Showing papers by "Tufts University published in 1996"

Political Science and the Three New Institutionalisms

Abstract: The ‘new institutionalism’ is a term that now appears with growing frequency in political science. However, there is considerable confusion about just what the ‘new institutionalism’ is, how it differs from other approaches, and what sort of promise or problems it displays. The object of this essay is to provide some preliminary answers to these questions by reviewing recent work in a burgeoning literature. Some of the ambiguities surrounding the new institutionalism can be dispelled if we recognize that it does not constitute a unified body of thought. Instead, at least three different analytical approaches, each of which calls itself a ‘new institutionalism’, have appeared over the past fifteen years. We label these three schools of thought: historical institutionalism, rational choice institutionalism, and sociological institutionalism.’ All of these approaches developed in reaction to the behavioural perspectives that were influential during the 1960s and 1970s and all seek to elucidate the role that institutions play in the determination of social and political outcomes. However, they paint quite different pictures of the political world. In the sections that follow, we provide a brief account of the genesis of each school and characterize what is distinctive about its approach to social and political problems. We then compare their analytical strengths and weaknesses, * An earlier version of this paper WLS presented at the 1994 Annual Meeting of the American Political Science Association and at a Conference on ‘What is Institutionalism Now? at the

The molecular structure of green fluorescent protein

Abstract: The crystal structure of recombinant wild-type green fluorescent protein (GFP) has been solved to a resolution of 1.9 A by multiwavelength anomalous dispersion phasing methods. The protein is in the shape of a cylinder, comprising 11 strands of s-sheet with an α-helix inside and short helical segments on the ends of the cylinder. This motif, with s-structure on the outside and α-helix on the inside, represents a new protein fold, which we have named the s-can. Two protomers pack closely together to form a dimer in the crystal. The fluorophores are protected inside the cylinders, and their structures are consistent with the formation of aromatic systems made up of Tyr86 with reduction of its Cα-Cs bond coupled with cyclization of the neighboring glycine and serine residues. The environment inside the cylinder explains the effects of many existing mutants of GFP and suggests specific side chains that could be modified to change the spectral properties of GFP. Furthermore, the identification of the dimer contacts may allow mutagenic control of the state of assembly of the protein.

Clinical Correlates of White Matter Findings on Cranial Magnetic Resonance Imaging of 3301 Elderly People: The Cardiovascular Health Study

Abstract: Background and Purpose Our aim was to identify potential risk factors for and clinical manifestations of white matter findings on cranial MRI in elderly people. Methods Medicare eligibility lists were used to obtain a representative sample of 5888 community-dwelling people aged 65 years or older. Correlates of white matter findings were sought among 3301 participants who underwent MRI scanning and denied a history of stroke or transient ischemic attack. Participants underwent extensive standardized evaluations at baseline and on follow-up, including standard questionnaires, physical examination, multiple blood tests, electrocardiogram, pulmonary function tests, carotid sonography, and M-mode echocardiography. Neuroradiologists graded white matter findings from 0 (none) to 9 (maximal) without clinical information. Results Many potential risk factors were related to the white matter grade, but in the multivariate model the factors significantly (all P<.01) and independently associated with increased grade w...

Periodontal Disease and Cardiovascular Disease

Abstract: It is our central hypothesis that periodontal diseases, which are chronic Gramnegative infections, represent a previously unrecognized risk factor for atherosclerosis and thromboembolic events. Previous studies have demonstrated an association between periodontal disease severity and risk of coronary heart disease and stroke. We hypothesize that this association may be due to an underlying inflammatory response trait, which places an individual at high risk for developing both periodontal disease and atherosclerosis. We further suggest that periodontal disease, once established, provides a biological burden of endotoxin (lipopolysaccharide) and inflammatory cytokines (especially TxA2 , IL-1β, PGE2 , and TNF-α) which serve to initiate and exacerbate atherogenesis' and thromboembolic events. A cohort study was conducted using combined data from the Normative Aging Study and the Dental Longitudinal Study sponsored by the United States Department of Veterans Affairs. Mean bone loss scores and worst probing pocket depth scores per tooth were measured on 1,147 men during 1968 to 1971. Information gathered during follow-up examinations showed that 207 men developed coronary heart disease (CHD), 59 died of CHD, and 40 had strokes. Incidence odds ratios adjusted for established cardiovascular risk factors were 1.5, 1.9, and 2.8 for bone loss and total CHD, fatal CHD, and stroke, respectively. Levels of bone loss and cumulative incidence of total CHD and fatal CHD indicated a biologic gradient between severity of exposure and occurrence of disease. J Periodontol 1996;67:1123-1137.

Relation Between Folate Status, a Common Mutation in Methylenetetrahydrofolate Reductase, and Plasma Homocysteine Concentrations

Abstract: Background Methylenetetrahydrofolate reductase (MTHFR) synthesizes 5-methyltetrahydrofolate, the major carbon donor in remethylation of homocysteine to methionine. A common MTHFR mutation, an alanine-to-valine substitution, renders the enzyme thermolabile and may cause elevated plasma levels of the amino acid homocysteine. Methods and Results To assess the potential interaction between this mutation and vitamin coenzymes in homocysteine metabolism, we screened 365 individuals from the NHLBI Family Heart Study. Among individuals with lower plasma folate concentrations (<15.4 nmol/L), those with the homozygous mutant genotype had total fasting homocysteine levels that were 24% greater (P<.05) than individuals with the normal genotype. A difference between genotypes was not seen among individuals with folate levels ≥15.4 nmol/L. Conclusions Individuals with thermolabile MTHFR may have a higher folate requirement for regulation of plasma homocysteine concentrations; folate supplementation may be necessary to ...

A role for melanin-concentrating hormone in the central regulation of feeding behaviour

Abstract: The hypothalamus plays a central role in the integrated regulation of energy homeostasis and body weight, and a number of hypothalamic neuropeptides, such as neuropeptide Y (ref. 1), galanin, CRH (ref. 3) and GLP-1 (ref. 4), have been implicated in the mediation of these effects. To discover new hypothalmic peptides involved in the regulation of body weight, we used differential display polymerase chain reaction to identify messenger RNAs that are differentially expressed in the hypothalamus of ob/+ compared with ob/ob C57B1/6J mice. We show here that one mRNA that is overexpressed in the hypothalamus of ob/ob mice encodes the neuropeptide melanin-concentrating hormone (MCH). Fasting further increased expression of MCH mRNA in both normal and obese animals. Neurons containing MCH are located in the zona incerta and in the lateral hypothalamus. These areas are involved in regulation of ingestive behaviour, but the role of MCH in mammalian physiology is unknown. To determine whether MCH is involved in the regulation of feeding, we injected MCH into the lateral ventricles of rats and found that their food consumption increased. These findings suggest that MCH participates in the hypothalamic regulation of body weight.

'Malignant' Middle Cerebral Artery Territory Infarction: Clinical Course and Prognostic Signs

Abstract: Background: Although the clinical features of space-occupying ischemic stroke are well known, there are limited prospective data on the clinical course of complete middle cerebral artery territory infarction and on the predisposing factors leading to subsequent herniation and brain death. Methods: The clinical course of patients with complete middle cerebral artery territory infarction, defined by computed tomography and vascular imaging, was evaluated. Initial clinical presentation was assessed by the Scandinavian Stroke Scale and the Glasgow Coma Scale. Serial computed tomography with measurement of midline and septum pellucidum shift and data on the presence and location of vascular occlusion by angiography or Doppler ultrasound were obtained directly after admission. Time course and outcome were analyzed with regard to the clinical findings on admission and at follow-up. The functional status of surviving patients was assessed using the Barthel Index. Results: Fifty-five patients with complete middle cerebral artery territory infarction caused by occlusion of either the distal intracranial carotid artery or the proximal middle cerebral artery trunk were studied. In all patients, embolic infarction was presumed. The mean Scandinavian Stroke Scale score on admission was 20, and the time course of deterioration varied between 2 and 5 days. Forty-nine patients required ventilator assistance during the acute stage of disease. Only 12 patients (22%) survived the infarct. The cause of death was transtentorial herniation with subsequent brain death in 43 patients. Survivors had a mean Barthel Index score of 60 (range, 45 to 70). Conclusions: The prognosis of complete middle cerebral artery territory stroke is very poor and can be estimated by early clinical and neuroradiological data within the first few hours after the onset of symptoms. A space-occupying mass effect develops rapidly and predictably over the initial 5 days after presentation. Herniation occurred as an end point in 43 (78%) of these patients.

Television viewing as a cause of increasing obesity among children in the united states, 1986-1990

Abstract: Background and Methods: The prevalence of obesity among children and adolescents has increased, and television viewing has been suggested as a cause. We examined the relation between hours of television viewed and the prevalence of overweight in 1990, and the incidence and remission of overweight from 1986 to 1990 in a nationally representative cohort of 746 youths aged 10 to 15 years in 1990 whose mothers were 25 to 32 years old. Overweight was defined as a body mass index higher than the 85th percentile for age and gender. Results: We observed a strong dose-response relationship between the prevalence of overweight in 1990 and hours of television viewed. The odds of being overweight were 4.6 (95% confidence interval, 2.2 to 9.6) times greater for youth watching more than 5 hours of television per day compared with those watching for 0 to 2 hours. When adjustments were made for previous overweight (in 1986), baseline maternal overweight, socioeconomic status, household structure, ethnicity, and maternal and child aptitude test scores, results were similar (odds ratio, 5.3; 95% confidence interval, 2.3 to 12.1). We also found significant relations between television viewing and increased incidence and decreased remission of overweight during this 4-year period, adjusted for baseline covariates. The adjusted odds of incidence were 8.3 (95% confidence interval, 2.6 to 26.5) times greater for youth watching more than 5 hours of television per day compared with those watching for 0 to 2 hours. Estimates of attributable risk indicate that more 60% of overweight incidence in this population can be linked to excess television viewing time. Conclusion: Television viewing affects overweight among youth, and reductions in viewing time could help prevent this increasingly common chronic health condition. (Arch Pediatr Adolesc Med. 1996;150:356-362)

E7 Protein of Human Papilloma Virus-16 Induces Degradation of Retinoblastoma Protein through the Ubiquitin-Proteasome Pathway

Abstract: Rb protein is a critical regulator of entry into the cell cycle, and loss of Rb function by deletions, mutations, or interaction with DNA viral oncoproteins leads to oncogenic transformation. We have shown that the human papilloma virus (HPV)-16 E7 gene is sufficient to induce the immortalization of mammary epithelial cells (MECs). Surprisingly, the steady-state level of Rb protein in these immortal cells was drastically decreased. Here, we used pulse-chase analysis to show that the in vivo loss of Rb protein in E7-immortalized MECs is a consequence of enhanced degradation. Expression of HPV16 E7 in a cell line with a temperature-sensitive mutation in the E1 enzyme of the ubiquitin pathway demonstrated that degradation of Rb was ubiquitin dependent. Treatment of E7-immortalized MECs with aldehyde inhibitors of proteasome-associated proteases led to a marked stabilization of Rb protein, particularly the hypophosphorylated form. Taken together, our results provide evidence for HPV-16 E7-induced enhanced degradation of Rb protein via a ubiquitin-proteasome pathway and suggest a second mechanism of oncogenic transformation by E7, in addition to its previously identified ability to sequester Rb from E2F. Our analyses also show that normal Rb levels are regulated by the ubiquitin-proteasome degradation pathway.

A Receptor for the Selective Uptake and Degradation of Proteins by Lysosomes

Abstract: Multiple pathways of protein degradation operate within cells. A selective protein import pathway exists for the uptake and degradation of particular cytosolic proteins by lysosomes. Here, the lysosomal membrane glycoprotein LGP96 was identified as a receptor for the selective import and degradation of proteins within lysosomes. Specific substrates of this proteolytic pathway bound to the cytosolic tail of a 96-kilodalton lysosomal membrane protein in two different binding assays. Overexpression of human LGP96 in Chinese hamster ovary cells increased the activity of the selective lysosomal proteolytic pathway in vivo and in vitro.

Cyclin D2 is an FSH-responsive gene involved in gonadal cell proliferation and oncogenesis

Abstract: THE D-type cyclins (Dl, D2 and D3) are critical governors of the cell-cycle clock apparatus during the Gl phase of the mammalian cell cycle. These three D-type cyclins are expressed in overlapping, apparently redundant fashion in the proliferating tissues1,2. To investigate why mammalian cells need three distinct D-type cyclins, we have generated mice bearing a disrupted cyclin D2 gene by using gene targeting in embryonic stem cells. Cyclin D2-deficient females are sterile owing to the inability of ovarian granulosa cells to proliferate normally in response to follicle-stimulating hormone (FSH), whereas mutant males display hypoplastic testes. In ovarian granulosa cells, cyclin D2 is specifically induced by FSH via a cyclic-AMP-dependent pathway, indicating that expression of the various D-type cyclins is under control of distinct intracellular signalling pathways. The hypoplasia seen in cyclin D2−/− ovaries and testes prompted us to examine human cancers deriving from corresponding tissues. We find that some human ovarian and testicular tumours contain high levels of cyclin D2 messenger RNA.

Myogenin expression, cell cycle withdrawal, and phenotypic differentiation are temporally separable events that precede cell fusion upon myogenesis.

Abstract: During terminal differentiation of skeletal myoblasts, cells fuse to form postmitotic multinucleated myotubes that cannot reinitiate DNA synthesis. Here we investigated the temporal relationships among these events during in vitro differentiation of C2C12 myoblasts. Cells expressing myogenin, a marker for the entry of myoblasts into the differentiation pathway, were detected first during myogenesis, followed by the appearance of mononucleated cells expressing both myogenin and the cell cycle inhibitor p21. Although expression of both proteins was sustained in mitogen-restimulated myocytes, 5-bromodeoxyuridine incorporation experiments in serum-starved cultures revealed that myogenin-positive cells remained capable of replicating DNA. In contrast, subsequent expression of p21 in differentiating myoblasts correlated with the establishment of the postmitotic state. Later during myogenesis, postmitotic (p21-positive) mononucleated myoblasts activated the expression of the muscle structural protein myosin heavy chain, and then fused to form multinucleated myotubes. Thus, despite the asynchrony in the commitment to differentiation, skeletal myogenesis is a highly ordered process of temporally separable events that begins with myogenin expression, followed by p21 induction and cell cycle arrest, then phenotypic differentiation, and finally, cell fusion.

Double-Blind, Placebo-Controlled Study of the Effects of Carvedilol in Patients With Moderate to Severe Heart Failure The PRECISE Trial

Abstract: Background Carvedilol has improved the symptomatic status of patients with moderate to severe heart failure in single-center studies, but its clinical effects have not been evaluated in large, multicenter trials. Methods and Results We enrolled 278 patients with moderate to severe heart failure (6-minute walk distance, 150 to 450 m) and a left ventricular ejection fraction ≤0.35 at 31 centers. After an open-label, run-in period, each patient was randomly assigned (double-blind) to either placebo (n=145) or carvedilol (n=133; target dose, 25 to 50 mg BID) for 6 months, while background therapy with digoxin, diuretics, and an ACE inhibitor remained constant. Compared with placebo, patients in the carvedilol group had a greater frequency of symptomatic improvement and lower risk of clinical deterioration, as evaluated by changes in the NYHA functional class (P=.014) or by a global assessment of progress judged either by the patient (P=.002) or by the physician (P<.001). In addition, treatment with carvedilol...

Kinds of Minds: Towards an Understanding of Consciousness

Abstract: What kinds of minds are there,and how do we know? The first question is about what exists - about ontology, in philosophical parlance - and the second question is about our knowledge - about epistemology. The aim of Kinds of Minds is to answer these questions, in general outline, and to show why these two questions have to be answered together. What exists is one thing, and what we can know about it is something else. There may be things that are completely unknowable to us so we must be careful not to treat the limits of our knowledge as sure guides to the limits of what there is. But we know enough about minds, Dennett argues, to know that one of the things that makes them different from everything else in the Universe is the way we know about them.

Resistance to Apoptosis Conferred by Cdk Inhibitors During Myocyte Differentiation

Abstract: Proliferating murine C2C12 myoblasts can undergo either terminal differentiation or programmed cell death under conditions of mitogen deprivation Unlike myoblasts, differentiated myotubes were resistant to apoptosis During myogenesis the appearance of the apoptosis-resistant phenotype was correlated with the induction of the cyclin-dependent kinase (Cdk) inhibitor p21CIP1 but not with the appearance of myogenin, a marker expressed earlier in differentiation Forced expression of the Cdk inhibitors p21CIP1 or p16INK4A blocked apoptosis during myocyte differentiation These data indicate that induction of Cdk inhibitors may serve to protect differentiating myocytes from programmed cell death as well as play a role in establishing the postmitotic state

Direct Intramuscular Gene Transfer of Naked DNA Encoding Vascular Endothelial Growth Factor Augments Collateral Development and Tissue Perfusion

Abstract: Background Striated muscle has been shown to be capable of taking up and expressing foreign genes transferred in the form of naked plasmid DNA, although typically with a low level of gene expression. In the case of genes that encode secreted proteins, however, low transfection efficiency may not preclude bioactivity of the secreted gene product. Accordingly, we investigated the hypothesis that intramuscular (IM) gene therapy with naked plasmid DNA encoding vascular endothelial growth factor (VEGF) could augment collateral development and tissue perfusion in an animal model of hindlimb ischemia. Methods and Results Ten days after ischemia was induced in one rabbit hindlimb, 500 μg of phVEGF165, or the reporter gene LacZ, was injected IM into the ischemic hindlimb muscles. Thirty days later, angiographically recognizable collateral vessels and histologically identifiable capillaries were increased in VEGF transfectants compared with controls. This augmented vascularity improved perfusion to the ischemic lim...

Single or multiple daily doses of aminoglycosides: a meta- analysis

Abstract: Objective: To assess relative efficacy and toxicity of aminoglycosides given by single daily dose compared with multiple daily doses. Design: Meta-analysis of 21 randomised trials identified through MEDLARS (1966 to January 1995). Data were overviewed with fixed effects and random effects models and with meta-regression analysis. Subjects: Total of 3091 patients with bacterial infection, most without pre-existing renal disease. Interventions: Patients were randomised to receive aminoglycosides once daily or multiple times daily with similar total daily dose. Main outcome measures: Clinical failure of treatment, nephrotoxicity, ototoxicity, and mortality. Results: Single daily dose regimen produced a non-significant decrease in risk of antibiotic failures (random effects risk ratio 0.83 (95% confidence interval 0.57 to 1.21)). Benefit of once daily dosing was greater when the percentage of pseudomonas isolates in a trial was larger. Once daily administration reduced risk of nephrotoxicity (fixed effects risk ratio 0.74 (0.54 to 1.00)). Similar trends were noted for patients with febrile neutropenia and for children. There was no significant difference in ototoxicity between the two dosing regimens, but the power of the pooled trials to detect a meaningful difference was low. There was no significant difference in mortality. Conclusions: Once daily administration of aminoglycosides in patients without pre-existing renal impairment is as effective as multiple daily dosing, has a lower risk of nephrotoxicity, and no greater risk of ototoxicity. Given the additional convenience and reduced cost, once daily dosing should be the preferred mode of administration. Key messages Key messages This meta-analysis shows that single daily doses of aminoglycosides were about 25% less nephrotoxic than and at least as effective clinically as multiple daily doses The dosing schedule did not significantly affect the incidence of ototoxicity, but the power to detect a difference was small Once daily dosing was non-significantly more effective in patients with febrile neutropenia and in children, and the apparent benefit of once daily dosing increased with increasing proportion of pseudomonas isolates in a trial Besides the convenience of once daily dosing, reduced costs of drug administration and omission of measurements of peak antibiotic concentrations should result in substantial cost savings

A chemical-detecting system based on a cross-reactive optical sensor array

Abstract: The vertebrate olfactory system has long been recognized for its extraordinary sensitivity and selectivity for odours. Chemical sensors have been developed recently that are based on analogous distributed sensing properties, but although an association between artificial devices and the olfactory system has been made explicit in some previous studies, none has incorporated comparable mechanisms into the mode of detection. Here we describe a multi-analyte fibre-optic sensor modelled directly on the olfactory system, in the sense that complex, time-dependent signals from an array of sensors provide a 'signature' of each analyte. In our system, polymer-immobilized dye molecules on the fibre tips give different fluorescent response patterns (including spectral shifts, intensity changes, spectral shape variations and temporal responses) on exposure to organic vapours, depending on the physical and chemical nature (for example, polarity, shape and size) of both the vapour and the polymer. We use video images of temporal responses of the multi-fibre tip as the input signals to train a neural network for vapour recognition. The system is able to identify individual vapours at different concentrations with great accuracy. 'Artificial noses' such as this should have wide potential application, most notably in environmental and medical monitoring.

Mice lacking the myotonic dystrophy protein kinase develop a late onset progressive myopathy.

Abstract: Myotonic dystrophy (DM) is an autosomal dominant disorder resulting from the expansion of a CTG repeat in the 3' untranslated region of a putative protein kinase (DMPK). To elucidate the role of DMPK in DM pathogenesis we have developed Dmpk deficient (Dmpk-/-) mice. Dmpk-/-mice develop a late-onset, progressive skeletal myopathy that shares some pathological features with DM. Muscles from mature mice show variation in fibre size, increased fibre degeneration and fibrosis. Adult Dmpk-/-mice show ultrastructural changes in muscle and a 50% decrease in force generation compared to young mice. Our results indicate that DMPK may be necessary for the maintenance of skeletal muscle structure and function and suggest that a decrease in DMPK levels may contribute to DM pathology.

Prognostic Significance of Plasma Norepinephrine in Patients With Asymptomatic Left Ventricular Dysfunction

Abstract: Background Elevated plasma neurohormonal levels are associated with increased mortality rates in patients with symptomatic heart failure. A previous Studies of Left Ventricular Dysfunction (SOLVD) trial suggested that neurohumoral activation precedes the development of symptoms as demonstrated by increased neurohormonal levels in patients with asymptomatic left ventricular dysfunction. However, the significance of this early neurohumoral activation is unclear. The goals of this study were to determine the prognostic significance of the plasma concentrations of plasma norepinephrine (PNE) and atrial natriuretic peptide (ANP) and the renin activity (PRA) in patients with asymptomatic left ventricular dysfunction. Methods and Results PNE and PRA were measured before randomization in 514 patients with left ventricular ejection fractions ≤35% who did not require treatment for congestive heart failure and were enrolled in the SOLVD Prevention Trial. Plasma ANP levels were measured in a subset of 241 patients ow...

Hypoxia-induced paracrine regulation of vascular endothelial growth factor receptor expression

Abstract: Vascular endothelial growth factor (VEGF)/vascular permeability factor (VPF), an endothelial cell (EC)-specific mitogen, stimulates angiogenesis in vivo, particularly in ischemic regions. VEGF/VPF expression by cells of hypoxic tissues coincides with expression of its two receptors, KDR and flt-1, by ECs in the same tissues. We investigated whether hypoxia or hypoxia-dependent conditions operate in coordinating this phenomenon. Human umbilical vein and microvascular ECs were exposed to direct hypoxia or to medium conditioned (CM) by myoblasts maintained in hypoxia for 4 d. Control ECs were maintained in normoxia or normoxia-CM. Binding of 125I-VEGF to ECs was then evaluated. Hypoxic treatment of ECs had no effect on 125I-VEGF binding. However, treatment of ECs with hypoxia-CM produced a threefold increase in 125I-VEGF binding, with peak at 24 h (P < 0.001, ANOVA). Scatchard analysis disclosed that increased binding was due to a 13-fold increase in KDR receptors/cell, with no change in KDR affinity (Kd = 260 +/- 51 pM, normoxia-CM versus Kd = 281 +/- 94 pM, hypoxia-CM) and no change in EC number (35.6 +/- 5.9 x 10(3) ECs/cm2, normoxia-CM versus 33.5 +/- 5.5 x 10(3) ECs/cm2, hypoxia-CM). Similar results were obtained using CM from hypoxic smooth muscle cells. KDR upregulation was not prevented by addition to the hypoxia-CM of neutralizing antibodies against VEGF, tumor necrosis factor-alpha, transforming growth factor beta 1 or basic fibroblast growth factor. Similarly, addition of VEGF or lactic acid to the normoxia-CM had no effect on VEGF binding. We conclude that mechanism(s) initiated by hypoxia can induce KDR receptor upregulation in ECs. Hypoxic cells, normal or neoplastic, not only can produce VEGF/VPF, but can also modulate its effects via paracrine induction of VEGF/VPF receptors in ECs.