Showing papers by "University of Vermont published in 2005"

Randomized Trial of Letrozole Following Tamoxifen as Extended Adjuvant Therapy in Receptor-Positive Breast Cancer: Updated Findings from NCIC CTG MA.17

Abstract: BACKGROUND: Most recurrences in women with breast cancer receiving 5 years of adjuvant tamoxifen occur after 5 years. The MA.17 trial, which was designed to determine whether extended adjuvant therapy with the aromatase inhibitor letrozole after tamoxifen reduces the risk of such late recurrences, was stopped early after an interim analysis showed that letrozole improved disease-free survival. This report presents updated findings from the trial. METHODS: Postmenopausal women completing 5 years of tamoxifen treatment were randomly assigned to a planned 5 years of letrozole (n = 2593) or placebo (n = 2594). The primary endpoint was disease-free survival (DFS); secondary endpoints included distant disease-free survival, overall survival, incidence of contralateral tumors, and toxic effects. Survival was examined using Kaplan-Meier analysis and log-rank tests. Planned subgroup analyses included those by axillary lymph node status. All statistical tests were two-sided. RESULTS: After a median follow-up of 30 months (range = 1.5-61.4 months), women in the letrozole arm had statistically significantly better DFS and distant DFS than women in the placebo arm (DFS: hazard ratio [HR] for recurrence or contralateral breast cancer = 0.58, 95% confidence interval [CI] = 0.45 to 0.76; P

Functional consequences of a CKIδ mutation causing familial advanced sleep phase syndrome

Abstract: Familial advanced sleep phase syndrome (FASPS) is a human behavioural phenotype characterized by early sleep times and early-morning awakening. It was the first human, mendelian circadian rhythm variant to be well-characterized, and was shown to result from a mutation in a phosphorylation site within the casein kinase I (CKI)-binding domain of the human PER2 gene. To gain a deeper understanding of the mechanisms of circadian rhythm regulation in humans, we set out to identify mutations in human subjects leading to FASPS. We report here the identification of a missense mutation (T44A) in the human CKIdelta gene, which results in FASPS. This mutant kinase has decreased enzymatic activity in vitro. Transgenic Drosophila carrying the human CKIdelta-T44A gene showed a phenotype with lengthened circadian period. In contrast, transgenic mice carrying the same mutation have a shorter circadian period, a phenotype mimicking human FASPS. These results show that CKIdelta is a central component in the mammalian clock, and suggest that mammalian and fly clocks might have different regulatory mechanisms despite the highly conserved nature of their individual components.

Victimization over the life span: a comparison of lesbian, gay, bisexual, and heterosexual siblings.

Abstract: Lifetime victimization was examined in a primarily European American sample that comprised 557 lesbian/gay, 163 bisexual, and 525 heterosexual adults. Lesbian, gay, and bisexual (LGB) participants were recruited via LGB e-mail lists, periodicals, and organizations; these participants recruited 1 or more siblings for participation in the study (81% heterosexual, 19% LGB). In hierarchical linear modeling analyses, sexual orientation was a significant predictor of most of the victimization variables. Compared with heterosexual participants, LGB participants reported more childhood psychological and physical abuse by parents or caretakers, more childhood sexual abuse, more partner psychological and physical victimization in adulthood, and more sexual assault experiences in adulthood. Sexual orientation differences in sexual victimization were greater among men than among women.

Cardiovascular Mortality Risk in Chronic Kidney Disease: Comparison of Traditional and Novel Risk Factors

Abstract: ContextElderly persons with chronic kidney disease have substantial risk for cardiovascular mortality, but the relative importance of traditional and novel risk factors is unknown.ObjectiveTo compare traditional and novel risk factors as predictors of cardiovascular mortality.Design, Setting, and PatientsA total of 5808 community-dwelling persons aged 65 years or older living in 4 communities in the United States participated in the Cardiovascular Health Study cohort. Participants were initially recruited from 1989 to June 1990; an additional 687 black participants were recruited in 1992-1993. The average length of follow-up in this longitudinal study was 8.6 years.Main Outcome MeasuresCardiovascular mortality among those with and without chronic kidney disease. Chronic kidney disease was defined as an estimated glomerular filtration rate of less than 60 mL/min per 1.73 m2.ResultsAmong the participants, 1249 (22%) had chronic kidney disease at baseline. The cardiovascular mortality risk rate was 32 deaths/1000 person-years among those with chronic kidney disease vs 16/1000 person-years among those without it. In multivariate analyses, diabetes, systolic hypertension, smoking, low physical activity, nonuse of alcohol, and left ventricular hypertrophy were predictors of cardiovascular mortality in persons with chronic kidney disease (all P values <.05). Among the novel risk factors, only log C-reactive protein (P = .05) and log interleukin 6 (P<.001) were associated with the outcome as linear predictors. Traditional risk factors were associated with the largest absolute increases in risks for cardiovascular deaths among persons with chronic kidney disease: for left ventricular hypertrophy, there were 25 deaths per 1000 person-years; current smoking, 20 per 1000 person-years; physical inactivity, 15 per 1000 person-years; systolic hypertension, 14 per 1000 person-years; diabetes, 14 per 1000 person-years; and nonuse of alcohol, 11 per 1000 person-years vs 5 deaths per 1000 person-years for those with increased C-reactive protein and 5 per 1000 person-years for those with increased interleukin 6 levels. A receiver operating characteristic analysis found that traditional risk factors had an area under the curve of 0.73 (95% confidence interval, 0.70-0.77) among those with chronic kidney disease. Adding novel risk factors only increased the area under the curve to 0.74 (95% confidence interval, 0.71-0.78; P for difference = .15).ConclusionsTraditional cardiovascular risk factors had larger associations with cardiovascular mortality than novel risk factors in elderly persons with chronic kidney disease. Future research should investigate whether aggressive lifestyle intervention in patients with chronic kidney disease can reduce their substantial cardiovascular risk.

Lower tidal volume ventilation and plasma cytokine markers of inflammation in patients with acute lung injury.

Abstract: Objectives:To evaluate the association between interleukin-6, interleukin-8, and interleukin-10 and clinical outcomes including mortality in patients with acute lung injury and to determine whether lower tidal volume ventilation was associated with a decrease in plasma cytokines in patients with acu

Treatment of Anterior Cruciate Ligament Injuries, Part I:

Abstract: Anterior cruciate ligament tears, common among athletes, are functionally disabling; they predispose the knee to subsequent injuries and the early onset of osteoarthritis. A total of 3810 studies published between January 1994 and the present were identified and reviewed to determine the current state of knowledge regarding the treatment of anterior cruciate ligament injuries. Part 1 of this article focused on studies pertaining to the biomechanical behavior of the anterior cruciate ligament, the prevalence of and risk factors for injuries related to it, the natural history of the ligament-deficient knee, injuries associated with anterior cruciate ligament disruption, indications for the treatment of anterior cruciate ligament injuries, as well as nonoperative and operative treatments. Part 2 includes technical aspects of anterior cruciate ligament surgery, bone tunnel widening, graft healing, rehabilitation after anterior cruciate ligament reconstruction, and the effects of sex, age, and activity level o...

Food sources and intakes of caffeine in the diets of persons in the United States

Abstract: This study provides information on the caffeine intakes of a representative sample of the US population using the US Department of Agriculture 1994 to 1996 and 1998 Continuing Survey of Food Intakes by Individuals. The percentage of caffeine consumers of the total sample (N=18,081) and by age and sex groups and for pregnant women were determined. Among caffeine consumers (n=15,716), the following were determined: mean intakes of caffeine (milligrams per day and milligrams per kilogram per day) for all caffeine consumers, as well as for each age and sex group and pregnant women; mean intakes (milligrams per day) of caffeine by food and beverage sources; and the percent contribution of each food and beverage category to total caffeine intake for all caffeine consumers, as well as each age and sex group and pregnant women. Eight-seven percent of the sample consumed food and beverages containing caffeine. On average, caffeine consumers' intakes were 193 mg caffeine per day and 1.2 mg caffeine per kilogram of body weight per day. As age increased, caffeine consumption increased among people aged 2 to 54 years. Men and women aged 35 to 64 years were among the highest consumers of caffeine. Major sources of caffeine were coffee (71%), soft drinks (16%), and tea (12%). Coffee was the major source of caffeine in the diets of adults, whereas soft drinks were the primary source for children and teens.

Testing the Dimensionality of Place Attachment in Recreational Settings

Abstract: The purpose of this investigation was to examine the psychometric properties of a place-attachment scale using data collected from visitors to the Appalachian Trail in the United States. These data...

Developing a Cancer-Specific Geriatric Assessment: A Feasibility Study

Abstract: Background As the U.S. population ages, there is an emerging need to characterize the "functional age" of older patients with cancer to tailor treatment decisions and stratify outcomes based on factors other than chronologic age. The goals of the current study were to develop a brief, but comprehensive, primarily self-administered cancer-specific geriatric assessment measure and to determine its feasibility as measured by 1) the percentage of patients able to complete the measure on their own, 2) the length of time to complete, and 3) patient satisfaction with the measure. Methods The geriatric and oncology literature was reviewed to choose validated measures of geriatric assessment across the following domains: functional status, comorbidity, cognition, psychological status, social functioning and support, and nutritional status. Criteria applied to geriatric assessment measurements included reliability, validity, brevity, and ability to self-administer. The measure was administered to patients with breast carcinoma, lung carcinoma, colorectal carcinoma, or lymphoma who were fluent in English and receiving chemotherapy at Memorial Sloan-Kettering Cancer Center (New York, NY) or the University of Chicago (Chicago, IL). Results The instrument was completed by 43 patients (mean age, 74 yrs; range, 65-87 yrs). The majority had AJCC Stage IV disease (68%). The mean time to completion of the assessment was 27 minutes (range, 8-45 mins). Most patients were able to complete the self-administered portion of the assessment without assistance (78%) and were satisfied with the questionnaire length (90%). There was no association noted between age (P = 0.56) or educational level (P = 0.99) and the ability to complete the assessment without assistance. Conclusions In this cohort, this brief but comprehensive geriatric assessment could be completed by the majority of patients without assistance. Prospective trials of its generalizability, reliability, and validity are justified.

A prospective study of anemia status, hemoglobin concentration, and mortality in an elderly cohort: the Cardiovascular Health Study.

Abstract: Background Anemia is viewed as a negative prognostic factor in the elderly population; its independent impact on survival is unclear. Methods Baseline hemoglobin quintiles and anemia, as defined by the World Health Organization criteria, were assessed in relation to mortality in the Cardiovascular Health Study, a prospective cohort study with 11.2 years of follow-up of 5888 community-dwelling men and women 65 years or older, enrolled in 1989-1990 or 1992-1993 in 4 US communities. Results A total of 1205 participants were in the lowest hemoglobin quintile ( Conclusions Lower and higher hemoglobin concentrations and anemia by World Health Organization criteria were independently associated with increased mortality. The World Health Organization criteria did not identify risk as well as a lower hemoglobin value. Additional study is needed on the clinically valid definition for and causes of anemia in the elderly and on the increased mortality at the extremes of hemoglobin concentrations.

TRPV4 Forms a Novel Ca2+ Signaling Complex With Ryanodine Receptors and BKCa Channels

Abstract: Vasodilatory factors produced by the endothelium are critical for the maintenance of normal blood pressure and flow. We hypothesized that endothelial signals are transduced to underlying vascular smooth muscle by vanilloid transient receptor potential (TRPV) channels. TRPV4 message was detected in RNA from cerebral artery smooth muscle cells. In patch-clamp experiments using freshly isolated cerebral myocytes, outwardly rectifying whole-cell currents with properties consistent with those of expressed TRPV4 channels were evoked by the TRPV4 agonist 4alpha-phorbol 12,13-didecanoate (4alpha-PDD) (5 micromol/L) and the endothelium-derived arachidonic acid metabolite 11,12 epoxyeicosatrienoic acid (11,12 EET) (300 nmol/L). Using high-speed laser-scanning confocal microscopy, we found that 11,12 EET increased the frequency of unitary Ca2+ release events (Ca2+ sparks) via ryanodine receptors located on the sarcoplasmic reticulum of cerebral artery smooth muscle cells. EET-induced Ca2+ sparks activated nearby sarcolemmal large-conductance Ca2+-activated K+ (BKCa) channels, measured as an increase in the frequency of transient K+ currents (referred to as "spontaneous transient outward currents" [STOCs]). 11,12 EET-induced increases in Ca2+ spark and STOC frequency were inhibited by lowering external Ca2+ from 2 mmol/L to 10 micromol/L but not by voltage-dependent Ca2+ channel inhibitors, suggesting that these responses require extracellular Ca2+ influx via channels other than voltage-dependent Ca2+ channels. Antisense-mediated suppression of TRPV4 expression in intact cerebral arteries prevented 11,12 EET-induced smooth muscle hyperpolarization and vasodilation. Thus, we conclude that TRPV4 forms a novel Ca2+ signaling complex with ryanodine receptors and BKCa channels that elicits smooth muscle hyperpolarization and arterial dilation via Ca2+-induced Ca2+ release in response to an endothelial-derived factor.

Identification of the moving junction complex of Toxoplasma gondii: a collaboration between distinct secretory organelles.

Abstract: Apicomplexan parasites, including Toxoplasma gondii and Plasmodium sp., are obligate intracellular protozoa. They enter into a host cell by attaching to and then creating an invagination in the host cell plasma membrane. Contact between parasite and host plasma membranes occurs in the form of a ring-shaped moving junction that begins at the anterior end of the parasite and then migrates posteriorly. The resulting invagination of host plasma membrane creates a parasitophorous vacuole that completely envelops the now intracellular parasite. At the start of this process, apical membrane antigen 1 (AMA1) is released onto the parasite surface from specialized secretory organelles called micronemes. The T. gondii version of this protein, TgAMA1, has been shown to be essential for invasion but its exact role has not previously been determined. We identify here a trio of proteins that associate with TgAMA1, at least one of which associates with TgAMA1 at the moving junction. Surprisingly, these new proteins derive not from micronemes, but from the anterior secretory organelles known as rhoptries and specifically, for at least two, from the neck portion of these club-shaped structures. Homologues for these AMA1-associated proteins are found throughout the Apicomplexa strongly suggesting that this moving junction apparatus is a conserved feature of this important class of parasites. Differences between the contributing proteins in different species may, in part, be the result of selective pressure from the different niches occupied by these parasites.

Supervised tensor learning

Abstract: This paper aims to take general tensors as inputs for supervised learning. A supervised tensor learning (STL) framework is established for convex optimization based learning techniques such as support vector machines (SVM) and minimax probability machines (MPM). Within the STL framework, many conventional learning machines can be generalized to take n/sup th/-order tensors as inputs. We also study the applications of tensors to learning machine design and feature extraction by linear discriminant analysis (LDA). Our method for tensor based feature extraction is named the tenor rank-one discriminant analysis (TR1DA). These generalized algorithms have several advantages: 1) reduce the curse of dimension problem in machine learning and data mining; 2) avoid the failure to converge; and 3) achieve better separation between the different categories of samples. As an example, we generalize MPM to its STL version, which is named the tensor MPM (TMPM). TMPM learns a series of tensor projections iteratively. It is then evaluated against the original MPM. Our experiments on a binary classification problem show that TMPM significantly outperforms the original MPM.

C-Reactive Protein and the 10-Year Incidence of Coronary Heart Disease in Older Men and Women The Cardiovascular Health Study

Abstract: Background— High C-reactive protein (CRP) is associated with increased coronary heart disease risk. Few long-term data in the elderly are available. Methods and Results— Baseline CRP was measured in 3971 men and women ≥65 years of age without prior vascular diseases; 26% had elevated concentrations (>3 mg/L). With 10 years of follow-up, 547 participants developed coronary heart disease (CHD; defined as myocardial infarction or coronary death). With elevated CRP, the 10-year cumulative CHD incidences were 33% in men and 17% in women. The age-, ethnicity-, and sex-adjusted relative risk of CHD for CRP >3 mg/L compared with <1 mg/L was 1.82 (95% CI, 1.46 to 2.28). Adjusting for conventional risk factors reduced the relative risk to 1.45 (95% CI, 1.14 to 1.86). The population-attributable risk of CHD for elevated CRP was 11%. Risk relationships did not differ in subgroups defined by baseline risk factors. We assessed whether CRP improved prediction by the Framingham Risk Score. Among men with a 10-year Framin...

Environmental marketing strategy and firm performance: Effects on new product performance and market share

Abstract: Recent studies on marketing and the natural environment have called for research that links environmental marketing strategies to the performance of the firm. This research operationalizes the enviropreneurial marketing (EM) construct and examines its relationship with firm performance. It is the first empirical research to operationalize the EM construct. The new scale, albeit a first attempt, demonstrates encouraging psychometric properties. According to the resource-based view of the firm, a resource such as EM should directly influence firms’ capabilities (e.g., new product development success) but not competitive advantage (e.g., change in market share). A nationwide study of top-level marketing managers supports this perspective. In addition, although market turbulence also affects new product development success, it does not have an impact on EM. This suggests that EM formation is driven by internal rather than external forces.

Protecting privacy against location-based personal identification

Abstract: This paper presents a preliminary investigation on the privacy issues involved in the use of location-based services. It is argued that even if the user identity is not explicitly released to the service provider, the geo-localized history of user-requests can act as a quasi-identifier and may be used to access sensitive information about specific individuals. The paper formally defines a framework to evaluate the risk in revealing a user identity via location information and presents preliminary ideas about algorithms to prevent this to happen.

The evolving role of inflammation in obesity and the metabolic syndrome.

Abstract: Advances in adipose tissue biology over the past 10 years have led to an improved understanding of the mechanisms linking obesity with the metabolic syndrome and other complications. Obesity is characterized by a chronic, systemic low-grade state of inflammation. Biomarkers of inflammation, such as the leukocyte count, tumor necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6), and C-reactive protein, are increased in obesity, associated with insulin resistance, and predict the development of type 2 diabetes and cardiovascular disease. It is now clear that the adipocyte is an active participant in the generation of the inflammatory state in obesity. Adipocytes secrete a variety of cytokines, including IL-6 and TNF-alpha, that promote inflammation. Moreover, recent studies suggest that obesity is associated with an increase in adipose tissue macrophages, which also participate in the inflammatory process through the elaboration of cytokines. An improved understanding of the role of adipose tissue in the activation of inflammatory pathways may suggest novel treatment and prevention strategies aimed at reducing obesity-associated morbidities and mortality.

Assessment of Adult Psychopathology: Meta-Analyses and Implications of Cross-Informant Correlations

Abstract: Assessment of adult psychopathology relies heavily on self-reports. To determine how well self-reports agree with reports by "informants" who know the person being assessed, the authors examined 51,000 articles published over 10 years in 52 peer-reviewed journals for correlations between self-reports and "informants" reports. Qualifying correlations were found in 108 (0.2%) of the articles. When self-reports and informant reports were obtained with parallel instruments, mean cross-informant correlations were .681 for substance use, .428 for internalizing, and .438 for externalizing problems. When based on different instruments, the mean cross-informant correlation was .304. The moderate sizes of the correlations argue for systematically obtaining multi-informant data. National survey findings were used to illustrate practical ways to obtain and use such data.

Multiscale, resurgent epidemics in a hierarchical metapopulation model.

Abstract: Although population structure has long been recognized as relevant to the spread of infectious disease, traditional mathematical models have understated the role of nonhomogenous mixing in populations with geographical and social structure. Recently, a wide variety of spatial and network models have been proposed that incorporate various aspects of interaction structure among individuals. However, these more complex models necessarily suffer from limited tractability, rendering general conclusions difficult to draw. In seeking a compromise between parsimony and realism, we introduce a class of metapopulation models in which we assume homogeneous mixing holds within local contexts, and that these contexts are embedded in a nested hierarchy of successively larger domains. We model the movement of individuals between contexts via simple transport parameters and allow diseases to spread stochastically. Our model exhibits some important stylized features of real epidemics, including extreme size variation and temporal heterogeneity, that are difficult to characterize with traditional measures. In particular, our results suggest that when epidemics do occur the basic reproduction number R 0 may bear little relation to their final size. Informed by our model's behavior, we suggest measures for characterizing epidemic thresholds and discuss implications for the control of epidemics. math model population structure

Polymorphisms within the C-Reactive Protein (CRP) Promoter Region Are Associated with Plasma CRP Levels

Abstract: Elevated plasma levels of C-reactive protein (CRP), an inflammation-sensitive marker, have emerged as an important predictor of future cardiovascular disease and metabolic abnormalities in apparently healthy men and women. Here, we performed a systematic survey of common nucleotide variation across the genomic region encompassing the CRP gene locus. Of the common single-nucleotide polymorphisms (SNPs) identified, several in the CRP promoter region are strongly associated with CRP levels in a large cohort study of cardiovascular risk in European American and African American young adults. We also demonstrate the functional importance of these SNPs in vitro.

Genetically enhanced cows resist intramammary Staphylococcus aureus infection.

Abstract: Mastitis, the most consequential disease in dairy cattle, costs the US dairy industry billions of dollars annually. To test the feasibility of protecting animals through genetic engineering, transgenic cows secreting lysostaphin at concentrations ranging from 0.9 to 14 mg/ml in their milk were produced. In vitro assays demonstrated the milk's ability to kill Staphylococcus aureus. Intramammary infusions of S. aureus were administered to three transgenic and ten nontransgenic cows. Increases in milk somatic cells, elevated body temperatures and induced acute phase proteins, each indicative of infection, were observed in all of the nontransgenic cows but in none of the transgenic animals. Protection against S. aureus mastitis appears to be achievable with as little as 3 mg/ml of lysostaphin in milk. Our results indicate that genetic engineering can provide a viable tool for enhancing resistance to disease and improve the well-being of livestock.

Practice Parameters for the Treatment of Perianal Abscess and Fistula-in-Ano (Revised)

Abstract: The American Society of Colon and Rectal Surgeons is dedicated to assuring high-quality patient care by advancing the science, prevention, and management of disorders and diseases of the colon, rectum, and anus. The Standards Committee is composed of Society members who are chosen because they have demonstrated expertise in the specialty of colon and rectal surgery. This Committee was created to lead international efforts in defining quality care for conditions related to the colon, rectum, and anus. This is accompanied by developing Clinical Practice Guidelines based on the best available evidence. These guidelines are inclusive, and not prescriptive. Their purpose is to provide information on which decisions can be made, rather than dictate a specific form of treatment. These guidelines are intended for the use of all practitioners, health care workers, and patients who desire information about the management of the conditions addressed by the topics covered in these guidelines. It should be recognized that these guidelines should not be deemed inclusive of all proper methods of care or exclusive of methods of care reasonably directed to obtaining the same results. The ultimate judgment regarding the propriety of any specific procedure must be made by the physician in light of all of the circumstances presented by the individual patient.

An Analysis of the Quality of Cartilage Repair Studies

Abstract: Background: Most lesions of articular cartilage do not heal spontaneously and may lead to secondary osteoarthritis. It is not known whether the optimistic reports on the short and long-term results of several different cartilage repair techniques are based on sound methodological quality. Methods: We performed a literature search in MEDLINE, CINAHL, the Cochrane Central Register, and EMBASE and included studies in which the primary aim of the investigation was to report the outcome after cartilage repair in the knee with use of microfracture, autologous osteochondral transplantation, autologous periosteal transplantation, or autologous chondrocyte implantation. We scored the quality of the studies using a modified Coleman Methodology Score with ten criteria, which results in a final score between 0 and 100. Studies were also assessed with use of the level-of-evidence rating used in the American Volume of The Journal of Bone and Joint Surgery. We collected data on the year of publication, the reported postoperative results, and the outcome measures used to assess the results. Results: Sixty-one studies involving a total of 3987 surgical procedures were included. The average methodology score was 43.5 of 100. Methodological deficiencies were found with respect to five criteria: the type of study, description of the rehabilitation protocol, outcome criteria, outcome assessment, and subject selection process. Large variations in the reported outcome were seen within each treatment modality, and no significant differences were found between each kind of therapy (p = 0.11). The methodology score correlated positively with the level-of-evidence rating (r = 0.668, p < 0.0001), but there were large variations in the methodology score within each level. The linear regression analysis weighted by the number of patients demonstrated a negative yet not significant correlation between the methodology score and the results reported in nineteen studies with use of the Lysholm Scale (r = -0.29, p = 0.19). A total of twenty-seven different clinical outcome measurement scales were used to assess outcome. Conclusions: The generally low methodological quality found in the studies included in this analysis indicates that caution is required when interpreting results after surgical cartilage repair. Firm recommendations on which procedure to choose cannot be given at this time on the basis of these studies. More attention should be paid to methodological quality when designing, performing, and reporting clinical studies. Level of Evidence: Therapeutic Level III. See Instructions to Authors for a complete description of levels of evidence.