Showing papers by "University of Vermont published in 2004"
TL;DR: The steps of model selection are outlined and several ways that it is now being implemented are highlighted, so that researchers in ecology and evolution will find a valuable alternative to traditional null hypothesis testing, especially when more than one hypothesis is plausible.
Abstract: Recently, researchers in several areas of ecology and evolution have begun to change the way in which they analyze data and make biological inferences. Rather than the traditional null hypothesis testing approach, they have adopted an approach called model selection, in which several competing hypotheses are simultaneously confronted with data. Model selection can be used to identify a single best model, thus lending support to one particular hypothesis, or it can be used to make inferences based on weighted support from a complete set of competing models. Model selection is widely accepted and well developed in certain fields, most notably in molecular systematics and mark-recapture analysis. However, it is now gaining support in several other areas, from molecular evolution to landscape ecology. Here, we outline the steps of model selection and highlight several ways that it is now being implemented. By adopting this approach, researchers in ecology and evolution will find a valuable alternative to traditional null hypothesis testing, especially when more than one hypothesis is plausible.
3,489 citations
TL;DR: In this paper, the authors describe the development of a short, general measure of experiential avoidance, based on a specific theoretical approach to this process, which is incorporated into Acceptance and Commitment Therapy.
Abstract: The present study describes the development of a short, general measure of experiential avoidance, based on a specific theoretical approach to this process. A theoretically driven iterative exploratory analysis using structural equation modeling on data from a clinical sample yielded a single factor comprising 9 items. A fully confirmatory factor analysis upheld this same 9-item factor in an independent clinical sample. The operational characteristics of the Acceptance and Action Questionnaire (AAQ) were then examined in 8 additional samples. All totaled, over 2,400 participants were studied. As expected, higher levels of experiential avoidance were associated with higher levels of general psychopathology, depression, anxiety, a variety of specific fears, trauma, and a lower quality of life. The AAQ related to more specific measures of avoidant coping and to self-deceptive positivity, but the relation to psychopathology could not be fully accounted for by these alternative measures. The data provide some initial support for the model of experiential avoidance based on Relational Frame Theory that is incorporated into Acceptance and Commitment Therapy, and provides researchers with a preliminary measure for use in population-based studies on experiential avoidance.
1,879 citations
TL;DR: Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic and preventive aspects of care to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case.
1,771 citations
TL;DR: Evidence that extinction does not destroy the original learning, but instead generates new learning that is especially context-dependent is reviewed, consistent with behavioral models that emphasize the role of generalization decrement and expectation violation.
Abstract: This article provides a selective review and integration of the behavioral literature on Pavlovian extinction. The first part reviews evidence that extinction does not destroy the original learning, but instead generates new learning that is especially context-dependent. The second part examines insights provided by research on several related behavioral phenomena (the interference paradigms, conditioned inhibition, and inhibition despite reinforcement). The final part examines four potential causes of extinction: the discrimination of a new reinforcement rate, generalization decrement, response inhibition, and violation of a reinforcer expectation. The data are consistent with behavioral models that emphasize the role of generalization decrement and expectation violation, but would be more so if those models were expanded to better accommodate the finding that extinction involves a context-modulated form of inhibitory learning.
1,633 citations
TL;DR: The relapse curve and rate of long-term prolonged abstinence among smokers who try to quit without treatment are described and more reports of relapse curves of self-quitters are needed.
Abstract: Objective To describe the relapse curve and rate of long-term prolonged abstinence among smokers who try to quit without treatment.
Method Systematic literature review.
Data sources Cochrane Reviews, Dissertation Abstracts, Excerpt Medica, Medline, Psych Abstracts and US Center for Disease Control databases plus bibliographies of articles and requests of scientists.
Study selection Prospective studies of self-quitters or studies that included a no-treatment control group.
Data extraction Two reviewers independently extracted data in a non-blind manner.
Data synthesis The number of studies was too small and the data too heterogeneous for meta-analysis or other statistical techniques.
Results There is a paucity of studies reporting relapse curves of self-quitters. The existing eight relapse curves from two studies of self-quitters and five no-treatment control groups indicate most relapse occurs in the first 8 days. These relapse curves were heterogeneous even when the final outcome was made similar. In terms of prolonged abstinence rates, a prior summary of 10 self-quitting studies, two other studies of self-quitters and three no-treatment control groups indicate 3–5% of self-quitters achieve prolonged abstinence for 6–12 month after a given quit attempt.
Conclusions More reports of relapse curves of self-quitters are needed. Smoking cessation interventions should focus on the first week of abstinence. Interventions that produce abstinence rates of 5–10% may be effective. Cessation studies should report relapse curves.
1,277 citations
TL;DR: Lumpectomy plus adjuvant therapy with tamoxifen alone is a realistic choice for the treatment of women 70 years of age or older who have early, estrogen-receptor-positive breast cancer.
Abstract: BACKGROUND In women 70 years of age or older who have early breast cancer, it is unclear whether lumpectomy plus tamoxifen is as effective as lumpectomy followed by tamoxifen plus radiation therapy. METHODS Between July 1994 and February 1999, we randomly assigned 636 women who were 70 years of age or older and who had clinical stage I (T1N0M0 according to the tumor-node-metastasis classification), estrogen-receptor-positive breast carcinoma treated by lumpectomy to receive tamoxifen plus radiation therapy (317 women) or tamoxifen alone (319 women). Primary end points were the time to local or regional recurrence, the frequency of mastectomy for recurrence, breast-cancer-specific survival, the time to distant metastasis, and overall survival. RESULTS The only significant difference between the two groups was in the rate of local or regional recurrence at five years (1 percent in the group given tamoxifen plus irradiation and 4 percent in the group given tamoxifen alone, P<0.001). There were no significant differences between the two groups with regard to the rates of mastectomy for local recurrence, distant metastases, or five-year rates of overall survival (87 percent in the group given tamoxifen plus irradiation and 86 percent in the tamoxifen group, P=0.94). Assessment by physicians and patients of cosmetic results and adverse events uniformly rated tamoxifen plus irradiation inferior to tamoxifen alone. CONCLUSIONS Lumpectomy plus adjuvant therapy with tamoxifen alone is a realistic choice for the treatment of women 70 years of age or older who have early, estrogen-receptor-positive breast cancer.
939 citations
TL;DR: In this paper, the authors synthesize the literature on poverty and disasters in the United States and present the results from a wide range of studies conducted over the past twenty years, which illustrates that the poor are more vulnerable to natural disasters due to such factors as place and type of residence, building construction, and social exclusion.
Abstract: This article synthesizes the literature on poverty and disasters in the United States and presents the results from a wide range of studies conducted over the past twenty years. The findings are organized into eight categories based on the stages of a disaster event. The review illustrates how people of different socioeconomic statuses perceive, prepare for, and respond to natural hazard risks, how low-income populations may be differentially impacted, both physically and psychologically, and how disaster effects vary by social class during the periods of emergency response, recovery, and reconstruction. The literature illustrates that the poor in the United States are more vulnerable to natural disasters due to such factors as place and type of residence, building construction, and social exclusion. The results have important implications for social equity and recommendations for future research and policy implementation are offered.
835 citations
TL;DR: The incidence of venous thromboembolism in this cohort of middle- and older-aged subjects was similar to that observed in more geographically homogeneous samples, and short-term mortality and 2-year recurrence rates were appreciable, especially among subjects with cancer.
798 citations
TL;DR: Findings support the assertion that disordered gastrointestinal function in IBS involves changes intrinsic to the bowel and suggest that shared defects in 5-HT signaling may underlie the altered motility, secretion, and sensation.
716 citations
TL;DR: The development of an eosinophil-less mouse now permits an unambiguous assessment of a number of human diseases that have been linked to this granulocyte, including allergic diseases, parasite infections, and tumorigenesis.
Abstract: Eosinophils are often dominant inflammatory cells present in the lungs of asthma patients. Nonetheless, the role of these leukocytes remains poorly understood. We have created a transgenic line of mice (PHIL) that are specifically devoid of eosinophils, but otherwise have a full complement of hematopoietically derived cells. Allergen challenge of PHIL mice demonstrated that eosinophils were required for pulmonary mucus accumulation and the airway hyperresponsiveness associated with asthma. The development of an eosinophil-less mouse now permits an unambiguous assessment of a number of human diseases that have been linked to this granulocyte, including allergic diseases, parasite infections, and tumorigenesis.
708 citations
TL;DR: The inverse association of total cholesterol level with mortality in dialysis patients is likely due to the cholesterol-lowering effect of systemic inflammation and malnutrition, not to a protective effect of high cholesterol concentrations.
Abstract: ContextTotal cholesterol level is inversely associated with mortality in dialysis
patients, a group at high risk of cardiovascular disease (CVD). This paradox
may be explained by systemic inflammation and/or malnutrition, which are associated
with lower cholesterol levels and higher mortality.ObjectiveTo determine the relationship between cholesterol level and outcome
in patients undergoing dialysis, accounting for inflammation and malnutrition.Design, Setting, and ParticipantsProspective study of 823 patients enrolled from October 1995 to June
1998 who recently initiated dialysis, from 79 clinics, classified by absence
or presence of inflammation and/or malnutrition (defined as serum albumin
levels <3.6 mg/dL, C-reactive protein ≥10 mg/L, or interleukin 6 ≥3.09
pg/mL).Main Outcome MeasuresAll-cause and cardiovascular disease mortality.ResultsDuring a median follow-up of 2.4 years, 324 deaths (159 CVD deaths),
153 renal transplantations, and 10 losses to follow-up occurred. Average serum
cholesterol level was lower in the presence of inflammation/malnutrition than
in its absence. In a Cox model adjusted for age, race, and sex, a 40-mg/dL
(1.0-mmol/L) increment in baseline total serum cholesterol level was associated
with a decreased risk of all-cause mortality overall (relative hazard [RH],
0.92; 95% confidence interval [CI], 0.87-0.98) and in the presence of inflammation/malnutrition
(RH, 0.89; CI, 0.84-0.95). In contrast, serum cholesterol level was associated
with an increased risk in the absence of inflammation/malnutrition (RH, 1.32;
95% CI, 1.07-1.63). For CVD mortality, an inverse trend was not statistically
significant in the presence of inflammation/malnutrition, and a positive association
was evident in the absence of inflammation/malnutrition (RH, 1.41; 95% CI,
1.04-1.89). Further adjustment for traditional CVD risk factors, dialysis
modality, comorbidity, and inflammatory markers attenuated the inverse association
but strengthened the positive association.ConclusionsThe inverse association of total cholesterol level with mortality in
dialysis patients is likely due to the cholesterol-lowering effect of systemic
inflammation and malnutrition, not to a protective effect of high cholesterol
concentrations. These findings support treatment of hypercholesterolemia in
this population.
TL;DR: It is reported that selective activation of the Akt3 protein promotes cell survival and tumor development in 43 to 60% of nonfamilial melanomas and provides new therapeutic opportunities for patients in the advanced stages of this disease.
Abstract: Malignant melanoma is the skin cancer with the most significant impact on man, carrying the highest risk of death from metastasis. Both incidence and mortality rates continue to rise each year, with no effective long-term treatment on the horizon. In part, this reflects lack of identification of critical genes involved and specific therapies targeted to correct these defects. We report that selective activation of the Akt3 protein promotes cell survival and tumor development in 43 to 60% of nonfamilial melanomas. The predominant Akt isoform active in melanomas was identified by showing that small interfering RNA (siRNA) against only Akt3, and not Akt1 or Akt2, lowered the amount of phosphorylated (active) Akt in melanoma cells. The amount of active Akt3 increased progressively during melanoma tumor progression with highest levels present in advanced-stage metastatic melanomas. Mechanisms of Akt3 deregulation occurred through a combination of overexpression of Akt3 accompanying copy number increases of the gene and decreased PTEN protein function occurring through loss or haploinsufficiency of the PTEN gene. Targeted reduction of Akt3 activity with siRNA or by expressing active PTEN protein stimulated apoptotic signaling, which reduced cell survival by increasing apoptosis rates thereby inhibiting melanoma tumor development. Identifying Akt3 as a selective target in melanoma cells provides new therapeutic opportunities for patients in the advanced stages of this disease.
TL;DR: An overview of the 21 MDE studies published to date reveals a substantial signature of MDE in natural patterns and justifies continued work, and calls for assessment of Mde on an equal statistical footing with other candidate explanations for richness gradients.
Abstract: If species' ranges are randomly shuffled within a bounded geographical domain free of environmental gradients, ranges overlap increasingly toward the center of the domain, creating a “mid‐domain” peak of species richness. This “mid‐domain effect” (MDE) has been controversial both in concept and in application. Empirical studies assess the degree to which the evolutionary, ecological, and historical processes that undeniably act on individual species and clades produce geographical patterns that resemble those produced by MDE models. MDE models that resample empirical range size frequency distributions (RSFDs) balance the risk of underestimating and overestimating the role of MDE, whereas theoretical RSFDs are generally biased toward underestimating MDE. We discuss the inclusion of nonendemic species in MDE models, rationales for setting domain limits, and the validity of one‐ and two‐dimensional MDE models. MDE models, though null models, are not null hypotheses to be simplistically rejected or ...
TL;DR: The authors examined the effect of place attachment on respondents' perceptions of social and environmental conditions along the Appalachian Trail (AT) in the United States using a social judgment framework and found that place attachment, place identity and place dependence had opposing effects on the condition domains.
TL;DR: In this article, a double-blind randomized controlled trial of 16,608 women between the ages of 50 and 79 years, who were enrolled in 1993 through 1998 at 40 US clinical centers with 5.6 years of follow up; and a nested case-control.
Abstract: Context
Postmenopausal hormone therapy increases the risk of venous thrombosis.
It is not known whether other factors influencing thrombosis add to this risk.
Objective
To report final data on incidence of venous thrombosis in the Women’s
Health Initiative Estrogen Plus Progestin clinical trial and the association
of hormone therapy with venous thrombosis in the setting of other thrombosis
risk factors.
Design, Setting, and Participants
Double-blind randomized controlled trial of 16 608 postmenopausal
women between the ages of 50 and 79 years, who were enrolled in 1993 through
1998 at 40 US clinical centers with 5.6 years of follow up; and a nested case-control
study. Baseline gene variants related to thrombosis risk were measured in
the first 147 women who developed thrombosis and in 513 controls.
Intervention
Random assignment to 0.625 mg/d of conjugated equine estrogen plus 2.5
mg/d of medroxyprogesterone acetate, or placebo.
Main Outcome MeasuresCentrally validated deep vein thrombosis and pulmonary embolus.Results
Venous thrombosis occurred in 167 women taking estrogen plus progestin
(3.5 per 1000 person-years) and in 76 taking placebo (1.7 per 1000 person-years);
hazard ratio (HR), 2.06 (95% confidence interval [CI], 1.57-2.70). Compared
with women between the ages of 50 and 59 years who were taking placebo, the
risk associated with hormone therapy was higher with age: HR of 4.28 (95%
CI, 2.38-7.72) for women aged 60 to 69 years and 7.46 (95% CI, 4.32-14.38)
for women aged 70 to 79 years. Compared with women who were of normal weight
and taking placebo, the risk associated with taking estrogen plus progestin
was increased among overweight and obese women: HR of 3.80 (95% CI, 2.08-6.94)
and 5.61 (95% CI, 3.12-10.11), respectively. Factor V Leiden enhanced the
hormone-associated risk of thrombosis with a 6.69-fold increased risk compared
with women in the placebo group without the mutation (95% CI, 3.09-14.49).
Other genetic variants (prothrombin 20210A, methylenetetrahydrofolate reductase
C677T, factor XIII Val34Leu, PAI-1 4G/5G, and factor V HR2) did not modify
the association of hormone therapy with venous thrombosis.
Conclusions
Estrogen plus progestin was associated with doubling the risk of venous
thrombosis. Estrogen plus progestin therapy increased the risks associated
with age, overweight or obesity, and factor V Leiden.
TL;DR: In this article, the authors explored factors that affect the adoption or intention to adopt three e-banking technologies and changes in these factors over time, and found that relative advantage, complexity/simplicity, compatibility, observability, risk tolerance, and product involvement are associated with adoption.
Abstract: Is there an electronic banking (e‐banking) revolution in the USA? Millions of Americans are currently using a variety of e‐banking technologies and millions more are expected to come “online.” However, millions of others have not or will not. This paper explores factors that affect the of adoption or intention to adopt three e‐banking technologies and changes in these factors over time. Using a Federal Reserve Board commissioned data set, the paper finds that relative advantage, complexity/simplicity, compatibility, observability, risk tolerance, and product involvement are associated with adoption. Income, assets, education, gender and marital status, and age also affect adoption. Adoption changed over time, but the impacts of other factors on adoption have not changed. Implications for both the banking industry and public policy are discussed.
TL;DR: The American Diabetes Association, the North American Association for the Study of Obesity, and the American Society for Clinical Nutrition have joined together to issue this statement on the use of lifestyle modification in the prevention and management of type 2 diabetes.
Abstract: The prevalence of diabetes in the U.S. continues to rise by epidemic proportions. This increase parallels the rising rates of obesity and overweight observed over the past decade (1,2). Indeed, as BMI increases, the risk of developing type 2 diabetes increases in a “dose-dependent” manner (3,4). The prevalence of type 2 diabetes is 3–7 times higher in obese than in normal-weight adults, and those with a BMI >35 kg/m2 are 20 times more likely to develop diabetes than those with a BMI between 18.5 and 24.9 kg/m2 (5,6). In addition, weight gain during adulthood is also directly correlated with an increased risk of type 2 diabetes (3,7–9).
Obesity also complicates the management of type 2 diabetes by increasing insulin resistance and blood glucose concentrations (10). It is an independent risk factor for dyslipidemia, hypertension, and cardiovascular disease (6,11–14) and, thus, increases the risk of cardiovascular complications and cardiovascular mortality in patients with type 2 diabetes (15).
The purpose of this statement is to review the important role of weight management in the prevention and management of type 2 diabetes and to describe strategies for achieving and maintaining a healthy body weight through lifestyle modification. The use of weight loss medications and bariatric surgery in the management of obesity will not be discussed in this document. Pharmacotherapy can be a useful adjunct to lifestyle modification in the long-term management of obesity in selected patients (16). Weight loss medications may be considered for those with a BMI ≥30 or those with a BMI ≥27 plus obesity-related comorbid conditions. Weight loss surgery may be a therapeutic alternative for patients with a BMI ≥40 or a BMI ≥35 plus comorbid conditions (16). Comprehensive review articles that …
TL;DR: This paper presents an efficient method for mining both positive and negative association rules in databases, and extends traditional associations to include association rules of forms A ⇒ ¬ , which indicate negative associations between itemsets.
Abstract: This paper presents an efficient method for mining both positive and negative association rules in databases. The method extends traditional associations to include association rules of forms A ⇒ ¬ B, ¬ A ⇒ B, and ¬ A ⇒ ¬ B, which indicate negative associations between itemsets. With a pruning strategy and an interestingness measure, our method scales to large databases. The method has been evaluated using both synthetic and real-world databases, and our experimental results demonstrate its effectiveness and efficiency.
TL;DR: A primary goal in the management of diabetes is the regulation of blood glucose to achieve near-normal blood glucose, and the total carbohydrate intake from a meal or snack is a relatively reliable predictor of postprandial blood glucose.
Abstract: Diabetes has long been viewed as a disorder of carbohydrate metabolism due to its hallmark feature of hyperglycemia. Indeed, hyperglycemia is the cause of the acute symptoms associated with diabetes such as polydypsia, polyuria, and polyphagia (1). The long-term complications (retinopathy, nephropathy, and neuropathy) associated with diabetes are also believed to result from chronically elevated blood glucose levels (2–6). In addition, hyperglycemia may contribute to the development of macrovascular disease, which is associated with the development of coronary artery disease, the leading cause of death in individuals with diabetes (7–9). Thus, a primary goal in the management of diabetes is the regulation of blood glucose to achieve near-normal blood glucose.
Blood glucose concentration following a meal is determined by the rate of appearance of glucose into the blood stream (absorption) and its clearance/disappearance from the circulation (10). The rate of disappearance of glucose is largely influenced by insulin secretion and its action on target tissues (11).
The component of the diet that has the greatest influence on blood glucose is carbohydrate. Other macronutrients in the diet, i.e., fat and protein, can influence the postprandial blood glucose level, however. For example, dietary fat slows glucose absorption, delaying the peak glycemic response to the ingestion of a food that contains glucose (12–14). In addition, although glucose is the primary stimulus for insulin release, protein/amino acids augment insulin release when ingested with carbohydrate, thereby increasing the clearance of glucose from the blood (15–17).
Both the quantity and the type or source of carbohydrate found in foods influence postprandial glucose level (18,19). Although most experts agree that the total carbohydrate intake from a meal or snack is a relatively reliable predictor of postprandial blood glucose (18,20–22), the impact …
TL;DR: The authors determined the incidence of acute and delayed chemotherapy‐induced nausea and emesis (vomiting) (CINV) among patients receiving highly (HEC) or moderately (MEC) emetogenic chemotherapy and whether physicians and nurses accurately recognized the incidence in their own practices.
Abstract: BACKGROUND
The authors determined the incidence of acute and delayed chemotherapy-induced nausea and emesis (vomiting) (CINV) among patients receiving highly (HEC) or moderately (MEC) emetogenic chemotherapy. They also assessed whether physicians and nurses accurately recognized the incidence of acute and delayed CINV in their own practices.
METHODS
A prospective, observational study of adult patients receiving HEC or MEC for the first time was performed. Before patient enrollment, medical oncologists and oncology nurses estimated the incidence of acute (Day 1) and delayed (Days 2–5) CINV after first administration of HEC and MEC in their own practices. Eligible patients from their practices then completed a 6-day diary including emetic episodes, nausea assessment, and antiemetic medication use. Observed incidence rates of acute and delayed CINV were compared with physician/nurse predictions.
RESULTS
Twenty-four physicians and nurses and 298 eligible patients (67 receiving HEC and 231 receiving MEC) were recruited from 14 oncology practices in 6 countries. Greater than 35% of patients overall experienced acute nausea, whereas 13% experienced acute emesis. Delayed nausea and emesis were observed in 60% and 50% of HEC patients, respectively, and in 52% and 28% of MEC patients, respectively. Delayed symptoms appeared without acute symptoms after HEC (emesis, 38%; nausea, 33%) and MEC (emesis, 19%; nausea, 21%). Physicians and nurses accurately predicted the incidence of acute CINV but underestimated the incidence of delayed nausea and emesis after HEC by 21 and 28 percentage points, respectively, and delayed nausea after MEC by 28 percentage points. Greater than 75% of physicians and nurses underestimated the incidence of delayed CINV after both HEC and MEC.
CONCLUSIONS
Physicians and nurses markedly underestimated the incidence of delayed nausea and emesis after both HEC and MEC. Delayed nausea and emesis, which may appear even in the absence of acute nausea and emesis, remain important targets for improved therapeutic intervention. Cancer 2004. © 2004 American Cancer Society.
TL;DR: Converging evidence from basic laboratory and clinical studies indicates that a withdrawal syndrome reliably follows discontinuation of chronic heavy use of cannabis or tetrahydrocannabinol, and findings suggest that the syndrome has clinical importance.
Abstract: The authors review the literature examining the validity and significance of cannabis withdrawal syndrome. Findings from animal laboratory research are briefly reviewed, and human laboratory and clinical studies are surveyed in more detail. Converging evidence from basic laboratory and clinical studies indicates that a withdrawal syndrome reliably follows discontinuation of chronic heavy use of cannabis or tetrahydrocannabinol. Common symptoms are primarily emotional and behavioral, although appetite change, weight loss, and physical discomfort are also frequently reported. The onset and time course of these symptoms appear similar to those of other substance withdrawal syndromes. The magnitude and severity of these symptoms appear substantial, and these findings suggest that the syndrome has clinical importance. Diagnostic criteria for cannabis withdrawal syndrome are proposed.
TL;DR: Evidence that dietary fatty acids can modulate markers of inflammation is provided, although stearic acid minimally affects LDL cholesterol, it does appear to increase fibrinogen concentrations.
TL;DR: Although no treatment benefit was seen on the time to confirmed progression of disability, relapse- and MRI-related outcomes showed significant benefit with both dosing regimens tested, a result consistent with the outcomes of earlier clinical trials.
Abstract: Objective To evaluate the efficacy and safety of interferon beta-1b (IFNbeta-1b) in subjects with secondary progressive multiple sclerosis (SPMS). Methods This 3-year, multicenter, double-blind, placebo-controlled, randomized trial of IFNbeta-1b included 939 subjects from the United States and Canada with SPMS and Expanded Disability Status Scale (EDSS) scores ranging from 3.0 to 6.5. Subjects were randomly assigned to receive either placebo or IFNbeta-1b (250 microg or 160 microg/m2 body surface area), administered subcutaneously every other day. The primary outcome was time to progression by > or =1.0 EDSS point (0.5 point if EDSS score was 6.0 to 6.5 at entry) confirmed at 6 months. Secondary outcomes included mean change in EDSS score from baseline, relapse-related measures, MRI activity, and a standardized neuropsychological function test. Results There was no significant difference in time to confirmed progression of EDSS scores between placebo-treated patients and either of the IFNbeta-1b treatment groups. However, IFNbeta-1b treatment resulted in improvement on secondary outcome measures involving clinical relapses, newly active MRI lesions, and accumulated burden of disease on T2-weighted MRI. Effects were similar for both IFNbeta-1b treatment groups. Neutralizing antibodies to IFNbeta-1b were detected in 23% of 250-microg and 32% of 160-microg/m2 recipients, but their presence did not consistently affect clinical or MRI outcomes. IFNbeta-1b was also well tolerated at both doses. Conclusions Although no treatment benefit was seen on the time to confirmed progression of disability, relapse- and MRI-related outcomes showed significant benefit with both dosing regimens tested, a result consistent with the outcomes of earlier clinical trials.
TL;DR: Although normal individuals are unlikely to show cognitive benefits after nicotinic stimulation except under extreme task conditions, individuals with a variety of disease states can benefit from Nicotinic drugs.
TL;DR: The Strategic Alliance Formative Assessment Rubric (SAFAR) as mentioned in this paper is an assessment tool that captures central principles of collaboration and has been used as part of a four-step evaluation process to help alliance leaders, managers, and members in Safe School/Healthy Student Initiatives to quantitatively and qualitatively gauge, celebrate, and communicate the relative strength of their collaborative endeavor over time.
Abstract: Increasingly, collaboration between business, non-profit, health and educational agencies is being championed as a powerful strategy to achieve a vision otherwise not possible when independent entities work alone. But the definition of collaboration is elusive and it is often difficult for organizations to put collaboration into practice and assess it with certainty. Program evaluators can assist practitioners concerned with the development of a strategic alliance predicated on collaboration by understanding and utilizing principles of collaboration theory. The Strategic Alliance Formative Assessment Rubric (SAFAR) is an assessment tool that captures central principles of collaboration and has been used as part of a four-step evaluation process to help alliance leaders, managers, and members in Safe School/Healthy Student Initiatives to quantitatively and qualitatively gauge, celebrate, and communicate the relative strength of their collaborative endeavor over time. The collaboration principles and corres...
TL;DR: It is demonstrated here that S-nitrosothiols (SNO) caused a dose-dependent inhibition of the enzymatic activity of IKK, in lung epithelial cells and in Jurkat T cells, which was associated with S- Nitrosylation of the IKK complex, providing an additional mechanism for its antiinflammatory properties.
Abstract: Nitric oxide (NO) possesses antiinflammatory effects, which may be exerted via its ability to inhibit the transcription factor, NF-κB. A commonly proposed mode of action for inhibition of NF-κBbyNO involves interference with NF-κB binding to DNA. Because activation of inhibitory κB kinase (IKK), the prerequisite enzyme complex necessary to induce NF-κB, is subject to redox regulation, we assessed whether IKK could present a more proximal target for NO to inhibit NF-κB activation. We demonstrate here that S-nitrosothiols (SNO) caused a dose-dependent inhibition of the enzymatic activity of IKK, in lung epithelial cells and in Jurkat T cells, which was associated with S-nitrosylation of the IKK complex. Using biotin derivatization of SNO, we revealed that IKKβ, the catalytic subunit required for NF-κB activation, was a direct target for S-nitrosylation. A mutant version of IKKβ containing a Cys-179-to-Ala mutation was refractory to inhibition by SNO or to increases in S-nitrosylation, in contrast to wild-type IKKβ, demonstrating that Cys-179 is the main target for attack by SNO. Importantly, inhibition of NO synthase activity in Jurkat T cells resulted in activation of IKK, in association with its denitrosylation. Moreover, NO synthase inhibition enhanced the ability of tumor necrosis factor α to activate IKK, illustrating the importance of endogenous NO in regulating the extent of NF-κB activation by cytokines. Collectively, our findings demonstrate that IKKβ is an important target for the redox regulation of NF-κB by endogenous or exogenous NO, providing an additional mechanism for its antiinflammatory properties.
TL;DR: Activation of TRPM4-dependent currents contributed to myogenic vasoconstriction of cerebral arteries, and biophysical properties consistent with a role for control of membrane potential of excitable cells were found.
Abstract: Local control of cerebral blood flow is regulated in part through myogenic constriction of resistance arteries. Although this response requires Ca2+ influx via voltage-dependent Ca2+ channels secondary to smooth muscle cell depolarization, the mechanisms responsible for alteration of vascular smooth muscle (VSM) cell membrane potential are not fully understood. A previous study from our laboratory demonstrated a critical role for a member of the transient receptor potential (TRP) superfamily of ion channels, TRPC6, in this response. Several other of the approximately 22 identified TRP proteins are also present in cerebral arteries, but their functions have not been elucidated. Two of these channels, TRPM4 and TRPM5, exhibit biophysical properties that are consistent with a role for control of membrane potential of excitable cells. We hypothesized that TRPM4/TRPM5-dependent currents contribute to myogenic vasoconstriction of cerebral arteries. Cation channels with unitary conductance, ion selectivity and Ca2+-dependence similar to those of cloned TRPM4 and TRPM5 were present in freshly isolated VSM cells. We found that TRPM4 mRNA was detected in both whole cerebral arteries and in isolated VSM cells whereas TRPM5 message was absent from cerebral artery myocytes. We also found that pressure-induced smooth muscle cell depolarization was attenuated in isolated cerebral arteries treated with TRPM4 antisense oligodeoxynucleotides to downregulate channel subunit expression. In agreement with these data, myogenic vasoconstriction of intact cerebral arteries administered TRPM4 antisense was attenuated compared with controls, whereas KCl-induced constriction did not differ between groups. We concluded that activation of TRPM4-dependent currents contributed to myogenic vasoconstriction of cerebral arteries.
TL;DR: A central role for BK channels in urinary bladder function is revealed and it is indicated that BK channel dysfunction leads to overactive bladder and urinary incontinence.
TL;DR: Recent treatment-outcome studies on voucher-based contingency management and community reinforcement therapy are reviewed demonstrating how reinforcement and related principles can be used to improve outcomes across a wide range of different substance use disorders and populations.
Abstract: Extensive scientific evidence indicates that reinforcement plays an important role in the genesis, maintenance, and recovery from substance use disorders. In this chapter, we review recent clinical research from laboratory, clinic, and naturalistic settings examining the role of reinforcement in substance use disorders. Well-controlled human laboratory studies are reviewed characterizing orderly interactions between the reinforcing effects of drugs and environmental context that have important implications for understanding risk factors for substance use disorders and for the development of efficacious interventions. Recent treatment-outcome studies on voucher-based contingency management and community reinforcement therapy are reviewed demonstrating how reinforcement and related principles can be used to improve outcomes across a wide range of different substance use disorders and populations. Overall, the chapter characterizes a vigorous area of clinical research that has much to contribute to a scientific analysis of substance use disorders.
TL;DR: The growing literature that supports the hypothesis that PKA plays a central role in cytoskeletal regulation and cell migration is discussed.