomes 1 and 7, and more modest evidence for a locus on chromosome 2. In addition, there was suggestive evidence for a protective locus on chromosome 4 near the alcohol dehydrogenase genes, for which protective effects have been reported in Asian populations.
TL;DR: In this article, the authors integrate the notion of extra role performance with the current understanding of the relationships among salesperson job attitudes (job satisfaction and organization) to find out the relationship between extra-role performance and job satisfaction.
Abstract: The purpose of this study is to integrate the notion of extra-role performance with the current understanding of the relationships among salesperson job attitudes (job satisfaction and organization...
TL;DR: In this article, the authors found that the acceleration of incidence rates for AD and dementia slows down with the increase in age, although there is no sign of a decline in the incidence rates themselves.
Abstract: Background Prevalence studies on dementia and Alzheimer disease (AD) have reported a positive association with age. However, the trend of the association in the oldest-old categories has been the subject of discussion. The relationship between sex and AD has been inconsistent with these studies. Prevalence rates are influenced by the survival and disease incidence. Incidence rates provide a better measure of disease risk. Methods English-language articles identified through a MEDLINE search on "incidence dementia" and "incidence Alzheimer's disease" were examined and references from identified articles were reviewed. Population-based studies using personal interviews, standard clinical diagnosis criteria ( DSM-III for dementia, National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorder Association for AD) and reporting age-specific incidence rates were included in the meta-analysis. Data from the selected studies were extracted and verified. Mixed-effect models were used in the meta-analysis to accommodate the heterogeneity of the studies. Results Incident dementia and AD are associated with a significant quadratic age effect indicating that the increase in incidence rates slows down with the increase in age, although there is no sign of a decline in the incidence rates themselves. The odds ratios for women to develop incidence of dementia and AD relative to men are 1.18 (95% confidence interval, 0.95-1.46) and 1.56 (95% confidence interval, 1.16-2.10), respectively. Conclusions The acceleration of incidence rates for AD and dementia slows down with the increase in age, although we find no evidence of a rate decline. Women are at higher risk of developing AD than men.
TL;DR: In this paper, the authors investigate whether clear reporting of comprehensive income and its components facilitates detection of earnings management by buy-side financial analysts and predictably affects their common stock price judgments, and they conclude that such reporting standards allow companies considerable flexibility in determining which accounts are aggregated into the individual line items in the primary financial statements.
Abstract: This paper investigates whether clear reporting of comprehensive income (CI) and its components facilitates detection of earnings management by buy-side financial analysts and predictably affects their common stock price judgments. Financial reporting standards allow companies considerable flexibility in determining which accounts are aggregated into the individual line items in the primary financial statements. Because of the difficulty inherent in assessing the relevance and persistence of these amounts, users of financial accounting information often
TL;DR: Evidence was found that individual differences in externalizing behavior problems were stable over time and were related to individual risk factors as well as the number of risk factors present, and there were multiple clusters of risks that led to similar outcomes.
Abstract: The aim of this study was to test whether individual risk factors as well as the number of risk factors (cumulative risk) predicted children's externalizing behaviors over middle childhood. A sample of 466 European American and 100 African American boys and girls from a broad range of socioeconomic levels was followed from age 5 to 10 years. Twenty risk variables from four domains (child, sociocultural, parenting, and peer-related) were measured using in-home interviews at the beginning of the study, and annual assessments of externalizing behaviors were conducted. Consistent with past research, individual differences in externalizing behavior problems were stable over time and were related to individual risk factors as well as the number of risk factors present. Particular risks accounted for 36% to 45% of the variance, and the number of risks present (cumulative risk status) accounted for 19% to 32% of the variance, in externalizing outcomes. Cumulative risk was related to subsequent externalizing even after initial levels of externalizing had been statistically controlled. All four domains of risk variables made significant unique contributions to this statistical prediction, and there were multiple clusters of risks that led to similar outcomes. There was also evidence that this prediction was moderated by ethnic group status, most of the prediction of externalizing being found for European American children. However, this moderation effect varied depending on the predictor and outcome variables included in the model.
TL;DR: In this article, the absence of hMLH1 protein was associated with the methylation of the HMLH 1 gene promoter, which is intimately associated with this epigenetic silencing mechanism.
Abstract: Mutations of DNA mismatch repair genes, including the hMLH1 gene, have been linked to human colon and other cancers in which defective DNA repair is evidenced by the associated instability of DNA microsatellite sequences (MSI). Germ-line hMLH1 mutations are causally associated with inherited MSI colon cancer, and somatic mutations are causally associated with sporadic MSI colon cancer. Previ- ously however, we demonstrated that in many sporadic MSI colon cancers hMLH1 and all other DNA mismatch repair genes are wild type. To investigate this class of tumors further, we examined a group of MSI cancer cell lines, most of which were documented as established from antecedent MSI- positive malignant tumors. In five of six such cases we found that hMLH1 protein was absent, even though hMLH1-coding sequences were wild type. In each such case, absence of hMLH1 protein was associated with the methylation of the hMLH1 gene promoter. Furthermore, in each case, treatment with the demethylating agent 5-azacytidine induced expres- sion of the absent hMLH1 protein. Moreover, in single cell clones, hMLH1 expression could be turned on, off, and on again by 5-azacytidine exposure, washout, and reexposure. This epigenetic inactivation of hMLH1 additionally accounted for the silencing of both maternal and paternal tumor hMLH1 alleles, both of which could be reactivated by 5-azacytidine. In summary, substantial numbers of human MSI cancers appear to arise by hMLH1 silencing via an epigenetic mechanism that can inactivate both of the hMLH1 alleles. Promoter methyl- ation is intimately associated with this epigenetic silencing mechanism.
TL;DR: The findings of the present study suggest that age and obesity do not have a negative impact on patient-relevant outcomes (pain and physical function) and have the potential to increase appropriate referrals for knee replacement and thereby reduce the pain and functional disability due to osteoarthrosis of the knee.
Abstract: A cross-sectional, community-based survey of a random sample of 1750 of 242,311 Medicare recipients was performed. The patients were at least sixty-five years old and had had a primary or revision knee replacement (either unilaterally or bilaterally) between 1985 and 1989. Three samples were surveyed separately: a national sample (to reflect the United States as a whole) and samples from Indiana and the western part of Pennsylvania (sites chosen for convenience to assess the validity of the findings for the national sample on a regional level). Each sample was stratified by race, age, residence (urban or rural), and the year of the procedure. Valid and reliable questionnaires were used to elicit the participants' assessments of pain, physical function, and satisfaction two to seven years after the knee replacement. Of the 1486 patients who were eligible for inclusion in the survey, 1193 (80.3 per cent) responded. The mean age of the respondents was 72.6 years. Eight hundred and forty-nine respondents (71.2 per cent) were white, and 849 (71.2 per cent) were women. The participants reported that they had little or no pain in the knee at the time of the survey, regardless of the age at the time of the knee replacement, the body-mass index, or the length of time since the knee replacement. After adjustment for potential confounding variables, predictors of better physical function after the replacement were an absence of problems with the contralateral knee, primary knee replacement (rather than revision) (Indiana sample only), and a lower body-mass index (Indiana and western Pennsylvania samples). Four hundred and fifteen (85.2 per cent) of the 487 patients in the national sample were satisfied with the result of the knee replacement. In what we believe to be the first community-based study of the outcome of knee replacement, patients reported having significant (p = 0.0001) and persistent relief of pain, improved physical function, and satisfaction with the result two to seven years postoperatively. The findings of the present study suggest that age and obesity do not have a negative impact on patient-relevant outcomes (pain and physical function). Dissemination of these findings has the potential to increase appropriate referrals for knee replacement and thereby reduce the pain and functional disability due to osteoarthrosis of the knee.
TL;DR: The identification of a new gene called TRANSPORT InhIBITor RESPONSE 1 (TIR1), which contains a series of leucine-rich repeats and a recently identified motif called an F box, indicates that TIR1 is also required for normal response to auxin.
Abstract: Genetic analysis in Arabidopsis has led to the identification of several genes that are required for auxin response. One of these genes, AXR1, encodes a protein related to yeast Aos1p, a protein that functions to activate the ubiquitin-related protein Smt3p. Here we report the identification of a new gene called TRANSPORT INHIBITOR RESPONSE 1 (TIR1). The tir1 mutants are deficient in a variety of auxin-regulated growth processes including hypocotyl elongation and lateral root formation. These results indicate that TIR1 is also required for normal response to auxin. Further, mutations in TIR1 display a synergistic interaction with mutations in AXR1, suggesting that the two genes function in overlapping pathways. The TIR1 protein contains a series of leucine-rich repeats and a recently identified motif called an F box. Sequence comparisons indicate that TIR1 is related to the yeast protein Grr1p and the human protein SKP2. Because Grr1p and other F-box proteins have been implicated in ubiquitin-mediated processes, we speculate that auxin response depends on the modification of a key regulatory protein(s) by ubiquitin or a ubiquitin-related protein.
TL;DR: The cognitive effects of acute and chronic moderate intake of ethanol is reviewed, and although a number of studies have noted a measurable diminution in neuropsychologic parameters in habitual consumers of moderate amounts of ethanol, others have not found such changes.
Abstract: The concept of moderate consumption of ethanol (beverage alcohol) has evolved over time from considering this level of intake to be nonintoxicating and noninjurious, to encompassing levels defined as "statistically" normal in particular populations, and the public health-driven concepts that define moderate drinking as the level corresponding to the lowest overall rate of morbidity or mortality in a population. The various approaches to defining moderate consumption of ethanol provide for a range of intakes that can result in blood ethanol concentrations ranging from 5 to 6 mg/dl, to levels of over 90 mg/dl (i.e., approximately 20 mM). This review summarizes available information regarding the effects of moderate consumption of ethanol on the adult and the developing nervous systems. The metabolism of ethanol in the human is reviewed to allow for proper appreciation of the important variables that interact to influence the level of exposure of the brain to ethanol once ethanol is orally consumed. At the neurochemical level, the moderate consumption of ethanol selectively affects the function of GABA, glutamatergic, serotonergic, dopaminergic, cholinergic, and opioid neuronal systems. Ethanol can affect these systems directly, and/or the interactions between and among these systems become important in the expression of ethanol's actions. The behavioral consequences of ethanol's actions on brain neurochemistry, and the neurochemical effects themselves, are very much dose- and time-related, and the collage of ethanol's actions can change significantly even on the rising and falling phases of the blood ethanol curve. The behavioral effects of moderate ethanol intake can encompass events that the human or other animal can perceive as reinforcing through either positive (e.g., pleasurable, activating) or negative (e.g., anxiolysis, stress reduction) reinforcement mechanisms. Genetic factors and gender play an important role in the metabolism and behavioral actions of ethanol, and doses of ethanol producing pleasurable feelings, activation, and reduction of anxiety in some humans/animals can have aversive, sedative, or no effect in others. Research on the cognitive effects of acute and chronic moderate intake of ethanol is reviewed, and although a number of studies have noted a measurable diminution in neuropsychologic parameters in habitual consumers of moderate amounts of ethanol, others have not found such changes. Recent studies have also noted some positive effects of moderate ethanol consumption on cognitive performance in the aging human. The moderate consumption of ethanol by pregnant women can have significant consequences on the developing nervous system of the fetus. Consumption of ethanol during pregnancy at levels considered to be in the moderate range can generate fetal alcohol effects (behavioral, cognitive anomalies) in the offspring. A number of factors--including gestational period, the periodicity of the mother's drinking, genetic factors, etc.--play important roles in determining the effect of ethanol on the developing central nervous system. A series of recommendations for future research endeavors, at all levels, is included with this review as part of the assessment of the effects of moderate ethanol consumption on the central nervous system.
TL;DR: It is proposed that these same neurochemical and neuroanatomical patterns will emerge as key substrates in the neurobiology of infant attachments to their caregivers.
TL;DR: This review discusses efforts to develop rodent models for the study of neurobiological mechanisms underlying chronic alcohol drinking, alcoholism, and abnormal alcohol-seeking behavior in rodents, and indicates innate differences exist between the high alcohol-consuming and low alcohol- consuming rodents in various CNS limbic structures.
Abstract: This review discusses efforts to develop rodent models for the study of neurobiological mechanisms underlying chronic alcohol drinking, alcoholism, and abnormal alcohol-seeking behavior. Selective breeding has produced stable lines of rats that reliably exhibit high and (for comparison purposes) low voluntary alcohol consumption. In addition, animal models of chronic ethanol self-administration have been developed in rodents, who do not have a genetic predisposition for high alcohol-seeking behavior, to explore environmental influences in ethanol drinking and the effects of physical dependence on alcohol self-administration. The selectively bred high-preference animals reliably self-administer ethanol by free-choice drinking and operantly respond for oral ethanol in amounts that produce pharmacologically meaningful blood alcohol concentrations (50 to 200 mg% and higher). In addition, the alcohol-preferring rats will self-administer ethanol by intragastric infusion. With chronic free-choice drinking, the high alcohol-preferring rats develop tolerance to the high-dose effects of ethanol and show signs of physical dependence after the withdrawal of alcohol. Compared with nonpreferring animals, the alcohol-preferring rats are less sensitive to the sedative-hypnotic effects of ethanol and develop tolerance more quickly to high-dose ethanol. Nonselected common stock rats can be trained to chronically self-administer ethanol following its initial presentation in a palatable sucrose or saccharin solution, and the gradual replacement of the sucrose or saccharin with ethanol (the sucrose/saccharin-fade technique). Moreover, rats that are trained in this manner and then made dependent by ethanol-vapor inhalation or liquid diet increase their ethanol self-administration during the withdrawal period. Both the selectively bred rats and common-stock rats demonstrate "relapse" and an alcohol deprivation effect following 2 or more weeks of abstinence. Systemic administration of agents that (1) increase synaptic levels of serotonin (5-HT) or dopamine (DA); (2) activate 5-HT1A, 5-HT2, D2, D3, or GABA(A) receptors; or (3) block opioid and 5-HT3 receptors decrease ethanol intake in most animal models. Neurochemical, neuroanatomical, and neuropharmacological studies indicate innate differences exist between the high alcohol-consuming and low alcohol-consuming rodents in various CNS limbic structures. In addition, reduced mesolimbic DA and 5-HT function have been observed during alcohol withdrawal in common stock rats. Depending on the animal model under study, abnormalities in the mesolimbic dopamine pathway, and/or the serotonin, opioid, and GABA systems that regulate this pathway may underlie vulnerability to the abnormal alcohol-seeking behavior in the genetic animal models.