Showing papers by "Tufts University published in 1999"

The Disease Burden Associated with Overweight and Obesity

Abstract: ContextOverweight and obesity are increasing dramatically in the United States and most likely contribute substantially to the burden of chronic health conditions.ObjectiveTo describe the relationship between weight status and prevalence of health conditions by severity of overweight and obesity in the US population.Design and SettingNationally representative cross-sectional survey using data from the Third National Health and Nutrition Examination Survey (NHANES III), which was conducted in 2 phases from 1988 to 1994.ParticipantsA total of 16,884 adults, 25 years and older, classified as overweight and obese (body mass index [BMI] ≥25 kg/m2) based on National Institutes of Health recommended guidelines.Main Outcome MeasuresPrevalence of type 2 diabetes mellitus, gallbladder disease, coronary heart disease, high blood cholesterol level, high blood pressure, or osteoarthritis.ResultsSixty-three percent of men and 55% of women had a body mass index of 25 kg/m2 or greater. A graded increase in the prevalence ratio (PR) was observed with increasing severity of overweight and obesity for all of the health outcomes except for coronary heart disease in men and high blood cholesterol level in both men and women. With normal-weight individuals as the reference, for individuals with BMIs of at least 40 kg/m2 and who were younger than 55 years, PRs were highest for type 2 diabetes for men (PR, 18.1; 95% confidence interval [CI], 6.7-46.8) and women (PR, 12.9; 95% CI, 5.7-28.1) and gallbladder disease for men (PR, 21.1; 95% CI, 4.1-84.2) and women (PR, 5.2; 95% CI, 2.9-8.9). Prevalence ratios generally were greater in younger than in older adults. The prevalence of having 2 or more health conditions increased with weight status category across all racial and ethnic subgroups.ConclusionsBased on these results, more than half of all US adults are considered overweight or obese. The prevalence of obesity-related comorbidities emphasizes the need for concerted efforts to prevent and treat obesity rather than just its associated comorbidities.

Bone Marrow Origin of Endothelial Progenitor Cells Responsible for Postnatal Vasculogenesis in Physiological and Pathological Neovascularization

Abstract: —Circulating endothelial progenitor cells (EPCs) have been isolated in peripheral blood of adult species. To determine the origin and role of EPCs contributing to postnatal vasculogenesis, transgenic mice constitutively expressing β-galactosidase under the transcriptional regulation of an endothelial cell–specific promoter (Flk-1/LZ or Tie-2/LZ) were used as transplant donors. Localization of EPCs, indicated by flk-1 or tie-2/lacZ fusion transcripts, were identified in corpus luteal and endometrial neovasculature after inductive ovulation. Mouse syngeneic colon cancer cells (MCA38) were implanted subcutaneously into Flk-1/LZ/BMT (bone marrow transplantation) and Tie-2/LZ/BMT mice; tumor samples harvested at 1 week disclosed abundant flk-1/lacZ and tie-2/lacZ fusion transcripts, and sections stained with X-gal demonstrated that the neovasculature of the developing tumor frequently comprised Flk-1– or Tie-2–expressing EPCs. Cutaneous wounds examined at 4 days and 7 days after skin removal by punch b...

Intra-arterial Prourokinase for Acute Ischemic Stroke: The PROACT II Study: A Randomized Controlled Trial

Abstract: ContextIntravenous tissue-type plasminogen activator can be beneficial to some patients when given within 3 hours of stroke onset, but many patients present later after stroke onset and alternative treatments are needed.ObjectiveTo determine the clinical efficacy and safety of intra-arterial (IA) recombinant prourokinase (r-proUK) in patients with acute stroke of less than 6 hours' duration caused by middle cerebral artery (MCA) occlusion.DesignPROACT II (Prolyse in Acute Cerebral Thromboembolism II), a randomized, controlled, multicenter, open-label clinical trial with blinded follow-up conducted between February 1996 and August 1998.SettingFifty-four centers in the United States and Canada.PatientsA total of 180 patients with acute ischemic stroke of less than 6 hours' duration caused by angiographically proven occlusion of the MCA and without hemorrhage or major early infarction signs on computed tomographic scan.InterventionPatients were randomized to receive 9 mg of IA r-proUK plus heparin (n = 121) or heparin only (n = 59).Main Outcome MeasuresThe primary outcome, analyzed by intention-to-treat, was based on the proportion of patients with slight or no neurological disability at 90 days as defined by a modified Rankin score of 2 or less. Secondary outcomes included MCA recanalization, the frequency of intracranial hemorrhage with neurological deterioration, and mortality.ResultsFor the primary analysis, 40% of r-proUK patients and 25% of control patients had a modified Rankin score of 2 or less (P = .04). Mortality was 25% for the r-proUK group and 27% for the control group. The recanalization rate was 66% for the r-proUK group and 18% for the control group (P<.001). Intracranial hemorrhage with neurological deterioration within 24 hours occurred in 10% of r-proUK patients and 2% of control patients (P = .06).ConclusionDespite an increased frequency of early symptomatic intracranial hemorrhage, treatment with IA r-proUK within 6 hours of the onset of acute ischemic stroke caused by MCA occlusion significantly improved clinical outcome at 90 days.

Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization.

Abstract: Endothelial progenitor cells (EPCs) have been isolated from circulating mononuclear cells in human peripheral blood and shown to be incorporated into foci of neovascularization, consistent with postnatal vasculogenesis1. We determined whether endogenous stimuli (tissue ischemia) and exogenous cytokine therapy (granulocyte macrophage-colony stimulating factor, GM-CSF) mobilize EPCs and thereby contribute to neovascularization of ischemic tissues. The development of regional ischemia in both mice and rabbits increased the frequency of circulating EPCs. In mice, the effect of ischemia-induced EPC mobilization was demonstrated by enhanced ocular neovascularization after cornea micropocket surgery in mice with hindlimb ischemia compared with that in non-ischemic control mice. In rabbits with hindlimb ischemia, circulating EPCs were further augmented after pretreatment with GM-CSF, with a corresponding improvement in hindlimb neovascularization. There was direct evidence that EPCs that contributed to enhanced corneal neovascularization were specifically mobilized from the bone marrow in response to ischemia and GM-CSF in mice transplanted with bone marrow from transgenic donors expressing β-galactosidase transcriptionally regulated by the endothelial cell-specific Tie-2 promoter. These findings indicate that circulating EPCs are mobilized endogenously in response to tissue ischemia or exogenously by cytokine therapy and thereby augment neovascularization of ischemic tissues.

Ambiguity and the process of knowledge transfer in strategic alliances

Abstract: This research examines the role played by the ‘causally ambiguous’ nature of knowledge in the process of knowledge transfer between strategic alliance partners. Based on a cross-sectional sample of 147 multinationals and a structural equation methodology, this study empirically investigates the simultaneous effects of knowledge ambiguity and its antecedents—tacitness, asset specificity, prior experience, complexity, partner protectiveness, cultural distance, and organizational distance—on technological knowledge transfer. In contrast to past research that generally assumed a direct relation between these explanatory variables and transfer outcomes, this study’s findings highlight the critical role played by knowledge ambiguity as a full mediator of tacitness, prior experience, complexity, cultural distance, and organizational distance on knowledge transfer. These significant effects are further found to be moderated by the firm’s level of collaborative know-how, its learning capacity, and the duration of the alliance. Copyright © 1999 John Wiley & Sons, Ltd.

VEGF contributes to postnatal neovascularization by mobilizing bone marrow‐derived endothelial progenitor cells

Abstract: Vascular endothelial growth factor (VEGF) has been shown to promote neovascularization in animal models and, more recently, in human subjects. This feature has been assumed to result exclusively from its direct effects on fully differentiated endothelial cells, i.e. angiogenesis. Given its regulatory role in both angiogenesis and vasculogenesis during fetal development, we investigated the hypothesis that VEGF may modulate endothelial progenitor cell (EPC) kinetics for postnatal neovascularization. Indeed, we observed an increase in circulating EPCs following VEGF administration in vivo. VEGF-induced mobilization of bone marrow-derived EPCs resulted in increased differentiated EPCs in vitro and augmented corneal neovascularization in vivo. These findings thus establish a novel role for VEGF in postnatal neovascularization which complements its known impact on angiogenesis.

The double-deficit hypothesis for the developmental dyslexias.

Abstract: The authors propose an alternative conceptualization of the developmental dyslexias, the double-deficit hypothesis (i.e., phonological deficits and processes underlying naming-speed deficits represent 2 separable sources of reading dysfunction). Data from cross-sectional, longitudinal, and cross-linguistic studies are reviewed supporting the presence of 2 single-deficit subtypes with more limited reading impairments and 1 double-deficit subtype with more pervasive and severe impairments. Naming-speed and phonological-awareness variables contribute uniquely to different aspects of reading according to this conception, with a model of visual letter naming illustrating both the multicomponential nature of naming speed and why naming speed Should not be subsumed under phonological processes. Two hypotheses concerning relationships between naming-speed processes and reading are considered. The implications of processing speed as a second core deficit in dyslexia are described for diagnosis and intervention.

Risks and consequences of childhood and adolescent obesity.

Abstract: This report reviews the risks and consequences associated with childhood and adolescent obesity. Although no consensus definition of childhood obesity exists, the various measures encountered in the literature are moderately well correlated. The paper is organized in three parts. The first section reviews childhood obesity sequelae that occur during childhood. These short-term risks, for orthopedic, neurological, pulmonary, gasteroenterological, and endocrine conditions, although largely limited to severely overweight children, are becoming more common as the prevalence of severe overweight rises. The social burden of pediatric obesity, especially during middle childhood and adolescence, may have lasting effects on self-esteem, body image and economic mobility. The second section examines the intermediate consequences, such as the development of cardiovascular risk factors and persistence of obesity into adulthood. These mid-range effects of early obesity presage later adult disease and premature mortality. In the final section, the small body of research on the long-term morbidity and mortality associated with childhood obesity is reviewed. These studies suggest that risk of cardiovascular disease and all-cause mortality is elevated among those who were overweight during childhood. The high prevalence and dramatic secular trend toward increasing childhood obesity suggest that without aggressive approaches to prevention and treatment, the attendant health and social consequences will be both substantial and long-lasting.

Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial.

Abstract: ContextThe protein hormone leptin is important to the homeostatic regulation of body weight. Treatment with exogenous leptin may affect weight loss.ObjectiveTo determine the relationship between increasing doses of exogenous leptin administration and weight loss in both lean and obese adults.DesignA randomized, double-blind, placebo-controlled, multicenter, escalating dose cohort trial conducted from April 1997 to October 1998.SettingFour university nutrition and obesity clinics and 2 contract clinical research clinics.ParticipantsFifty-four lean (body mass index, 20.0-27.5 kg/m2; mean [SD] body weight, 72.0 [9.7] kg) and 73 obese (body mass index, 27.6-36.0 kg/m2; mean [SD] body weight, 89.8 [11.4] kg) predominantly white (80%) men (n = 67) and women (n = 60) with mean (SD) age of 39 (10.3) years.InterventionsRecombinant methionyl human leptin self-administered by daily morning subcutaneous injection (0 [placebo], 0.01, 0.03, 0.10, or 0.30 mg/kg). In part A, lean and obese subjects were treated for 4 weeks; in part B, obese subjects were treated for an additional 20 weeks. Lean subjects consumed a eucaloric diet to maintain body weight at the current value, and obese subjects were prescribed a diet that reduced their daily energy intake by 2100 kJ/d (500-kcal/d) from the amount needed to maintain a stable weight.Main Outcome MeasuresBody weight, body fat, and incidence of adverse events.ResultsWeight loss from baseline increased with increasing dose of leptin among all subjects at 4 weeks (P = .02) and among obese subjects at 24 weeks (P = .01) of treatment. Mean (SD) weight changes at 4 weeks ranged from −0.4 (2.0) kg for placebo (n = 36) to −1.9 kg (1.6) kg for the 0.1 mg/kg dose (n = 29). Mean (SD) weight changes at 24 weeks ranged from −0.7 (5.4) kg for the 0.01 mg/kg dose (n = 6) to –7.1 (8.5) kg for the 0.30 mg/kg dose (n = 8). Fat mass declined from baseline as dose increased among all subjects at 4 weeks (P = .002) and among obese subjects at 24 weeks of treatment (P = .004); more than 95% of weight loss was fat loss in the 2 highest dose cohorts at 24 weeks. Baseline serum leptin concentrations were not related to weight loss at week 4 (P = .88) or at week 24 (P = .76). No clinically significant adverse effects were observed on major organ systems. Mild-to-moderate reactions at the injection site were the most commonly reported adverse effects.ConclusionsA dose-response relationship with weight and fat loss was observed with subcutaneous recombinant leptin injections in both lean and obese subjects. Based on this study, administration of exogenous leptin appears to induce weight loss in some obese subjects with elevated endogenous serum leptin concentrations. Additional research into the potential role for leptin and related hormones in the treatment of human obesity is warranted.

A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy

Abstract: SMN1 and SMN2 (survival motor neuron) encode identical proteins. A critical question is why only the homozygous loss of SMN1, and not SMN2, results in spinal muscular atrophy (SMA). Analysis of transcripts from SMN1/SMN2 hybrid genes and a new SMN1 mutation showed a direct relationship between presence of disease and exon 7 skipping. We have reported previously that the exon-skipped product SMNΔ7 is partially defective for self-association and SMN self-oligomerization correlated with clinical severity. To evaluate systematically which of the five nucleotides that differ between SMN1 and SMN2 effect alternative splicing of exon 7, a series of SMN minigenes was engineered and transfected into cultured cells, and their transcripts were characterized. Of these nucleotide differences, the exon 7 C-to-T transition at codon 280, a translationally silent variance, was necessary and sufficient to dictate exon 7 alternative splicing. Thus, the failure of SMN2 to fully compensate for SMN1 and protect from SMA is due to a nucleotide exchange (C/T) that attenuates activity of an exonic enhancer. These findings demonstrate the molecular genetic basis for the nature and pathogenesis of SMA and illustrate a novel disease mechanism. Because individuals with SMA retain the SMN2 allele, therapy targeted at preventing exon 7 skipping could modify clinical outcome.

Formation of mRNA 3′ Ends in Eukaryotes: Mechanism, Regulation, and Interrelationships with Other Steps in mRNA Synthesis

Abstract: Formation of mRNA 3′ ends in eukaryotes requires the interaction of transacting factors with cis-acting signal elements on the RNA precursor by two distinct mechanisms, one for the cleavage of most replication-dependent histone transcripts and the other for cleavage and polyadenylation of the majority of eukaryotic mRNAs. Most of the basic factors have now been identified, as well as some of the key protein-protein and RNA-protein interactions. This processing can be regulated by changing the levels or activity of basic factors or by using activators and repressors, many of which are components of the splicing machinery. These regulatory mechanisms act during differentiation, progression through the cell cycle, or viral infections. Recent findings suggest that the association of cleavage/polyadenylation factors with the transcriptional complex via the carboxyl-terminal domain of the RNA polymerase II (Pol II) large subunit is the means by which the cell restricts polyadenylation to Pol II transcripts. The processing of 3′ ends is also important for transcription termination downstream of cleavage sites and for assembly of an export-competent mRNA. The progress of the last few years points to a remarkable coordination and cooperativity in the steps leading to the appearance of translatable mRNA in the cytoplasm.

Production of goats by somatic cell nuclear transfer

Abstract: In this study, we demonstrate the production of transgenic goats by nuclear transfer of fetal somatic cells. Donor karyoplasts were obtained from a primary fetal somatic cell line derived from a 40-day transgenic female fetus produced by artificial insemination of a nontransgenic adult female with semen from a transgenic male. Live offspring were produced with two nuclear transfer procedures. In one protocol, oocytes at the arrested metaphase II stage were enucleated, electrofused with donor somatic cells, and simultaneously activated. In the second protocol, activated in vivo oocytes were enucleated at the telophase II stage, electrofused with donor somatic cells, and simultaneously activated a second time to induce genome reactivation. Three healthy identical female offspring were born. Genotypic analyses confirmed that all cloned offspring were derived from the donor cell line. Analysis of the milk of one of the transgenic cloned animals showed high-level production of human antithrombin III, similar to the parental transgenic line.

Estrogen receptor α mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen

Abstract: Estrogen is an important vasoprotective molecule that causes the rapid dilation of blood vessels by activating endothelial nitric oxide synthase (eNOS) through an unknown mechanism. In studies of intact ovine endothelial cells, 17beta-estradiol (E2) caused acute (five-minute) activation of eNOS that was unaffected by actinomycin D but was fully inhibited by concomitant acute treatment with specific estrogen receptor (ER) antagonists. Overexpression of the known transcription factor ERalpha led to marked enhancement of the acute response to E2, and this was blocked by ER antagonists, was specific to E2, and required the ERalpha hormone-binding domain. In addition, the acute response of eNOS to E2 was reconstituted in COS-7 cells cotransfected with wild-type ERalpha and eNOS, but not by transfection with eNOS alone. Furthermore, the inhibition of tyrosine kinases or mitogen-activated protein (MAP) kinase kinase prevented the activation of eNOS by E2, and E2 caused rapid ER-dependent activation of MAP kinase. These findings demonstrate that the short-term effects of estrogen central to cardiovascular physiology are mediated by ERalpha functioning in a novel, nongenomic manner to activate eNOS via MAP kinase-dependent mechanisms.

A Single Nucleotide Difference That Alters Splicing Patterns Distinguishes the SMA Gene SMN1 From the Copy Gene SMN2

Abstract: Spinal muscular atrophy (SMA) is a recessive disorder characterized by loss of motor neurons in the spinalcord. It is caused by mutations in the telomeric survival motor neuron 1 (SMN1) gene. Alterations within analmost identical copy gene, the centromeric survival motor neuron 2 (SMN2) gene produce no known pheno-typic effect. The exons of the two genes differ by just two nucleotides, neither of which alters the encodedamino acids. At the genomic level, only five nucleotides that differentiate the two genes from one anotherhave been reported. The entire genomic sequence of the two genes has not been determined. Thus, differ-ences which might explain why SMN1is the SMA gene are not readily apparent. In this study, we have com-pletely sequenced and compared genomic clones containing the SMNgenes. The two genes show strikingsimilarity, with the homology being unprecedented between two different yet functional genes. The only crit-ical difference in an ~32 kb region between the two SMNgenes is the C→→→→T base change 6 bp inside exon 7.This alteration but not other variations in the SMNgenes affects the splicing pattern of the genes. The majorityof the transcript from the SMN1locus is full length, whereas the majority of the transcript produced by theSMN2locus lacks exon 7. We suggest that the exon 7 nucleotide change affects the activity of an exon spliceenhancer. In SMA patients, the loss of SMN1but the presence of SMN2results in low levels of full-lengthSMNtranscript and therefore low SMN protein levels which causes SMA.INTRODUCTIONProximal spinal muscular atrophy (SMA) is an autosomalrecessive neuromuscular disorder characterized by destructionof motor neurons in the anterior horn of the spinal cord. SMAhas an estimated incidence of 1 in 10 000 live births, with a car-rier frequency of ~1 in 50 people (1). Childhood onset SMA isclassified into three groups on the basis of age at onset andclinical course (2); type I SMA (Werdnig–Hoffman disease) isthe most severe form, with onset before the age of 6 monthsand death usually occurring within the first 2 years. Type IISMA is intermediate in severity. Onset occurs at ~18 monthsand patients never gain the ability to walk. Type III SMA(Kugelberg–Welander disease) is the mildest form of the dis-ease with onset after 18 months. Type III patients are able tostand and walk.All three forms of proximal SMA are due to mutations in thetelomeric but not centromeric survival motor neuron (SMN)genes (3–11). The full-length cDNAs of the two genes areidentical except for single nucleotide differences in exons 7and 8, yet their transcriptional products are not the same.SMN1 produces a majority of the full-length cDNA;SMN2produces mostly transcript lacking exon 7 (3). We have shownpreviously that promoter differences do not account for the dif-ferent levels of full-length transcript from the two genes (12).Instead, the exon 7 difference between the two genes affectssplicing, causing increased levels of full-length transcript fromSMN1 as compared with SMN2 (13).The SMN protein is a 38 kDa polypeptide which is ubiqui-tously expressed (14,15). It is found at especially high levels inthe spinal motor neurons. The exact function of the proteinremains unknown. However, recent studies have implicated itsinvolvement in mRNA biogenesis. Specifically, SMN has been

Angiogenesis and vasculogenesis as therapeutic strategies for postnatal neovascularization

Abstract: The therapeutic implications of angiogenic growth factors were identified by the pioneering work of Folkman 2 decades ago (1). His laboratory’s work documented the extent to which tumor development was dependent upon neovascularization and suggested that this relationship might involve angiogenic growth factors that were specific for neoplasms. Subsequent investigations have established the feasibility of using recombinant formulations of such angiogenic growth factors to expedite and/or augment collateral artery development in animal models of myocardial and hindlimb ischemia. This novel strategy for the treatment of vascular insufficiency was termed therapeutic angiogenesis (2). More recent data suggests that the basis for native and therapeutic neovascularization is not restricted to angiogenesis but includes postnatal vasculogenesis as well. Data supporting these notions, as well as derivative concepts and concerns, are the subject of this Perspective.

Age-Dependent Impairment of Angiogenesis

Abstract: Background —The effect of aging on angiogenesis in ischemic vascular disease has not been studied. Accordingly, we investigated the hypothesis that angiogenesis is impaired as a function of age. Methods and Results —Forty days after the resection of 1 femoral artery, collateral vessel development was significantly impaired in old (aged 4 to 5 years; n=7) versus young (aged 6 to 8 months; n=6) New Zealand White (NZW) rabbits on the basis of reduced hindlimb perfusion (ischemic: normal blood pressure ratio=0.58±0.05 versus 0.77±0.06; P P 2 versus 171.4±9.5/mm 2 ; P 2 versus 713.3±63.4/mm 2 ; P Conclusions —Angiogenesis responsible for collateral development in limb ischemia is impaired with aging; responsible mechanisms include age-related endothelial dysfunction and reduced VEGF expression. Advanced age, however, does not preclude augmentation of collateral vessel development in response to exogenous angiogenic cytokines.

How We Know—and Sometimes Misjudge—What Others Know: Imputing One's Own Knowledge to Others

Abstract: To communicate effectively, people must have a reasonably accurate idea about what specific other people know. An obvious starting point for building a model of what another knows is what one oneself knows, or thinks one knows. This article reviews evidence that people impute their own knowledge to others and that, although this serves them well in general, they often do so uncritically, with the result of erroneously assuming that other people have the same knowledge. Overimputation of one's own knowledge can contribute to communication difficulties. Corrective approaches are considered. A conceptualization of where own-knowledge imputation fits in the process of developing models of other people's knowledge is proposed.

High glycemic index foods, overeating, and obesity.

Abstract: Objective. The prevalence of obesity has increased dramatically in recent years. However, the role of dietary composition in body weight regulation remains unclear. The purpose of this work was to investigate the acute effects of dietary glycemic index (GI) on energy metabolism and voluntary food intake in obese subjects. Methods. Twelve obese teenage boys were evaluated on three separate occasions using a crossover study protocol. During each evaluation, subjects consumed identical test meals at breakfast and lunch that had a low, medium, or high GI. The high- and medium-GI meals were designed to have similar macronutrient composition, fiber content, and palatability, and all meals for each subject had equal energy content. After breakfast, plasma and serum concentrations of metabolic fuels and hormones were measured. Ad libitum food intake was determined in the 5-hour period after lunch. Results. Voluntary energy intake after the high-GI meal (5.8 megajoule [mJ]) was 53% greater than after the medium-GI meal (3.8 mJ), and 81% greater than after the low-GI meal (3.2 mJ). In addition, compared with the low-GI meal, the high-GI meal resulted in higher serum insulin levels, lower plasma glucagon levels, lower postabsorptive plasma glucose and serum fatty acids levels, and elevation in plasma epinephrine. The area under the glycemic response curve for each test meal accounted for 53% of the variance in food intake within subjects. Conclusions. The rapid absorption of glucose after consumption of high-GI meals induces a sequence of hormonal and metabolic changes that promote excessive food intake in obese subjects. Additional studies are needed to examine the relationship between dietary GI and long-term body weight regulation. glycemic index, obesity, dietary carbohydrate, diets, insulin.

Interim Report and Recommendations of the World Health Organization Task-Force for Osteoporosis

Abstract: Harry K. Genant (Chairman) , Cyrus Cooper (Rapporteur) , Gyula Poor (Rapporteur) , Ian Reid (Rapporteur) , George Ehrlich (Editor), J. Kanis (Editor), B. E. Christopher Nordin (Editor), Elizabet h Barrett-Connor , Dennis Black, J.-P. Bonjour, Bess Dawson-Hughes , Pierre D. Delmas, J. Dequeker , Sergio Ragi Eis, Carlo Gennari , Olaf Johnell , C. Conrad Johnston, Jr, Edith M. C. Lau, Uri A. Liberman, Robert Lindsay, Thomas John Martin, Basel Masri, Carlos A. Mautalen, Pierre J. Meunier, Paul D. Miller , Ambrish Mithal, Hirotoshi Morii , Socrates Papapoul os, Anthony Woolf, Wei Yu and Nikolai Khaltaev (WHO Secretariat) 30

Transfer of Marketing Know-How in International Strategic Alliances: An Empirical Investigation of the Role and Antecedents of Knowledge Ambiguity

Abstract: The competitive nature of knowledge transfer and the process of organizational learning between partners constitute a fundamental challenge for both academics and practitioners alike. By focusing on one type of competency - marketing know-how - this research examines the role of knowledge ambiguity pertaining to the process of knowledge transfer in international strategic alliances. Based on a cross-sectional sample of 151 multinationals and a structural equation methodology, this study empirically investigates the antecedents of knowledge ambiguity: tacitness, asset specificity, complexity, experience, partner protectiveness, cultural distance, and organizational distance. Further, the strength of the relationships between these theoretical constructs and ambiguity is examined in light of the possible moderating effects of collaborative experience, firm size, and the duration of the alliance entered. Consistently, tacitness emerges as the most significant determinant of knowledge transferability. Moreover, the effects of cultural distance, asset specificity, and prior experience are moderated respectively by the firm's level of collaborative experience, the duration of the alliance, and the firm's size.

Growth Curves and Survival Characteristics of the Animals Used in the Biomarkers of Aging Program

Abstract: The collaborative Interagency Agreement between the National Center for Toxicological Research (NCTR) and the National Institute on Aging (NIA) was aimed at identifying and validating a panel of biomarkers of aging in rodents in order to rapidly test the efficacy and safety of interventions designed to slow aging. Another aim was to provide a basis for developing biomarkers of aging in humans, using the assumption that biomarkers that were useful across different genotypes and species were sensitive to fundamental processes that would extrapolate to humans. Caloric restriction (CR), the only intervention that consistently extends both mean and maximal life span in a variety of species, was used to provide a model with extended life span. C57BI/6NNia, DBA/2JNia, B6D2F1, and B6C3F1 mice and Brown Norway (BN/RijNia), Fischer (F344/NNia) and Fischer x Brown Norway hybrid (F344 x BN F1) rats were bred and maintained on study. NCTR generated data from over 60,000 individually housed animals of the seven different genotypes and both sexes, approximately half ad libitum (AL) fed, the remainder CR. Approximately half the animals were shipped to offsite NIA investigators internationally, with the majority of the remainder maintained at NCTR until they died. The collaboration supplied a choice of healthy, long-lived rodent models to investigators, while allowing for the development of some of the most definitive information on life span, food consumption, and growth characteristics in these genotypes under diverse feeding paradigms.

Thinking in Levels: A Dynamic Systems Approach to Making Sense of the World

Abstract: The concept of emergent "levels" (i.e., levels that arise from interactions of objects at lower levels) is fundamental to scientific theory. In this paper, we argue for an expanded role for this concept of levels in science education. We show confusion of levels (and "slippage" between levels) as the source of many of people's deep misunderstandings about patterns and phenomena in the world. These misunderstandings are evidenced not only in students' difficulties in the formal study of science but also in their misconceptions about experiences in their everyday lives. The StarLogo modeling language is designed as a medium for students to build models of multi-leveled phenomena and through these constructions explore the concept of levels. We describe several case studies of students working in StarLogo. The cases illustrate students' difficulties with the concept of levels, and how they can begin to develop richer understandings.

Regulation of Myosin Phosphatase by a Specific Interaction with cGMP- Dependent Protein Kinase Iα

Abstract: Contraction and relaxation of smooth muscle are regulated by myosin light-chain kinase and myosin phosphatase through phosphorylation and dephosphorylation of myosin light chains. Cyclic guanosine monophosphate (cGMP)–dependent protein kinase Iα (cGKIα) mediates physiologic relaxation of vascular smooth muscle in response to nitric oxide and cGMP. It is shown here that cGKIα is targeted to the smooth muscle cell contractile apparatus by a leucine zipper interaction with the myosin-binding subunit (MBS) of myosin phosphatase. Uncoupling of the cGKIα-MBS interaction prevents cGMP-dependent dephosphorylation of myosin light chain, demonstrating that this interaction is essential to the regulation of vascular smooth muscle cell tone.

The unreliability of individual physician "report cards" for assessing the costs and quality of care of a chronic disease.

Abstract: ContextPhysician profiling is widely used by many health care systems, but little is known about the reliability of commonly used profiling systems.ObjectivesTo determine the reliability of a set of physician performance measures for diabetes care, one of the most common conditions in medical practice, and to examine whether physicians could substantially improve their profiles by preferential patient selection.Design and SettingCohort study performed from 1990 to 1993 at 3 geographically and organizationally diverse sites, including a large staff-model health maintenance organization, an urban university teaching clinic, and a group of private-practice physicians in an urban area.ParticipantsA total of 3642 patients with type 2 diabetes cared for by 232 different physicians.Main Outcome MeasuresPhysician profiles for their patients' hospitalization and clinic visit rates, total laboratory resource utilization rate and level of glycemic control by average hemoglobin A1c level with and without detailed case-mix adjustment.ResultsFor profiles based on hospitalization rates, visit rates, laboratory utilization rates, and glycemic control, 4% or less of the overall variance was attributable to differences in physician practice and the reliability of the median physician's case-mix–adjusted profile was never better than 0.40. At this low level of physician effect, a physician would need to have more than 100 patients with diabetes in a panel for profiles to have a reliability of 0.80 or better (while more than 90% of all primary care physicians at the health maintenance organization had fewer than 60 patients with diabetes). For profiles of glycemic control, high outlier physicians could dramatically improve their physician profile simply by pruning from their panel the 1 to 3 patients with the highest hemoglobin A1clevels during the prior year. This advantage from gaming could not be prevented by even detailed case-mix adjustment.ConclusionsPhysician "report cards" for diabetes, one of the highest-prevalence conditions in medical practice, were unable to detect reliably true practice differences within the 3 sites studied. Use of individual physician profiles may foster an environment in which physicians can most easily avoid being penalized by avoiding or deselecting patients with high prior cost, poor adherence, or response to treatments.