Showing papers by "University of Vermont published in 1999"

Biovolume calculation for pelagic and benthic microalgae

Abstract: Microalgal biovolume is commonly calculated to assess the relative abundance (as biomass or carbon) of co-occurring algae varying in shape and/or size. However, a standardized set of equations for biovolume calculations from microscopically measured linear dimensions that includes the entire range of microalgal shapes is not available yet. In comparison with automated methods, the use of microscopical measurements allows high taxonomic resolution, up to the species level, and has fewer sources of error. We present a set of geometric shapes and mathematical equations for calculating biovolumes of >850 pelagic and benthic marine and freshwater microalgal genera. The equations are designed to minimize the effort of microscopic measurement. The similarities and differences between our proposal for standardization and previously published proposals are discussed and recommendations for quality standards given.

The Synergistic Effect of Market Orientation and Learning Orientation on Organizational Performance.

Abstract: Although a large body of research theoretically asserts a positive relationship between market orientation and organizational performance, fewer empirical studies demonstrate it using multiple and varied organizational performance measures. Additionally, a series of recent studies have theoretically proposed, but not empirically demonstrated, that a firm’s learning orientation is likely to indirectly affect organizational performance by improving the quality of its market-oriented behaviors and directly influence organizational performance by facilitating the type of generative learning that leads to innovations in products, procedures, and systems. This empirical study supports all of these specific contentions and the more global notion that higher order learning processes may be critical in creating a sustainable competitive advantage in the firm.

Impulsivity and cigarette smoking: delay discounting in current, never, and ex-smokers.

Abstract: Rationale: Impulsivity is implicated in drug dependence. Recent studies show problems with alcohol and opioid dependence are associated with rapid discounting of the value of delayed outcomes. Furthermore, discounting may be particularly steep for the drug of dependence. Objectives: We determined if these findings could be extended to the behavior of cigarette smokers. In particular, we compared the discounting of hypothetical monetary outcomes by current, never, and ex-smokers of cigarettes. We also examined discounting of delayed hypothetical cigarettes by current smokers. Methods: Current cigarette smokers (n=23), never-smokers (n=22) and ex-smokers (n=21) indicated preference for immediate versus delayed money in a titration procedure that determined indifference points at various delays. The titration procedure was repeated with cigarettes for smokers. The degree to which the delayed outcomes were discounted was estimated with two non-linear decay models: an exponential model and a hyperbolic model. Results: Current smokers discounted the value of delayed money more than did the comparison groups. Never- and ex-smokers did not differ in their discounting of money. For current smokers, delayed cigarettes lost subjective value more rapidly than delayed money. The hyperbolic equation provided better fits to the data than did the exponential equation for 74 out of 89 comparisons. Conclusions: Cigarette smoking, like other forms of drug dependence, is characterized by rapid loss of subjective value for delayed outcomes, particularly for the drug of dependence. Never- and ex-smokers could discount similarly because cigarette smoking is associated with a reversible increase in discounting or due to selection bias.

Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin.

Abstract: Pro-opiomelanocortin (POMC)-derived peptides (the melanocortins adrenocorticotropin, alpha-, beta- and gamma-melanocyte stimulating hormone; and the endogenous opioid beta-endorphin) have a diverse array of biological activities, including roles in pigmentation, adrenocortical function and regulation of energy stores, and in the immune system and the central and peripheral nervous systems. We show here that mice lacking the POMC-derived peptides have obesity, defective adrenal development and altered pigmentation. This phenotype is similar to that of the recently identified human POMC-deficient patients. When treated with a stable alpha-melanocyte-stimulating hormone agonist, mutant mice lost more than 40% of their excess weight after 2 weeks. Our results identify the POMC-null mutant mouse as a model for studying the human POMC-null syndrome, and indicate the therapeutic use of peripheral melanocortin in the treatment of obesity.

Ankle-Arm Index as a Predictor of Cardiovascular Disease and Mortality in the Cardiovascular Health Study

Abstract: Peripheral arterial disease (PAD) in the legs, measured noninvasively by the ankle-arm index (AAI) is associated with clinically manifest cardiovascular disease (CVD) and its risk factors. To determine risk of total mortality, coronary heart disease, or stroke mortality and incident versus recurrent CVD associated with a low AAI, we examined the relationship of the AAI to subsequent CVD events in 5888 older adults with and without CVD. The AAI was measured in 5888 participants >/=65 years old at the baseline examination of the Cardiovascular Health Study. All participants had a detailed assessment of prevalent CVD and were contacted every 6 months for total mortality and CVD events (including CVD mortality, fatal and nonfatal myocardial infarction, congestive heart failure, angina, stroke, and hospitalized PAD). The crude mortality rate at 6 years was highest (32.3%) in those participants with prevalent CVD and a low AAI (P<0.9), and it was lowest in those with neither of these findings (8.7%, P<0.01). Similar patterns emerged from analysis of recurrent CVD and incident CVD. The risk for incident congestive heart failure (relative risk [RR]=1.61) and for total mortality (RR=1.62) in those without CVD at baseline but with a low AAI remained significantly elevated after adjustment for cardiovascular risk factors. Hospitalized PAD events occurred months to years after the AAI was measured, with an adjusted RR of 5.55 (95% CI, 3.08 to 9.98) in those at risk for incident events. A statistically significant decline in survival was seen at each 0.1 decrement in the AAI. An AAI of <0.9 is an independent risk factor for incident CVD, recurrent CVD, and mortality in this group of older adults in the Cardiovascular Health Study.

Serum IL-6 level and the development of disability in older persons.

Abstract: BACKGROUND: The serum concentration of interleukin 6 (IL-6), a cytokine that plays a central role in inflammation, increases with age. Because inflammation is a component of many age-associated chronic diseases, which often cause disability, high circulating levels of IL-6 may contribute to functional decline in old age. We tested the hypothesis that high levels of IL-6 predict future disability in older persons who are not disabled. METHODS: Participants at the sixth annual follow-up of the Iowa site of the Established Populations for Epidemiologic Studies of the Elderly aged 71 years or older were considered eligible for this study if they had no disability in regard to mobility or in selected activities of daily living (ADL), and they were re-interviewed 4 years later. Incident cases of mobility-disability and of ADL-disability were identified based on responses at the follow-up interview. Measures of IL-6 were obtained from specimens collected at baseline from the 283 participants who developed any disability and from 350 participants selected randomly (46.9%) from those who continued to be non-disabled. FINDINGS: Participants in the highest IL-6 tertile were 1.76 (95% CI, 1.17-2.64) times more likely to develop at least mobility-disability and 1.62 (95% CI, 1.02-2.60) times more likely to develop mobility plus ADL-disability compared with to the lowest IL-6 tertile. The strength of this association was almost unchanged after adjusting for multiple confounders. The increased risk of mobility-disability over the full spectrum of IL-6 concentration was nonlinear, with the risk rising rapidly beyond plasma levels of 2.5 pg/mL. INTERPRETATION: Higher circulating levels of IL-6 predict disability onset in older persons. This may be attributable to a direct effect of IL-6 on muscle atrophy and/or to the pathophysiologic role played by IL-6 in specific diseases. J Am Geriatr Soc 47:639–646, 1999.

Effect of Postmenopausal Hormones on Inflammation-Sensitive Proteins The Postmenopausal Estrogen/Progestin Interventions (PEPI) Study

Abstract: Background—Observational studies in healthy women suggest postmenopausal hormone therapy reduces risk of coronary events. In contrast, in a recent clinical trial of women with coronary disease, a subgroup analysis demonstrated increased risk during the early months of therapy. Because higher levels of inflammation factors predict vascular disease outcomes, the effect of hormones on these factors is of interest. Methods and Results—Four inflammation-sensitive factors, C-reactive protein, soluble E-selectin, von Willebrand factor antigen, and coagulation factor VIIIc were measured at baseline, 12, and 36 months in 365 participants of the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial, a randomized, placebo-controlled trial of the effects of 4 hormone preparations on cardiovascular disease risk factors. Compared with placebo, all 4 active preparations resulted in a large sustained increase in the concentration of C-reactive protein and a decrease in soluble E-selectin (P=0.0001). There were no ...

Clinical Efficacy of an Automated High-Sensitivity C-Reactive Protein Assay

Abstract: Background: Prospective studies have shown that C-reactive protein (CRP) can be used to predict risk of future cardiovascular events. High-sensitivity methods for CRP (hs-CRP) measurement are needed for this purpose. Methods: We compared the clinical efficacy of an automated and commercially available latex-enhanced assay (Latex) for hs-CRP (Dade Behring) to a validated in-house ELISA, previously shown to predict future peripheral arterial disease (PAD) in asymptomatic populations. Using a prospective, nested, case-control design, we measured baseline hs-CRP concentrations in 144 apparently healthy men who subsequently developed symptomatic PAD and 144 age- and smoking habit-matched controls who remained free of vascular disease over the follow-up period of 60 months. Results: The two hs-CRP assays correlated highly ( r = 0.95; P <0.001), and all but two participants were classified into concordant quartiles or varied by only one quartile. The median hs-CRP of the case group was significantly higher than that of controls when measured by either the ELISA (1.34 vs 0.99 mg/L; P = 0.034) or the Latex method (1.80 vs 1.20 mg/L; P = 0.042). Furthermore, for both ELISA and the Latex method, the calculated relative risks of developing PAD increased significantly with each increasing quartile of hs-CRP. The calculated interquartile increase in relative risk of PAD was 31% (95% confidence interval, 5.2–62.2%; P = 0.01) for ELISA and 34% (95% confidence interval, 8.2–66.1%; P = 0.007) for the Latex method. Conclusions: Our findings indicate that the Latex method is equally as efficacious as the validated ELISA in classifying patients into cutoff points established by prospective studies for risk stratification for coronary and cerebrovascular disease.

Prevalence and risk factors of carotid plaque in women with systemic lupus erythematosus

Abstract: Objective To determine the prevalence of carotid atherosclerosis and associated risk factors in women with systemic lupus erythematosus (SLE). Methods Carotid plaque and intima-media wall thickness (IMT) were measured by B-mode ultrasound in women with SLE. Risk factors associated with carotid plaque and IMT were determined at the time of the ultrasound scan and included traditional cardiovascular risk factors, SLE-specific variables, and inflammation markers. Results The 175 women with SLE were predominantly white (87%), with a mean age of 44.9 years (SD 11.5). Twenty-six women (15%) had a previous arterial event (10 coronary [myocardial infarction or angina], 11 cerebrovascular [stroke or transient ischemic attack], and 5 both). The mean ± SD IMT was 0.71 ± 0.14 mm, and 70 women (40%) had focal plaque. Variables significantly associated with focal plaque (P < 0.05) included age, duration of lupus, systolic, diastolic, and pulse pressure, body mass index, menopausal status, levels of total and low-density lipoprotein (LDL) cholesterol, fibrinogen and C-reactive protein levels, SLE-related disease damage according to the Systemic Lupus International Collaborating Clinics (SLICC) damage index (modified to exclude cardiovascular parameters), and disease activity as determined by the Systemic Lupus Activity Measure. Women with longer duration of prednisone use and a higher cumulative dose of prednisone as well as those with prior coronary events were more likely to have plaque. In logistic regression models, independent determinants of plaque (P < 0.05) were older age, higher systolic blood pressure, higher levels of LDL cholesterol, prolonged treatment with prednisone, and a previous coronary event. Older age, a previous coronary event, and elevated systolic blood pressure were independently associated with increased severity of plaque (P < 0.01). Older age, elevated pulse pressure, a previous coronary event, and a higher SLICC disease damage score were independently related to increased IMT (P < 0.05). Conclusion B-mode ultrasound provides a useful noninvasive technique to assess atherosclerosis in women with SLE who are at high risk for cardiovascular disease. Potentially modifiable risk factors were found to be associated with the vascular disease detected using this method.

Cdc42: An Essential Rho-Type GTPase Controlling Eukaryotic Cell Polarity

Abstract: Cdc42p is an essential GTPase that belongs to the Rho/Rac subfamily of Ras-like GTPases. These proteins act as molecular switches by responding to exogenous and/or endogenous signals and relaying those signals to activate downstream components of a biological pathway. The 11 current members ofthe Cdc42p family display between 75 and 100% amino acid identity and are functional as well as structural homologs. Cdc42p transduces signals to the actin cytoskeleton to initiate and maintain polarized gorwth and to mitogen-activated protein morphogenesis. In the budding yeast Saccharomyces cerevisiae, Cdc42p plays an important role in multiple actin-dependent morphogenetic events such as bud emergence, mating-projection formation, and pseudohyphal growth. In mammalian cells, Cdc42p regulates a variety of actin-dependent events and induces the JNK/SAPK protein kinase cascade, which leads to the activation of transcription factors within the nucleus. Cdc42p mediates these processes through interactions with a myriad of downstream effectors, whose number and regulation we are just starting to understand. In addition, Cdc42p has been implicated in a number of human diseases through interactions with its regulators and downstream effectors. While much is known about Cdc42p sturcture and functional interactions, little is known about the mechanism(s) by which it transduces signals within the cell. Future research sould focus on this question as well as on the detailed analysis of the interactions of Cdc42p with its regulators and downstream effectors.

Basis for recognition of cisplatin-modified DNA by high-mobility-group proteins.

Abstract: The anticancer activity of cis-diamminedichloroplatinum(II) (cisplatin) arises from its ability to damage DNA, with the major adducts formed being intrastrand d(GpG) and d(ApG) crosslinks. These crosslinks bend and unwind the duplex, and the altered structure attracts high-mobility-group domain (HMG) and other proteins. This binding of HMG-domain proteins to cisplatin-modified DNA has been postulated to mediate the antitumour properties of the drug. Many HMG-domain proteins recognize altered DNA structures such as four-way junctions and cisplatin-modified DNA, but until now the molecular basis for this recognition was unknown. Here we describe mutagenesis, hydroxyl-radical footprinting and X-ray studies that elucidate the structure of a 1:1 cisplatin-modified DNA/HMG-domain complex. Domain A of the structure-specific HMG-domain protein HMG1 binds to the widened minor groove of a 16-base-pair DNA duplex containing a site-specific cis-[Pt(NH3)2[d(GpG)-N7(1),-N7(2)]] adduct. The DNA is strongly kinked at a hydrophobic notch created at the platinum-DNA crosslink and protein binding extends exclusively to the 3' side of the platinated strand. A phenylalanine residue at position 37 intercalates into a hydrophobic notch created at the platinum crosslinked d(GpG) site and binding of the domain is dramatically reduced in a mutant in which alanine is substituted for phenylalanine at this position.

Obesity stigmatization and coping: Relation to mental health symptoms, body image, and self-esteem.

Abstract: OBJECTIVE: To create inventories of stigmatizing situations faced by obese people and ways of coping with stigmatization, and to examine how stigma and coping are related to psychological distress in an obese patient population. DESIGN: Study 1: Items were generated by asking obese people to list stigmatizing situations they had encountered and their ways of coping. Study 2: Obese patients were surveyed about the frequency with which they encountered each form of stigmatization and employed each form of coping. Cross-sectional data on current psychological adjustment were obtained. SUBJECTS: Study 1: 63 obese patients (body mass index, BMI>40 kg/m2); 38 obese non-patients, seven professionals who work with obese patients and 32 obese female authors from the print media. Study 2: 112 gastric bypass patients (BMI 33.9–80.9 kg/m2) and 34 less obese patients (BMI 27.1–57.2 kg/m2). MEASUREMENT: Study 1: Collection of stigmatizing situations and coping responses. Study 2: Frequency of stigmatizing experiences and coping responses, psychological symptoms, body image, and self esteem measures. RESULTS: Study 1 resulted in two objective questionnaires, consisting of 50 situations and 99 responses. Study 2 found that stigmatization is a common experience, and that obese subjects frequently engage in some effort to cope with stigma. More frequent exposure to stigmatization was associated with greater psychological distress, more attempts to cope, and more severe obesity. Certain coping strategies are associated with greater distress.

Interleukin-6 Exacerbates Early Atherosclerosis in Mice

Abstract: Acute-phase proteins, which respond to systemic proinflammatory cytokines such as interleuken-6, are elevated in cardiovascular disease and are predictive markers of future ischemic events, even over decades. This suggests a role for proinflammatory cytokines and/or acute phase proteins in early lesion development. To explore this issue, we fed C57Bl/6 and nonobese diabetic male mice high-fat (20% total fat, 1.5% cholesterol) diets and ApoE-deficient male mice both high-fat and normal chow diets for 6 to 21 weeks, injecting them weekly with either 5000 U recombinant interleukin-6 (rIL-6) or saline buffer. Blood was collected when animals were euthanized and assayed for cytokines, acute-phase proteins, and cholesterol. Across all mice, IL-6 injection resulted in significant increases in proinflammatory cytokines (IL-6, 4.6-fold; IL-1beta, 1.6-fold; and tissue necrosis factor-alpha, 1.7-fold) and fibrinogen (1.2-fold) and with decreased concentrations of albumin (0.9-fold) in plasma. Total cholesterol levels were unchanged between rIL-6-treated and nontreated groups. Serial sections through the aortic sinus were stained with oil red O to detect fatty streaks, and area of the lesions was determined by image analysis. Although no fatty streaks were detected in the nonobese diabetic mice with or without rIL-6 treatment, rIL-6 treatment increased lesion size in C57Bl/6 and ApoE-deficient mice 1.9- to 5.1-fold over lesions in saline-treated animals. These results suggest that under the appropriate circumstances changes in circulating proinflammatory cytokines and acute-phase proteins may be more than just markers of atherosclerosis but actual participants in early lesion development.

Increased Blood Glucose and Insulin, Body Size, and Incident Colorectal Cancer

Abstract: Background: Abdominal obesity-an elevated level of visceral adipose tissue-has been linked to colorectal cancer. Furthermore, elevated levels of visceral adipose tissue have been associated with hyperinsulinemia, and insulin is a growth factor in the colon. We assessed whether waist circumference, a surrogate measure of visceral adipose tissue, and metabolic parameters associated with visceral adipose tissue were related to colorectal cancer. Methods: In the Cardiovascular Health Study cohort, we examined the relationship of baseline measurements of body size, glucose, insulin, and lipoproteins to incident colorectal cancer. All P values are two-sided. Results: Among 5849 participants, 102 incident cases of colorectal cancer were identified. Individuals in the highest quartile of fasting glucose had a nearly twofold increased risk of colorectal cancer (relative risk [RR] = 1.8; 95% confidence interval [CI] = 1.0-3.1), and the linear trend RR (LT RR = 1.2; 95% CI = 1.0-1.5) for fasting glucose level was statistically significant (P = .02). Glucose and insulin levels 2 hours after oral glucose challenge also exhibited statistically significant associations with colorectal cancer (2-hour glucose levels: RR = 2.4 [95% CI = 1.2-4.7]/LT RR = 1.3 [95% CI = 1.0-1.6; P = .02]; 2-hour insulin levels: RR = 2.0 [95% CI = 1.0-3.8]/LT RR = 1.2 [95% CI = 1.0-1.5; P = .04]). Analysis of fasting insulin levels suggested a threshold effect, with values above the median associated with colorectal cancer (RR = 1.6; 95% CI = 1.1-2.4 ; P = .02). Higher levels of waist circumference were also statistically significantly associated with colorectal cancer (RR = 1.9; 95% CI = 1.1-3.3; P = .02). Conclusions: These data provide, to our knowledge, the first direct evidence of an association between elevated visceral adipose tissue level, its associated metabolic effects, and colorectal cancer.

Learning Orientation, Market Orientation, and Innovation: Integrating and Extending Models of Organizational Performance

Abstract: Recent studies have demonstrated effects of learning orientation or market orientation on innovation-driven organizational performance. While these studies have enhanced our understanding of innovation processes in the firm, they have been unable to determine the relative contribution of learning orientation and market orientation to innovation. The integration of these two fundamental strategic orientations in this research enables such an assessment. The model in this research also measures the degree to which market orientation and learning orientation influence organizational performance, independent of their effect on product innovation. The most notable finding is the potential preeminence of learning orientation over market orientation. The implications are of critical importance to marketers because they provide insights into the type of organizational culture that is associated with high levels of performance.

Caspase Activation Is Required for T Cell Proliferation

Abstract: Triggering of Fas (CD95) by its ligand (FasL) rapidly induces cell death via recruitment of the adaptor protein Fas-associated death domain (FADD), resulting in activation of a caspase cascade It was thus surprising that T lymphocytes deficient in FADD were reported recently to be not only resistant to FasL-mediated apoptosis, but also defective in their proliferative capacity This finding suggested potentially dual roles of cell growth and death for Fas and possibly other death receptors We report here that CD3-induced proliferation and interleukin 2 production by human T cells are blocked by inhibitors of caspase activity This is paralleled by rapid cleavage of caspase-8 after CD3 stimulation, but no detectable processing of caspase-3 during the same interval The caspase contribution to T cell activation may occur via TCR-mediated upregulation of FasL, as Fas-Fc blocked T cell proliferation, whereas soluble FasL augmented CD3-induced proliferation These findings extend the role of death receptors to the promotion of T cell growth in a caspase-dependent manner

Psychological adjustment in breast cancer: processes of emotional distress.

Abstract: The process of psychological adjustment to breast cancer was examined at diagnosis and at 3- and 6-month follow-ups in a sample of 80 women with Stage I-Stage IV breast cancer. At diagnosis, symptoms of anxiety/depression were predicted by low dispositional optimism, and this path was partially mediated by use of emotion-focused disengagement coping. Younger age also was predictive of anxiety/depre ssion symptoms at time of diagnosis, and this relationship was fully mediated by magnitude of intrusive thoughts. At 3 months, changes in anxiety/depression symptoms were predicted only by intrusive thoughts. At 6 months, low dispositional optimism reemerged as a significant predictor of changes in anxiety/depre ssion and again was partially mediated by the use of emotion-focus ed disengagement coping. Independent effects for problem-focused engagement and disengagement and emotionfocused engagement coping were also found at 6 months. Implications of these data for psychosocial interventions with breast cancer patients are highlighted.

Biochemistry and physiology of blood coagulation.

Abstract: Introduction: The biochemical investigation of a biological process can be divided into three segments. The first is the development of an inventory of the components involved in the process, the second is the establishment of the connectivity between components, and the third is the establishment of the dynamics of the processes as they occur in the living organism.

Constipation in infants and children: evaluation and treatment. A medical position statement of the North American Society for Pediatric Gastroenterology and Nutrition.

Abstract: Background Constipation, defined as a delay or difficulty in defecation, present for 2 or more weeks, is a common pediatric problem encountered by both primary and specialty medical providers. Methods The Constipation Subcommittee of the Clinical Guidelines Committee of the North American Society for Pediatric Gastroenterology and Nutrition has formulated clinical practice guidelines for the management of pediatric constipation. The Constipation Subcommittee, consisting of two primary care pediatricians, a clinical epidemiologist, and pediatric gastroenterologists, based its recommendations on an integration of a comprehensive and systematic review of the medical literature combined with expert opinion. Consensus was achieved through Nominal Group Technique, a structured quantitative method. Results The Subcommittee developed two algorithms to assist with medical management, one for older infants and children and the second for infants less than 1 year of age. The guidelines provide recommendations for management by the primary care provider, including evaluation, initial treatment, follow-up management, and indications for consultation by a specialist. The Constipation Subcommittee also provided recommendations for management by the pediatric gastroenterologist. Conclusions This report, which has been endorsed by the Executive Council of the North American Society for Pediatric Gastroenterology and Nutrition, has been prepared as a general guideline to assist providers of medical care in the evaluation and treatment of constipation in children. It is not intended as a substitute for clinical judgment or as a protocol for the management of all patients with this problem.

Exercise-Induced Muscle Damage and Potential Mechanisms for the Repeated Bout Effect

Abstract: Unfamiliar, predominantly eccentric exercise, frequently results in muscle damage. A repeated bout of similar eccentric exercise results in less damage and is referred to as the ‘repeated bout effect’. Despite numerous studies that have clearly demonstrated the repeated bout effect, there is little consensus as to the actual mechanism. In general, the adaptation has been attributed to neural, connective tissue or cellular adaptations. Other possible mechanisms include, adaptation in excitation-contraction coupling or adaptation in the inflammatory response. The ‘neural theory’ predicts that the initial damage is a result of high stress on a relatively small number of active fast-twitch fibres. For the repeated bout, an increase in motor unit activation and/or a shift to slow-twitch fibre activation distributes the contractile stress over a larger number of active fibres. Although eccentric training results in marked increases in motor unit activation, specific adaptations to a single bout of eccentric exercise have not been examined. The ‘connective tissue theory’ predicts that muscle damage occurs when the noncontractile connective tissue elements are disrupted and myofibrillar integrity is lost. Indirect evidence suggests that remodelling of the intermediate filaments and/or increased intramuscular connective tissue are responsible for the repeated bout effect. The ‘cellular theory’ predicts that muscle damage is the result of irreversible sarcomere strain during eccentric contractions. Sarcomere lengths are thought to be highly non-uniform during eccentric contractions, with some sarcomeres stretched beyond myofilament overlap. Loss of contractile integrity results in sarcomere strain and is seen as the initial stage of damage. Some data suggest that an increase in the number of sarcomeres connected in series, following an initial bout, reduces sarcomere strain during a repeated bout and limits the subsequent damage. It is unlikely that one theory can explain all of the various observations of the repeated bout effect found in the literature. That the phenomenon occurs in electrically stimulated contractions in an animal model precludes an exclusive neural adaptation. Connective tissue and cellular adaptations are unlikely explanations when the repeated bout effect is demonstrated prior to full recovery, and when the fact that the initial bout does not have to cause appreciable damage in order to provide a protective effect is considered. It is possible that the repeated bout effect occurs through the interaction of various neural, connective tissue and cellular factors that are dependent on the particulars of the eccentric exercise bout and the specific muscle groups involved.

Transgenic mice demonstrate AP-1 (activator protein-1) transactivation is required for tumor promotion.

Abstract: Activator protein-1 (AP-1) is a transcription factor that consists of either a Jun-Jun homodimer or a Jun-Fos heterodimer. Transactivation of AP-1 is required for tumor promoter-induced transformation in mouse epidermal JB6 cells and for progression in mouse and human keratinocytes. Until now, the question of whether AP-1 transactivation is required for carcinogenesis in vivo has remained unanswered, as has the issue of functionally significant target genes. To address these issues we have generated a transgenic mouse in which transactivation mutant c-jun (TAM67), under the control of the human keratin-14 promoter, is expressed specifically in the basal cells of the epidermis where tumor induction is initiated. The keratin-14–TAM67 transgene was expressed in the epidermis, tongue, and cervix, with no apparent abnormalities in any tissue or organ. TAM67 expression blocked 12-O-tetradecanoylphorbol 13-acetate (TPA, phorbol 12-tetradecanoate 13-acetate) induction of the AP-1-regulated luciferase in AP-1 luciferase/TAM67 mice, but did not inhibit induction of candidate AP-1 target genes, collagenase-1 or stromelysin-3. More interestingly, TAM67 expression did not inhibit TPA-induced hyperproliferation. In two-stage skin carcinogenesis experiments, the transgenic animals showed a dramatic inhibition of papilloma induction. We conclude that transactivation of a subset of AP-1-dependent genes is required for tumor promotion and may be targeted for cancer prevention.

Reduction of Cisplatin-Induced Emesis by a Selective Neurokinin-1–Receptor Antagonist

Abstract: Background The localization of substance P in brain-stem regions associated with vomiting, and the results of studies in ferrets, led us to postulate that a neurokinin-1–receptor antagonist would be an antiemetic in patients receiving anticancer chemotherapy. Methods In a multicenter, double-blind, placebo-controlled trial involving 159 patients who had not previously received cisplatin, we evaluated the prevention of acute emesis (occurring within 24 hours) and delayed emesis (occurring on days 2 to 5) after a single dose of cisplatin therapy (70 mg or more per square meter of body-surface area). Before receiving cisplatin, all the patients received granisetron (10 μg per kilogram of body weight intravenously) and dexamethasone (20 mg orally). The patients were randomly assigned to one of three treatments in addition to granisetron and dexamethasone: 400 mg of an oral trisubstituted morpholine acetal (also known as L-754,030) before cisplatin and 300 mg on days 2 to 5 (group 1), 400 mg of L-754,030 befor...

Recent advances in the pharmacotherapy of smoking.

Abstract: Since the 1996 publication of guidelines on smoking cessation from the Agency for Health Care Policy and Research and the American Psychiatric Association, several new treatments have become available, including nicotine nasal spray, nicotine inhaler, and bupropion hydrochloride. In addition, nicotine gum and patch have become available over-the-counter. This article reviews the published literature and US Food and Drug Administration and pharmaceutical company reports on these therapies. Based on this review, clinical logic, and experience, we conclude that pharmacotherapy should be made available to all smokers. All currently available therapies appear to be equally efficacious, approximately doubling the quit rate compared with placebo. Concomitant behavioral or supportive therapy increases quit rates and should be encouraged but not required. Combining patch with gum or patch with bupropion may increase the quit rate compared with any single treatment. Because patient characteristics predictive of success with a particular therapy are not yet known, the best treatment choice for an individual patient should be guided by the patient's past experience and preference and the product's adverse effect profile.

Crystal Structure of the Zα Domain of the Human Editing Enzyme ADAR1 Bound to Left-Handed Z-DNA

Abstract: The editing enzyme double-stranded RNA adenosine deaminase includes a DNA binding domain, Zalpha, which is specific for left-handed Z-DNA. The 2.1 angstrom crystal structure of Zalpha complexed to DNA reveals that the substrate is in the left-handed Z conformation. The contacts between Zalpha and Z-DNA are made primarily with the "zigzag" sugar-phosphate backbone, which provides a basis for the specificity for the Z conformation. A single base contact is observed to guanine in the syn conformation, characteristic of Z-DNA. Intriguingly, the helix-turn-helix motif, frequently used to recognize B-DNA, is used by Zalpha to contact Z-DNA.

The Involvement of Hydrogen Peroxide in the Differentiation of Secondary Walls in Cotton Fibers

Abstract: H2O2 is a widespread molecule in many biological systems. It is created enzymatically in living cells during various oxidation reactions and by leakage of electrons from the electron transport chains. Depending on the concentration H2O2 can induce cell protective responses, programmed cell death, or necrosis. Here we provide evidence that H2O2 may function as a developmental signal in the differentiation of secondary walls in cotton (Gossypium hirsutum) fibers. Three lines of evidence support this conclusion: (a) the period of H2O2 generation coincided with the onset of secondary wall deposition, (b) inhibition of H2O2 production or scavenging the available H2O2 from the system prevented the wall differentiation process, and (c) exogenous addition of H2O2 prematurely promoted secondary wall formation in young fibers. Furthermore, we provide support for the concept that H2O2 generation could be mediated by the expression of the small GTPase Rac, the accumulation of which was shown previously to be strongly induced during the onset of secondary wall differentiation. In support of Rac's role in the activation of NADPH oxidase and the generation of reactive oxygen species, we transformed soybean (Glycine max) and Arabidopsis cells with mutated Rac genes. Transformation with a dominantly activated cotton Rac13 gene resulted in constitutively higher levels of H2O2, whereas transformation with the antisense and especially with dominant-negative Rac constructs decreased the levels of H2O2.