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  1. Glucose-dependent insulinotropic polypeptide (GIP) dose-dependently reduces osteoclast differentiation and resorption.

    PubMed

    Mabilleau, Guillaume; Perrot, Rodolphe; Mieczkowska, Aleksandra; Boni, Sébastien; Flatt, Peter R; Irwin, Nigel; Chappard, Daniel

    2016-10-01

    A role for glucose-dependent insulinotropic polypeptide (GIP) in controlling bone resorption has been suspected. However uncertainty remains to identify whether GIP act directly on osteoclasts. The aim of the present study were (i) to identify in different osteoclast differentiation models (human peripheral blood mononuclear cells-PBMC, murine bone marrow macrophage-BMM and murine Raw 264.7 cells) whether GIP was capable of reducing osteoclast formation and resorption; (ii) ascertain whether the highly potent GIP analogue N-AcGIP was capable of inducing a response at lower concentrations and (iii) to decipher the molecular mechanisms responsible for such effects. [d-Ala(2)]-GIP dose-dependently reduced osteoclast formation at concentration as low as 1nM in human PBMC and 10nM in murine BMM cultures. Furthermore, [d-Ala(2)]-GIP also reduced the extent of osteoclast resorption at concentration as low as 1nM in human PBMC and murine BMM cultures. The mechanism of action of [d-Ala(2)]-GIP appeared to be mediated by reduction in intracellular calcium concentration and oscillation that subsequently inhibited calcineurin activity and NFATc1 nuclear translocation. The potency of the highly potent N-AcGIP was determined and highlighted an effect on osteoclast formation and resorption at concentration ten times lower than observed with [d-Ala(2)]-GIP in vitro. Furthermore, N-AcGIP was also capable of reducing the number of osteoclast in ovariectomized mice as well as the circulating level of type I collagen C-telopeptide. Pharmacological concentrations required for reducing osteoclast formation and resorption provide the impetus to design and exploit enzymatically stable GIP analogues for the treatment of bone resorption disorders in humans. PMID:27451082

  2. Hypocretin receptor 2 antagonism dose-dependently reduces escalated heroin self-administration in rats.

    PubMed

    Schmeichel, Brooke E; Barbier, Estelle; Misra, Kaushik K; Contet, Candice; Schlosburg, Joel E; Grigoriadis, Dimitri; Williams, John P; Karlsson, Camilla; Pitcairn, Caleb; Heilig, Markus; Koob, George F; Vendruscolo, Leandro F

    2015-03-13

    The hypocretin/orexin (HCRT) system has been associated with both positive and negative drug reinforcement, implicating HCRT receptor 1 (HCRT-R1) signaling in drug-related behaviors for all major drug classes, including opioids. However, to date there are limited studies investigating the role of HCRT receptor 2 (HCRT-R2) signaling in compulsive-like drug seeking. Escalation of drug intake with extended access has been suggested to model the transition from controlled drug use to compulsive-like drug seeking/taking. The current study examined the effects of a HCRT-R2 antagonist, NBI-80713, on heroin self-administration in rats allowed short- (1 h; ShA) or long- (12 h; LgA) access to intravenous heroin self-administration. Results indicate that systemically administered NBI-80713 dose-dependently decreased heroin self-administration in LgA, but not in ShA, animals. Quantitative PCR analyses showed an increase in Hcrtr2 mRNA levels in the central amygdala, a stress-related brain region, of LgA rats. These observations suggest a functional role for HCRT-R2 signaling in compulsive-like heroin self-administration associated with extended access and indicate HCRT-R2 antagonism as a potential pharmacological target for the treatment of heroin dependence.

  3. Dose-dependent effect of caffeine on reducing leg muscle pain during cycling exercise is unrelated to systolic blood pressure.

    PubMed

    O'Connor, Patrick J; Motl, Robert W; Broglio, Steven P; Ely, Matthew R

    2004-06-01

    This double-blind, within-subjects experiment examined the effects of ingesting two doses of caffeine on perceptions of leg muscle pain and blood pressure during moderate intensity cycling exercise. Low caffeine consuming college-aged males (N=12) ingested one of two doses of caffeine (5 or 10 mg.kg(-1) body weight) or placebo and 1 h later completed 30 min of moderate intensity cycling exercise (60% VO2peak). The order of drug administration was counter-balanced. Resting blood pressure and heart rate were recorded immediately before and 1 h after drug administration. Perceptions of leg muscle pain as well as work rate, blood pressure, heart rate, and oxygen uptake (VO2) were recorded during exercise. Caffeine increased resting systolic pressure in a dose-dependent fashion but these blood pressure effects were not maintained during exercise. Caffeine had a significant linear effect on leg muscle pain ratings [F(2,22)=14.06; P < 0.0001; eta2=0.56 ]. The mean (+/-SD) pain intensity scores during exercise after ingesting 10 mg.kg(-1) body weight caffeine, 5 mg.kg(-1) body weight caffeine, and placebo were 2.1+/-1.4, 2.6+/-1.5, and 3.5+/-1.7, respectively. The results support the conclusion that caffeine ingestion has a dose-response effect on reducing leg muscle pain during exercise and that these effects do not depend on caffeine-induced increases in systolic blood pressure during exercise.

  4. Flaxseed reduces the pro-carcinogenic microenvironment in the ovaries of normal hens by altering the prostaglandin and estrogen pathways in a dose dependent manner

    PubMed Central

    Dikshit, Anushka; Filho, Manoel Adrião Gomes; Eilati, Erfan; McGee, Stacey; Small, Carrie; Gao, Chunqi; Klug, Thomas; Hales, Dale Buchanan

    2015-01-01

    The objective of this study was to find the optimum dose of flaxseed that would decrease prostaglandins and alter estrogen pathway endpoints implicated in ovarian cancer. Fifty 1.5-year-old chickens per group were fed different percentages of flaxseed (5%, 10%, 15%) for four months then sacrificed to collect blood and tissues. Levels of flaxseed lignan metabolites, Enterolactone (EL) and Enterodiol (ED), were measured in the serum, liver and ovaries by LC-MS/MS while omega-3 and 6 fatty acid levels were measured by GC. Effect of varying flaxseed doses was assessed by measuring levels of prostaglandin E2, estrogen metabolites (16-hydroxyestrone (16-OHE1), 2-hydroxyestrone (2-OHE1)) and analyzing the expression of E2 metabolizing enzymes (CYP3A4, CYP1B1, CYP1A1) and ERα in the ovaries. The ratio of omega-3 fatty acids/ omega-6 fatty acids increased with increase in flaxseed supplementation of diet corresponding to a dose dependent decrease in COX-2 protein and prostaglandin E2 levels. EL and ED increased in the liver, ovary and serum with increasing concentrations of flaxseed. Flaxseed decreased the expression of ERα in the ovary. The ratio of 2-hydroxyestrone to 16-hydroxyestrone in the serum increased significantly in the 15% flaxseed diet with a corresponding increase in CYP1A1 in the liver and a decrease in CYP3A4 in the ovary, respectively. CYP1B1 mRNA also decreased with flaxseed diet in the ovary. The 15% flaxseed supplemented diet significantly decreased inflammatory prostaglandin E2, ERα, CYP3A4, CYP1B1 and 16-OHE1 while it increased CYP1A1 and 2-OHE1, thus reducing the inflammatory and pro-carcinogenic microenvironment of the ovary. PMID:25850566

  5. Reducing Incidents of Cheating in Adolescence.

    ERIC Educational Resources Information Center

    Bopp, Mary; Gleason, Patricia; Misicka, Stacey

    This report describes a program implemented to raise the awareness of the dramatic increases of reported academic cheating, to influence the attitudes of the targeted students towards cheating, and ultimately to reduce incidents of cheating in the targeted classrooms. The targeted populations consisted of middle school students in growing…

  6. The omega-3 fatty acid DHA dose-dependently reduces atherosclerosis: a putative role for F4-neuroprostanes a specific class of peroxidized metabolites

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Objective. Consumption of long chain omega-3 polyunsaturated fatty acids is associated with reduced risks of cardiovascular disease but the role of their oxygenated metabolites remains unclear. We hypothesized that peroxidized metabolites of docosahexaenoic acid (DHA, 22:6 n-3) could play a role in ...

  7. The Placental Variant of Human Growth Hormone Reduces Maternal Insulin Sensitivity in a Dose-Dependent Manner in C57BL/6J Mice.

    PubMed

    Liao, Shutan; Vickers, Mark H; Stanley, Joanna L; Ponnampalam, Anna P; Baker, Philip N; Perry, Jo K

    2016-03-01

    The human placental GH variant (GH-V) is secreted continuously from the syncytiotrophoblast layer of the placenta during pregnancy and is thought to play a key role in the maternal adaptation to pregnancy. Maternal GH-V concentrations are closely related to fetal growth in humans. GH-V has also been proposed as a potential candidate to mediate insulin resistance observed later in pregnancy. To determine the effect of maternal GH-V administration on maternal and fetal growth and metabolic outcomes during pregnancy, we examined the dose-response relationship for GH-V administration in a mouse model of normal pregnancy. Pregnant C57BL/6J mice were randomized to receive vehicle or GH-V (0.25, 1, 2, or 5 mg/kg · d) by osmotic pump from gestational days 12.5 to 18.5. Fetal linear growth was slightly reduced in the 5 mg/kg dose compared with vehicle and the 0.25 mg/kg groups, respectively, whereas placental weight was not affected. GH-V treatment did not affect maternal body weights or food intake. However, treatment with 5 mg/kg · d significantly increased maternal fasting plasma insulin concentrations with impaired insulin sensitivity observed at day 18.5 as assessed by homeostasis model assessment. At 5 mg/kg · d, there was also an increase in maternal hepatic GH receptor/binding protein (Ghr/Ghbp) and IGF binding protein 3 (Igfbp3) mRNA levels, but GH-V did not alter maternal plasma IGF-1 concentrations or hepatic Igf-1 mRNA expression. Our findings suggest that at higher doses, GH-V treatment can cause hyperinsulinemia and is a likely mediator of the insulin resistance associated with late pregnancy.

  8. Reduced incidence of the somnolence syndrome after prophylactic cranial irradiation in children with acute lymphoblastic leukemia.

    PubMed

    Uzal, D; Ozyar, E; Hayran, M; Zorlu, F; Atahan, L; Yetkin, S

    1998-07-01

    A prospective double blind randomized trial comparing two different dose schedules of continuous steroid coverage during prophylactic cranial radiotherapy (CRT) in leukemic children was conducted to find out the optimum dose to be prescribed to reduce the incidence of Somnolence Syndrome (SS). Between April 1994 and February 1996, 32 patients with acute lymphoblastic leukemia received CRT of 18 Gy in 10 fractions. Patients were randomized to receive oral dexamethasone of 2 or 4 mg/m2 during radiotherapy. The diagnosis of SS was made clinically based on symptoms of somnolence. All patients were followed for a minimum of 8 months. The overall incidence of SS was 40%. The development of SS was steroid dose dependent. In low dose steroid arm the incidence of SS was 64.3% (9/14), compared to 17.6% (3/17) in high dose arm with statistically significant difference (P = 0.008). The median time to development of SS was 4 weeks. The most common symptom of SS was drowsiness followed by anorexia, headache, nausea, vomiting, decreased activity, irritability, fever and ataxia, respectively. The duration of symptoms ranged from 2 to 14 days. The development of SS was not related to the presence of acute reactions, age at the time of CRT and sex. In all cases the symptoms subsided completely and spontaneously. Our results suggest that steroid coverage at a dose of 4 mg/m2 during CRT reduces the incidence of SS. However, a multicentric prospective randomized trial is needed to determine the role and the optimal dose of steroid. PMID:9756169

  9. Reducing the incidence of nosocomial pneumonia in cardiovascular surgery patients.

    PubMed

    Houston, Susan; Gentry, Layne O; Pruitt, Vicki; Dao, Thanh; Zabaneh, Firas; Sabo, John

    2003-01-01

    Outcomes management provides a mechanism to foster development of patient-driven services through revision of practice and measurement of outcomes. Because nosocomial pneumonia is the most common hospital-acquired infection in intensive care units, reducing the rate of nosocomial pneumonia became on area of intense scrutiny at our institution. This article shares an outcome initiative that focused on reducing the incidence of nosocomial pneumonia in a hospital setting. Strategies used such as multidisciplinary team formation, case/control study, quality improvement activities, risk tool development, and protocol implementation, are discussed. Process and outcome data are provided to demonstrate the initiative's positive impact. The benefits of this outcome effort are easily identified and well-illustrated. The backbone of the initiative--proactive identification of problems and the methodical, reasoned search for answers--is universally applicable.

  10. Colchicine Significantly Reduces Incident Cancer in Gout Male Patients

    PubMed Central

    Kuo, Ming-Chun; Chang, Shun-Jen; Hsieh, Ming-Chia

    2015-01-01

    Abstract Patients with gout are more likely to develop most cancers than subjects without gout. Colchicine has been used for the treatment and prevention of gouty arthritis and has been reported to have an anticancer effect in vitro. However, to date no study has evaluated the relationship between colchicine use and incident cancers in patients with gout. This study enrolled male patients with gout identified in Taiwan's National Health Insurance Database for the years 1998 to 2011. Each gout patient was matched with 4 male controls by age and by month and year of first diagnosis, and was followed up until 2011. The study excluded those who were diagnosed with diabetes or any type of cancer within the year following enrollment. We calculated hazard ratio (HR), aged-adjusted standardized incidence ratio, and incidence of 1000 person-years analyses to evaluate cancer risk. A total of 24,050 male patients with gout and 76,129 male nongout controls were included. Patients with gout had a higher rate of incident all-cause cancers than controls (6.68% vs 6.43%, P = 0.006). A total of 13,679 patients with gout were defined as having been ever-users of colchicine and 10,371 patients with gout were defined as being never-users of colchicine. Ever-users of colchicine had a significantly lower HR of incident all-cause cancers than never-users of colchicine after adjustment for age (HR = 0.85, 95% CI = 0.77–0.94; P = 0.001). In conclusion, colchicine use was associated with a decreased risk of incident all-cause cancers in male Taiwanese patients with gout. PMID:26683907

  11. Prolonged organ culture reduces the incidence of endothelial immune reactions.

    PubMed

    Maier, P; Heinzelmann, S; Böhringer, D; Reinhard, T

    2016-01-01

    PURPOSE The number of antigen-presenting cells decreases during organ culture of corneoscleral discs. This might result in a decrease of immune reactions with increasing duration of organ culture. To investigate this hypothesis, we performed a retrospective analysis of all penetrating keratoplasties that were consecutively performed over the last 5 years.PATIENTS AND METHODS All cases of penetrating keratoplasties (n=1006) were divided into two groups, with the division made at the median of the storage time (21 days). These two groups were compared by a Cox proportional hazards survival model regarding the incidence of endothelial immune reactions, clear graft survival, and chronic endothelial cell loss following penetrating keratoplasty considering patient's age, donor's age, and risk situation as co-variates.RESULTS We observed statistically significantly fewer endothelial immune reactions (20.1% (95% confidence interval 15.5-24.5%) after 2 years) in the group with a storage time of more than 21 days compared with the group with a storage time of <21 days (26.5% (95% confidence interval 21.6-31.2%) after 2 years). However, the duration of organ culture did not have a statistically significant effect on clear graft survival or chronic endothelial cell loss.CONCLUSION Our results demonstrate that an increased duration of organ culture leads to a lower incidence of endothelial immune reactions following penetrating keratoplasty. However, we do not recommend increased storage times in general as overall graft survival did not improve. The reason for this apparent paradox may be that the endothelial cell count decreases during storage time. PMID:26493031

  12. Dose dependent pharmacokinetics of naproxen in man.

    PubMed

    Niazi, S K; Alam, S M; Ahmad, S I

    1996-05-01

    The pharmacokinetics of one of the most widely used non-steroidal antiinflammatory drugs, naproxen, were studied in 28 healthy human volunteers at the two most commonly used dose levels, viz., 250 mg and 500 mg, in a cross-over design. The plasma levels of naproxen were analysed by a modified high-pressure liquid chromatography method. The plasma concentrations at higher doses were not proportional to dose, indicating a non-linearity in the pharmacokinetics at the dose levels studied; this finding is new since earlier studies had studied only higher doses and assumed that at lower doses the pharmacokinetics would be linear. There was, however, no significant difference in the elimination half-life (rate constant), time to reach peak concentration (Cmax), mean residence time (MRT), or area under first moment curve (AUMC). The clearance and distribution volume of naproxen were substantially increased at higher dose resulting in statistically lower proportional concentration and the total area under the curve (AUC). These observations are explained on the basis of a change in the plasma protein binding resulting in more free naproxen available for quicker clearance and wider penetration into tissues. These findings have several important clinical implications for the long-term use of naproxen as an antiarthritic drug. It is proposed that the clinical efficacy of naproxen can be increased and side-effects reduced by giving it in small divided doses instead of large doses.

  13. Vaccine May Reduce Incidence of Meningitis-Related Hearing Impairment.

    ERIC Educational Resources Information Center

    Smith, Dorothy

    1988-01-01

    Hearing loss as a result of meningitis, now the leading nongenetic cause of deafness in infants and young children, may be reduced by the introduction of the HiB (Hemophilus influenzae type B) vaccine. It is highly effective, relatively safe, and recommended for most children over 24 months and high risk children 18-24 months old. (VW)

  14. Statins and Renin Angiotensin System Inhibitors Dose-Dependently Protect Hypertensive Patients against Dialysis Risk

    PubMed Central

    Wu, Szu-Yuan

    2016-01-01

    Background Taiwan has the highest renal disease incidence and prevalence in the world. We evaluated the association of statin and renin–angiotensin system inhibitor (RASI) use with dialysis risk in hypertensive patients. Methods Of 248,797 patients who received a hypertension diagnosis in Taiwan during 2001–2012, our cohort contained 110,829 hypertensive patients: 44,764 who used RASIs alone; 7,606 who used statins alone; 27,836 who used both RASIs and statins; and 33,716 who used neither RASIs or statins. We adjusted for the following factors to reduce selection bias by using propensity scores (PSs): age; sex; comorbidities; urbanization level; monthly income; and use of nonstatin lipid-lowering drugs, metformin, aspirin, antihypertensives, diuretics, and beta and calcium channel blockers. The statin and RASI use index dates were considered the hypertension confirmation dates. To examine the dose–response relationship, we categorized only statin or RASI use into four groups in each cohort: <28 (nonusers), 28–90, 91–365, and >365 cumulative defined daily doses (cDDDs). Results In the main model, PS-adjusted hazard ratios (aHRs; 95% confidence intervals [CIs]) for dialysis risk were 0.57 (0.50–0.65), 0.72 (0.53–0.98), and 0.47 (0.41–0.54) in the only RASI, only statin, and RASI + statin users, respectively. RASIs dose-dependently reduced dialysis risk in most subgroups and in the main model. RASI use significantly reduced dialysis risk in most subgroups, regardless of comorbidities or other drug use (P < 0.001). Statins at >365 cDDDs protected hypertensive patients against dialysis risk in the main model (aHR = 0.62, 95% CI: 0.54–0.71), regardless of whether a high cDDD of RASIs, metformin, or aspirin was used. Conclusion Statins and RASIs independently have a significant dose-dependent protective effect against dialysis risk in hypertensive patients. The combination of statins and RASIs can additively protect hypertensive patients against dialysis

  15. Dezocine attenuates fentanyl-induced cough in a dose-dependent manner-a randomized controlled trial

    PubMed Central

    Xu, Yajun; Zhu, Yun; Wang, Shilai; Ren, Yu; Miao, Changhong

    2015-01-01

    Fentanyl-induced cough (FIC) should be effectively prevented in patients requiring stable induction of general anesthesia. Our study was to evaluate the suppressive effects of different doses of intravenous dezocine on FIC during the induction of general anesthesia. A total of 400 patients of American Society of Anesthesiologists (ASA) physical status I and II were randomized into four groups (n = 100). Right before Fentanyl bolus, the four groups were given intravenously a matching placebo (group I) (equal volume of 0.9% saline), dezocine 0.025 mg/kg (group II), 0.05 mg/kg (group III), and 0.1 mg/kg (group IV), respectively. Patients were induced with fentanyl 3 µg/kg and the injection time of fentanyl was less than 5 s in all patients. The occurrence of cough was recorded 2 min after fentanyl bolus. The incidence of FIC was 40% in group I, 12% in group II, 4% in group III, and 0 in group IV. Group I had significantly higher incidence of FIC than Groups II, III and IV (P < 0.05). Group IV had lower incidence of FIC than Groups II (0% vs 12%; P = 0.0003) and III (0% vs 4%; P = 0.043). Our study showed that intravenous dezocine reduced the incidence of FIC during anesthetic induction. The suppressive effect was dose-dependent. PMID:26131209

  16. Marijuana's dose-dependent effects in daily marijuana smokers.

    PubMed

    Ramesh, Divya; Haney, Margaret; Cooper, Ziva D

    2013-08-01

    Active marijuana produces significant subjective, psychomotor, and physiological effects relative to inactive marijuana, yet demonstrating that these effects are dose-dependent has proven difficult. This within-subject, double-blind study was designed to develop a smoking procedure to obtain a marijuana dose-response function. In four outpatient laboratory sessions, daily marijuana smokers (N = 17 males, 1 female) smoked six 5-s puffs from 3 marijuana cigarettes (2 puffs/cigarette). The number of puffs from active (≥5.5% Δ⁹-tetrahydrocannabinol/THC) and inactive (0.0% THC) marijuana varied according to condition (0, 2, 4, or 6 active puffs); active puffs were always smoked before inactive puffs. Subjective, physiological, and performance effects were assessed prior to and at set time points after marijuana administration. Active marijuana dose-dependently increased heart rate and decreased marijuana craving, despite evidence (carbon monoxide expiration, weight of marijuana cigarettes post-smoking) that participants inhaled less of each active marijuana cigarette than inactive cigarettes. Subjective ratings of marijuana "strength," "high," "liking," "good effect," and "take again" were increased by active marijuana compared with inactive marijuana, but these effects were not dose-dependent. Active marijuana also produced modest, non-dose-dependent deficits in attention, psychomotor function, and recall relative to the inactive condition. In summary, although changes in inhalation patterns as a function of marijuana strength likely minimized the difference between dose conditions, dose-dependent differences in marijuana's cardiovascular effects and ratings of craving were observed, whereas subjective ratings of marijuana effects did not significantly vary as a function of dose.

  17. Marijuana's dose-dependent effects in daily marijuana smokers.

    PubMed

    Ramesh, Divya; Haney, Margaret; Cooper, Ziva D

    2013-08-01

    Active marijuana produces significant subjective, psychomotor, and physiological effects relative to inactive marijuana, yet demonstrating that these effects are dose-dependent has proven difficult. This within-subject, double-blind study was designed to develop a smoking procedure to obtain a marijuana dose-response function. In four outpatient laboratory sessions, daily marijuana smokers (N = 17 males, 1 female) smoked six 5-s puffs from 3 marijuana cigarettes (2 puffs/cigarette). The number of puffs from active (≥5.5% Δ⁹-tetrahydrocannabinol/THC) and inactive (0.0% THC) marijuana varied according to condition (0, 2, 4, or 6 active puffs); active puffs were always smoked before inactive puffs. Subjective, physiological, and performance effects were assessed prior to and at set time points after marijuana administration. Active marijuana dose-dependently increased heart rate and decreased marijuana craving, despite evidence (carbon monoxide expiration, weight of marijuana cigarettes post-smoking) that participants inhaled less of each active marijuana cigarette than inactive cigarettes. Subjective ratings of marijuana "strength," "high," "liking," "good effect," and "take again" were increased by active marijuana compared with inactive marijuana, but these effects were not dose-dependent. Active marijuana also produced modest, non-dose-dependent deficits in attention, psychomotor function, and recall relative to the inactive condition. In summary, although changes in inhalation patterns as a function of marijuana strength likely minimized the difference between dose conditions, dose-dependent differences in marijuana's cardiovascular effects and ratings of craving were observed, whereas subjective ratings of marijuana effects did not significantly vary as a function of dose. PMID:23937597

  18. Gastric Cancer: How Can We Reduce the Incidence of this Disease?

    PubMed

    den Hoed, Caroline M; Kuipers, Ernst J

    2016-07-01

    Gastric cancer remains a prevalent disease worldwide with a poor prognosis. Helicobacter pylori plays a major role in gastric carcinogenesis. H. pylori colonization leads to chronic gastritis, which predisposes to atrophic gastritis, intestinal metaplasia, dysplasia, and eventually gastric cancer. Screening, treatment, and prevention of H. pylori colonization can reduce the incidence of gastric cancer. Other interventions that may yield a similar effect, although of smaller magnitude, include promotion of a healthy lifestyle including dietary measures, non-smoking, low alcohol intake, and sufficient physical activity. This chapter reviews interventions that can lead to a decline in gastric cancer incidence in high and low incidence countries. PMID:27184043

  19. An Online Tutorial vs. Pre-Recorded Lecture for Reducing Incidents of Plagiarism

    ERIC Educational Resources Information Center

    Henslee, Amber M.; Goldsmith, Jacob; Stone, Nancy J.; Krueger, Merilee

    2015-01-01

    The current study compared an online academic integrity tutorial modified from Belter & du Pre (2009) to a pre-recorded online academic integrity lecture in reducing incidents of plagiarism among undergraduate students at a science and technology university. Participants were randomized to complete either the tutorial or the pre-recorded…

  20. Bedtime Routines for Young Children: A Dose-Dependent Association with Sleep Outcomes

    PubMed Central

    Mindell, Jodi A.; Li, Albert M.; Sadeh, Avi; Kwon, Robert; Goh, Daniel Y.T.

    2015-01-01

    Background: Establishment of a consistent bedtime routine (the activities that occur right before lights out) is often recommended as part of healthy sleep habits. However, no studies have investigated the dose-dependent association of a bedtime routine with sleep outcomes, especially in young children for whom they are particularly recommended. Thus, the aim of this study was to examine the associations of a consistent bedtime routine with sleep outcomes in young children (ages 0 through 5 y) in a large global sample and assess whether there is a dose-dependent relationship between the frequency of a bedtime routine both concurrently and retrospectively with sleep outcomes. Participants: Mothers of 10,085 children (Australia-New Zealand, Canada, China, Hong Kong, India, Japan, Korea, Malaysia, Philippines, Singapore, Thailand, United Kingdom, United States) completed the Brief Infant/Child Sleep Questionnaire. Results: A consistent bedtime routine was associated with better sleep outcomes, including earlier bedtimes, shorter sleep onset latency, reduced night wakings, and increased sleep duration. Decreased parent-perceived sleep problems and daytime behavior problems were also related to institution of a regular bedtime routine. Furthermore, there was a dose-dependent relationship, with better outcomes associated with increased “doses” of having a bedtime routine, both currently and retrospectively, and was found within both predominantly Asian and predominantly Caucasian cultural regions. Conclusions: These results indicate that having a regular nightly bedtime routine is associated with improved sleep in young children, and suggests that the more consistently a bedtime routine is instituted and the younger started the better. Citation: Mindell JA, Li AM, Sadeh A, Kwon R, Goh DY. Bedtime routines for young children: a dose-dependent association with sleep outcomes. SLEEP 2015;38(5):717–722. PMID:25325483

  1. Reducing the incidence of pressure ulcers in nursing home residents: a prospective 6-year evaluation.

    PubMed

    Tippet, Aletha W

    2009-11-01

    Despite numerous clinical efforts and regulatory mandates to reduce occurrence, pressure ulcers (PUs) continue to plague up to one fourth of patients in healthcare facilities. In 2003, staff and administrators of a 151-bed skilled nursing facility in the Midwest started a quality improvement project based on 1992 Agency for Health Care Policy and Research guidelines to reduce the incidence of facility-acquired PUs. Pre-initiative PU data collection suggested a 12% to 25% PU prevalence rate with an average pre-initiative incidence of 5.19% (168 acquired ulcers over 3,234 person-months). During the next 4 years post-initiative, the average incidence was 0.73% (47 acquired ulcers over 6,446 person-months). Implementation of the comprehensive preventive efforts involving an interdisciplinary team with strong leadership, intensive training, use of evidence-based protocols, carefully evaluated support surfaces and wound/skin products, and simplification of processes led to a significant (P <0.0001) and sustained reduction in the incidence and prevalence of PUs. Additional observations included a simultaneous and unexplained reduction in resident falls and an overall cost reduction of more than $124,000 per year. These results confirm that nosocomial pressure ulcers can be significantly reduced in long-term care when well-established standard guidelines are followed.

  2. A time- and dose-dependent STAT1 expression system

    PubMed Central

    Leitner, Nicole R; Strobl, Birgit; Bokor, Marion; Painz, Ronald; Kolbe, Thomas; Rülicke, Thomas; Müller, Mathias; Karaghiosoff, Marina

    2006-01-01

    Background The signal transducer and activator of transcription (STAT) family of transcription factors mediates a variety of cytokine dependent gene regulations. STAT1 has been mainly characterized by its role in interferon (IFN) type I and II signaling and STAT1 deficiency leads to high susceptibility to several pathogens. For fine-tuned analysis of STAT1 function we established a dimerizer-inducible system for STAT1 expression in vitro and in vivo. Results The functionality of the dimerizer-induced STAT1 system is demonstrated in vitro in mouse embryonic fibroblasts and embryonic stem cells. We show that this two-vector based system is highly inducible and does not show any STAT1 expression in the absence of the inducer. Reconstitution of STAT1 deficient cells with inducible STAT1 restores IFNγ-mediated gene induction, antiviral responses and STAT1 activation remains dependent on cytokine stimulation. STAT1 expression is induced rapidly upon addition of dimerizer and expression levels can be regulated in a dose-dependent manner. Furthermore we show that in transgenic mice STAT1 can be induced upon stimulation with the dimerizer, although only at low levels. Conclusion These results prove that the dimerizer-induced system is a powerful tool for STAT1 analysis in vitro and provide evidence that the system is suitable for the use in transgenic mice. To our knowledge this is the first report for inducible STAT1 expression in a time- and dose-dependent manner. PMID:17184522

  3. Pyrimidine dimer removal enhanced by DNA repair liposomes reduces the incidence of UV skin cancer in mice.

    PubMed

    Yarosh, D; Alas, L G; Yee, V; Oberyszyn, A; Kibitel, J T; Mitchell, D; Rosenstein, R; Spinowitz, A; Citron, M

    1992-08-01

    UV exposure has been linked to skin cancer in humans by epidemiology and the rare genetic disease xeroderma pigmentosum. However, UV produces multiple photoproducts in DNA, and their relative contribution is uncertain. An enzyme which specifically repairs cyclobutane pyrimidine dimers in DNA, T4 endonuclease V, was encapsulated in liposomes for topical delivery into mouse and human skin. In both species, liposomes applied after UV exposure localized in the epidermis and stimulated the removal of cyclobutane pyrimidine dimers. UV-irradiated mice treated with these liposomes had a dose-dependent decrease in the incidence of squamous cell carcinoma compared to controls. The results demonstrate that unrepaired cyclobutane pyrimidine dimers in DNA are a direct cause of cancer in mammalian skin.

  4. Dose-dependent elimination of 8-methoxypsoralen in the mouse

    SciTech Connect

    Cheney, P.; Pacula, C.M.; Gerber, N.; Mays, D.C.

    1986-03-01

    8-Methoxypsoralen (8-MOP), a photoactive linear furocoumarin, is effective in the treatment of several diseases, including psoriasis, mycosis fungoides and T-cell leukemia. Recently, a specific extraction procedure for /sup 14/C-8-MOP showed that the elimination of 8-MOP in the rat was dose-dependent. Similar pharmacokinetic studies were undertaken in mice. Purity of /sup 14/C-8-MOP, verified by a four-tube countercurrent distribution using hexane (8 ml) and pH 7.4 phosphate buffer (0.1 M 15 ml) as described by Bush, was >98% and distributed with a partition coefficient of 3.86. Male CD-1 mice were each given an i.p. dose of 10 or 50 mg/kg of /sup 14/C-8-MOP (3.4 ..mu..Ci/mg) sacrificed at timed intervals, homogenized in 150 ml of 0.1 M phosphate buffer (pH 7.4) and a portion (0.8 ml) of the homogenate used to quantify 8-MOP as described above. The elimination half-life measured in the first 45 min was 7.4 min at 10 mg/kg and 95 min at 50 mg/kg. A similar half-life of 9.2 min was measured in mice given an i.v. dose 10 mg/kg of 8-MOP. Explanations of dose-dependent elimination include enzyme saturation, product inhibition or both. Between 58-80% of the administered radioactivity was recovered in the urine within 24 hr. Nine peaks of radioactivity were observed in the urine by HPLC, two of which coeluted with 5,8-dihydroxypsoralen and 6-(7-hydroxy-8-methoxycoumaryl)-acetic acid.

  5. Folate supplementation induces differential dose-dependent modulation of proliferative phenotypes among cancerous and noncancerous oral cell lines in vitro.

    PubMed

    McCabe, Jonathan; Chang, Sarah; Hajibandeh, Jeffrey; Tran, Michael D; Meeder, Colby A; Sharma, Kanika; Nguyen, Dieu-Hoa; Moody, Michael; Keiserman, Mark A; Bergman, Christine J; Kingsley, Karl

    2010-12-01

    Sufficient folate intake confers positive health benefits, while deficiency is linked with many health problems. Although the US policy of dietary folic acid fortification has reduced the incidence of these deficiency-related health problems, recent evidence has demonstrated an association between folic acid supplementation and increased colorectal cancer incidence. Few studies have explored the possibility that folate affects other slowly developing cancers. This study sought to determine whether folic acid supplementation is sufficient to alter the growth and development of existing oral cancers. A series of in vitro growth, viability, and adhesion assays were performed using the well-characterized human oral squamous cell carcinoma cell lines, CAL27 and SCC25, to determine the effects of folic acid supplementation. Folic acid administration significantly stimulated CAL27 and SCC25 proliferation in a dose-dependent manner, but it was not sufficient to increase proliferation at any concentration tested in the normal control cell line, HGF-1. Neither oral cancer cell line harbored the common C677T DNA polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene, which might reduce folate bioavailability. Overexpression of p53 mRNA was observed in both cancerous cell lines, but it was differentially altered by folic acid administration in only SCC25 cells. These findings suggest folic acid administration may significantly alter growth of oral cancers in vitro via p53-dependent and p53-independent pathways. As oral cancer rates continue to rise in specific geographic areas, and among specific subsets of the US population, understanding environmental mediators, such as folic acid supplementation, becomes increasingly important for nutrition and public health scientists.

  6. Electron paramagnetic resonance in irradiated fingernails: variability of dose dependence and possibilities of initial dose assessment.

    PubMed

    Reyes, R A; Romanyukha, Alexander; Olsen, C; Trompier, F; Benevides, L A

    2009-08-01

    The results of electron paramagnetic resonance (EPR) measurements in irradiated fingernails are presented. In total, 83 samples of different fingernails were studied. Five different groups of samples were selected based on the collection time of fingernail samples, their level of mechanical stress, and the number and size of clippings: (1) recently (<24 h) cut, irradiated and measured with EPR without any treatment of samples, and with rigorous control of size and number of clippings (stressed-fresh, controlled); (2) recently (<24 h) cut, irradiated and measured with EPR after application of a special treatment (10 min of water soaking, 5 min of drying time) to reduce the mechanical stress caused by cutting the samples, and with rigorous control of size and number of clippings (unstressed-fresh, controlled); (3) previously (>24 h) cut, stored at room temperature, additionally cut into small pieces immediately prior to study, irradiated and measured with EPR without any treatment of samples, and with rigorous control of size and number of clippings (stressed-old, controlled); (4) previously (>24 h) cut, stored at room temperature, additionally cut into small pieces immediately prior to the study, irradiated and measured with EPR after application of a special treatment to reduce mechanical stress caused by cut, and with rigorous control of size and number of clippings (unstressed-old, controlled); and (5) recently (<24 h) cut, irradiated and measured with EPR after application of a special treatment to reduce the mechanical stress caused by cut, and without rigorous control of size and number of clippings (unstressed-fresh, uncontrolled). Except for the fifth selected group, variability of the dose dependence inside all groups was found to be not statistically significant, although the variability among the different groups was significant. Comparison of the mean dose dependences obtained for each group allowed selection of key factors responsible for radiation

  7. Febuxostat protects rats against lipopolysaccharide-induced lung inflammation in a dose-dependent manner.

    PubMed

    Fahmi, Alaa N A; Shehatou, George S G; Shebl, Abdelhadi M; Salem, Hatem A

    2016-03-01

    The aim of the present work was to investigate possible protective effects of febuxostat, a highly potent xanthine oxidase inhibitor, against acute lung injury (ALI) induced by lipopolysaccharide (LPS) in rats. Male Sprague Dawley rats were randomly divided into six groups, as follows: (i) vehicle control group; (ii) and (iii) febuxostat 10 and febuxostat 15 groups, drug-treated controls; (iv) LPS group, receiving an intraperitoneal injection of LPS (7.5 mg/kg); (v) and (vi) febuxostat 10-LPS and febuxostat 15-LPS groups, receiving oral treatment of febuxostat (10 and 15 mg/kg/day, respectively) for 7 days before LPS. After 18 h administration of LPS, blood was collected for C-reactive protein (CRP) measurement. Bronchoalveolar lavage fluid (BALF) was examined for leukocyte infiltration, lactate dehydrogenase (LDH) activity, protein content, and total nitrate/nitrite. Lung weight gain was determined, and lung tissue homogenate was prepared and evaluated for oxidative stress. Tumor necrosis factor-α (TNF-α) was assessed in BALF and lung homogenate. Moreover, histological changes of lung tissues were evaluated. LPS elicited lung injury characterized by increased lung water content (by 1.2 fold), leukocyte infiltration (by 13 fold), inflammation and oxidative stress (indicated by increased malondialdehyde (MDA), by 3.4 fold), and reduced superoxide dismutase (SOD) activity (by 34 %). Febuxostat dose-dependently decreased LPS-induced lung edema and elevations in BALF protein content, infiltration of leukocytes, and LDH activity. Moreover, the elevated levels of TNF-α in BALF and lung tissue of LPS-treated rats were attenuated by febuxostat pretreatment. Febuxostat also displayed a potent antioxidant activity by decreasing lung tissue levels of MDA and enhancing SOD activity. Histological analysis of lung tissue further demonstrated that febuxostat dose-dependently reversed LPS-induced histopathological changes. These findings demonstrate a significant dose-dependent

  8. Modeling inoculum dose dependent patterns of acute virus infections.

    PubMed

    Li, Yan; Handel, Andreas

    2014-04-21

    Inoculum dose, i.e. the number of pathogens at the beginning of an infection, often affects key aspects of pathogen and immune response dynamics. These in turn determine clinically relevant outcomes, such as morbidity and mortality. Despite the general recognition that inoculum dose is an important component of infection outcomes, we currently do not understand its impact in much detail. This study is intended to start filling this knowledge gap by analyzing inoculum dependent patterns of viral load dynamics in acute infections. Using experimental data for adenovirus and infectious bronchitis virus infections as examples, we demonstrate inoculum dose dependent patterns of virus dynamics. We analyze the data with the help of mathematical models to investigate what mechanisms can reproduce the patterns observed in experimental data. We find that models including components of both the innate and adaptive immune response are needed to reproduce the patterns found in the data. We further analyze which types of innate or adaptive immune response models agree with observed data. One interesting finding is that only models for the adaptive immune response that contain growth terms partially independent of viral load can properly reproduce observed patterns. This agrees with the idea that an antigen-independent, programmed response is part of the adaptive response. Our analysis provides useful insights into the types of model structures that are required to properly reproduce observed virus dynamics for varying inoculum doses. We suggest that such models should be taken as basis for future models of acute viral infections.

  9. Reducing Tobacco-Related Cancer Incidence and Mortality: Summary of an Institute of Medicine Workshop

    PubMed Central

    Dresler, Carolyn; Fleury, Mark E.; Gritz, Ellen R.; Kean, Thomas J.; Myers, Matthew L.; Nass, Sharyl J.; Nevidjon, Brenda; Toll, Benjamin A.; Warren, Graham W.; Herbst, Roy S.

    2014-01-01

    Tobacco use remains a serious and persistent national problem. Recognizing that progress in combating cancer will never be fully achieved without addressing the tobacco problem, the National Cancer Policy Forum of the Institute of Medicine convened a public workshop exploring current issues in tobacco control, tobacco cessation, and implications for cancer patients. Workshop participants discussed potential policy, outreach, and treatment strategies to reduce tobacco-related cancer incidence and mortality, and highlighted a number of potential high-value action items to improve tobacco control policy, research, and advocacy. PMID:24304712

  10. Hypothesis: Impregnated school uniforms reduce the incidence of dengue infections in school children.

    PubMed

    Wilder-Smith, A; Lover, A; Kittayapong, P; Burnham, G

    2011-06-01

    Dengue infection causes a significant economic, social and medical burden in affected populations in over 100 countries in the tropics and sub-tropics. Current dengue control efforts have generally focused on vector control but have not shown major impact. School-aged children are especially vulnerable to infection, due to sustained human-vector-human transmission in the close proximity environments of schools. Infection in children has a higher rate of complications, including dengue hemorrhagic fever and shock syndromes, than infections in adults. There is an urgent need for integrated and complementary population-based strategies to protect vulnerable children. We hypothesize that insecticide-treated school uniforms will reduce the incidence of dengue in school-aged children. The hypothesis would need to be tested in a community based randomized trial. If proven to be true, insecticide-treated school uniforms would be a cost-effective and scalable community based strategy to reduce the burden of dengue in children.

  11. Dose-dependent effects of tryptophan on learning and memory.

    PubMed

    Ikram, Huma; Mushtaq, Foqia; Haleem, Darakhshan Jabeen

    2014-09-01

    The concentration of 5-hydroxytryptamine (5-HT, Serotonin) varies as a result of physiological changes in the availability of its precursor tryptophan to the serotonergic neurons in the brain. Increase in brain tryptophan occurs following an increase in plasma tryptophan concentration. Tryptophan intake increases brain serotonin metabolism and enhances memory. The Present study was designed to investigate the effects of oral administration of tryptophan (TRP) at different doses (100, 300 and 500mg/kg) for two weeks on learning and memory functions and Neurochemical changes in rats. Control rats were given drinking water. Assessment of memory in rats was done by using the water Maze. on the 14th day trail training of water Maze was given to rats and after 1h of this 2nd trial of these rats were done. On the next day (After 24h of trail) long-term memories of these rats were monitored. After 1 hour of this all rats were killed by decapitation using guillotine. Brain and blood was collected and stored at -70°C. Neurochemical estimations of Plasma and brain tryptophan, 5-HT and 5-HIAA in brain were made by HPLC-EC. Result showed that administration of tryptophan enhanced performance on water Maze test. Tryptophan treated animals exhibited higher level of Plasma as well as brain tryptophan. 5-HT and 5-HIAA levels were also increased in tryptophan treated rats. Findings are discussed in context with the role of 5-HT metabolism in learning and memory process in rats. Results may help to understand the 5-HT changes following long term TRP administration in a dose dependent manner and will help to suggest the use of TRP in serotonin related illnesses.

  12. Electron Beam Irradiation Dose Dependently Damages the Bacillus Spore Coat and Spore Membrane

    PubMed Central

    Fiester, S. E.; Helfinstine, S. L.; Redfearn, J. C.; Uribe, R. M.; Woolverton, C. J.

    2012-01-01

    Effective control of spore-forming bacilli begs suitable physical or chemical methods. While many spore inactivation techniques have been proven effective, electron beam (EB) irradiation has been frequently chosen to eradicate Bacillus spores. Despite its widespread use, there are limited data evaluating the effects of EB irradiation on Bacillus spores. To study this, B. atrophaeus spores were purified, suspended in sterile, distilled water, and irradiated with EB (up to 20 kGy). Irradiated spores were found (1) to contain structural damage as observed by electron microscopy, (2) to have spilled cytoplasmic contents as measured by spectroscopy, (3) to have reduced membrane integrity as determined by fluorescence cytometry, and (4) to have fragmented genomic DNA as measured by gel electrophoresis, all in a dose-dependent manner. Additionally, cytometry data reveal decreased spore size, increased surface alterations, and increased uptake of propidium iodide, with increasing EB dose, suggesting spore coat alterations with membrane damage, prior to loss of spore viability. The present study suggests that EB irradiation of spores in water results in substantial structural damage of the spore coat and inner membrane, and that, along with DNA fragmentation, results in dose-dependent spore inactivation. PMID:22319535

  13. Suppository naproxen reduces incidence and severity of post-endoscopic retrograde cholangiopancreatography pancreatitis: Randomized controlled trial

    PubMed Central

    Mansour-Ghanaei, Fariborz; Joukar, Farahnaz; Taherzadeh, Zahra; Sokhanvar, Homayoon; Hasandokht, Tolou

    2016-01-01

    the naproxen group was significantly lower than that in the placebo (6 patients vs 23 patients, P < 0.01, RRR = 12%, AR = 0.3, 95%CI: 0.2-0.6). Naproxen reduced the PEP in patients with ≥ 3 pancreatic cannulations (P < 0.01, RRR = 25%, AR = 0.1, 95%CI: 0.1-0.4) and an ERCP duration > 40 min (P < 0.01, RRR = 20%, AR = 0.9, 95%CI: 0.4-1.2). CONCLUSION: Single dose of suppository naproxen administered immediately before ERCP reduces the incidence of PEP. PMID:27275104

  14. Resveratrol Reduces the Incidence of Portal Vein System Thrombosis after Splenectomy in a Rat Fibrosis Model

    PubMed Central

    Xu, Meng; Xue, Wanli; Ma, Zhenhua; Bai, Jigang

    2016-01-01

    Purpose. To investigate the preventive effect of resveratrol (RES) on the formation of portal vein system thrombosis (PVST) in a rat fibrosis model. Methods. A total of 64 male SD rats, weighing 200–300 g, were divided into five groups: Sham operation, Splenectomy I, Splenectomy II, RES, and low molecular weight heparin (LMWH), with the former two groups as nonfibrosis controls. Blood samples were subjected to biochemical assays. Platelet apoptosis was measured by flow cytometry. All rats were euthanized for PVST detection one week after operation. Results. No PVST occurred in nonfibrosis controls. Compared to Splenectomy II, the incidences of PVST in RES and LMWH groups were significantly decreased (both p < 0.05). Two rats in LMWH group died before euthanasia due to intra-abdominal hemorrhage. In RES group, significant decreases in platelet aggregation, platelet radical oxygen species (ROS) production, and increase in platelet nitric oxide (NO) synthesis and platelet apoptosis were observed when compared with Splenectomy II (all p < 0.001), while in LMWH group only significant decrease in platelet aggregation was observed. Conclusion. Prophylactic application of RES could safely reduce the incidence of PVST after splenectomy in cirrhotic rat. Regulation of platelet function and induction of platelet apoptosis might be the underlying mechanisms. PMID:27433290

  15. Resveratrol Reduces the Incidence of Portal Vein System Thrombosis after Splenectomy in a Rat Fibrosis Model.

    PubMed

    Xu, Meng; Xue, Wanli; Ma, Zhenhua; Bai, Jigang; Wu, Shengli

    2016-01-01

    Purpose. To investigate the preventive effect of resveratrol (RES) on the formation of portal vein system thrombosis (PVST) in a rat fibrosis model. Methods. A total of 64 male SD rats, weighing 200-300 g, were divided into five groups: Sham operation, Splenectomy I, Splenectomy II, RES, and low molecular weight heparin (LMWH), with the former two groups as nonfibrosis controls. Blood samples were subjected to biochemical assays. Platelet apoptosis was measured by flow cytometry. All rats were euthanized for PVST detection one week after operation. Results. No PVST occurred in nonfibrosis controls. Compared to Splenectomy II, the incidences of PVST in RES and LMWH groups were significantly decreased (both p < 0.05). Two rats in LMWH group died before euthanasia due to intra-abdominal hemorrhage. In RES group, significant decreases in platelet aggregation, platelet radical oxygen species (ROS) production, and increase in platelet nitric oxide (NO) synthesis and platelet apoptosis were observed when compared with Splenectomy II (all p < 0.001), while in LMWH group only significant decrease in platelet aggregation was observed. Conclusion. Prophylactic application of RES could safely reduce the incidence of PVST after splenectomy in cirrhotic rat. Regulation of platelet function and induction of platelet apoptosis might be the underlying mechanisms. PMID:27433290

  16. Dose dependence and therapeutic window for the neuroprotective effects of curcumin in thromboembolic model of rat.

    PubMed

    Dohare, Preeti; Garg, Puja; Jain, Vikas; Nath, Chandishwar; Ray, Madhur

    2008-11-21

    Curcumin (diferuloylmethane), an active ingredient of turmeric, obtained from the powdered rhizomes of Curcuma longa Linn., has been traditionally recognized for treatment of several diseases. To evaluate the potential clinical use of curcumin, we determined the dose dependence of its effects in the therapeutic window and of the neuroprotective efficacy in a cerebral thromboembolic model of the rat. Rats were subjected to occlusion of the middle cerebral artery (MCAo) by a thrombus and treated with different doses of curcumin or the vehicle at 4h after ischemia. The animals were assessed after 24h for motor performance and neurological deficit. The rats were sacrificed immediately afterwards for evaluation of infarct, edema volume, estimation of nitrate and nitrite levels, neutrophil infiltration and levels of GSH and glutathione peroxidase (GSH-Px) in brain tissue. Curcumin reduced in a dose-dependent manner the ischemia-induced cerebral infarct and edema volume and attenuated neurological deficits observed after 24h. Curcumin reduced post-ischemic brain neutrophil infiltration, nitrate and nitrite levels and ameliorated the loss of GSH-Px and tends to increase the GSH levels but not significantly in the brain tissue. Neuronal levels of reactive oxygen species, peroxynitrite, and nitric oxide were lowered and in brain cryosections inducible nitric oxide synthase expression were significantly inhibited after treatment with curcumin. The present study is the first evidence of effectiveness of curcumin when given 4h post-ischemia in the rat thromboembolic stroke models, as it reduces infarct volume, ameliorates the sensory motor function and significantly attenuated the nitrosative stress. PMID:18611416

  17. Healthy Lifestyles Reduce the Incidence of Chronic Diseases and Dementia: Evidence from the Caerphilly Cohort Study

    PubMed Central

    Elwood, Peter; Galante, Julieta; Pickering, Janet; Palmer, Stephen; Bayer, Antony; Ben-Shlomo, Yoav; Longley, Marcus; Gallacher, John

    2013-01-01

    Background Healthy lifestyles based on non-smoking, an acceptable BMI, a high fruit and vegetable intake, regular physical activity, and low/moderate alcohol intake, are associated with reductions in the incidence of certain chronic diseases, but to date there is limited evidence on cognitive function and dementia. Methods In 1979 healthy behaviours were recorded on 2,235 men aged 45–59 years in Caerphilly, UK. During the following 30 years incident diabetes, vascular disease, cancer and death were recorded, and in 2004 cognitive state was determined. Findings Men who followed four or five of the behaviours had an odds ratio (OR) and confidence intervals (CI) for diabetes, corrected for age and social class, of 0.50 (95% CI: 0.19, 1.31; P for trend with increasing numbers of healthy behaviours <0.0005). For vascular disease the OR was 0.50 (95% CI: 0.30, 0.84; P for trend <0.0005), and there was a delay in vascular disease events of up to 12 years. Cancer incidence was not significantly related to lifestyle although there was a reduction associated with non-smoking (OR: 0.65; 95% CI: 0.54, 0.79). All-cause mortality was reduced in men following four or five behaviours (OR 0.40; 95% CI: 0.24, 0.67; P for trend <0.005). After further adjustment for NART, the OR for men following four or five healthy behaviours was 0.36 (95% CI: 0.12, 1.09; P for trend <0.001) for cognitive impairment, and 0.36 (95% CI: 0.07, 1.99; P for trend <0.02) for dementia. The adoption of a healthy lifestyle by men was low and appears not to have changed during the subsequent 30 years, with under 1% of men following all five of the behaviours and 5% reporting four or more in 1979 and in 2009. Interpretation A healthy lifestyle is associated with increased disease-free survival and reduced cognitive impairment but the uptake remains low. PMID:24349147

  18. Dose-dependent protective effect of BPC 157 on capsaicin-induced rhinitis in rats.

    PubMed

    Kalogjera, L; Ries, M; Baudoin, T; Ferencic, Z; Trotic, R; Pegan, B

    1997-01-01

    Protection of BPC 157 on capsaicin-induced rhinitis was studied in Wistar rats for its effect on mastocyte infiltration, degranulation and inflammatory cell infiltration. Animals were pretreated with 10 microg/kg, 10 ng/kg or 2 ml saline i.p. and capsaicin (0.05 ml/nostril of 1750 nmol/l sol.) was applied intranasally. They were then euthanized at 1, 3 and 12 h after capsaicin provocation. Nasal mucosa was analyzed and scored for mastocyte infiltration, degranulation and inflammatory cell infiltration. BPC 157 pretreatment significantly prevented mastocyte infiltration at 1 h. Polymorphonuclear leukocyte infiltration was significantly reduced in rats pretreated with 10 microg/kg BPC 157. A dose-dependent effect of BPC 157 pretreatment was demonstrated only for polymorphonuclear leukocyte infiltration at 12 h. PMID:9065615

  19. Dose-Dependent Adverse Effects of Salinomycin on Male Reproductive Organs and Fertility in Mice

    PubMed Central

    Ojo, Olajumoke Omolara; Bhadauria, Smrati; Rath, Srikanta Kumar

    2013-01-01

    Salinomycin is used as an antibiotic in animal husbandry. Its implication in cancer therapy has recently been proposed. Present study evaluated the toxic effects of Salinomycin on male reproductive system of mice. Doses of 1, 3 or 5 mg/kg of Salinomycin were administered daily for 28 days. Half of the mice were sacrificed after 24 h of the last treatment and other half were sacrificed 28 days after withdrawal of treatment. Effects of SAL on body and reproductive organ weights were studied. Histoarchitecture of testis and epididymis was evaluated along with ultrastructural changes in Leydig cells. Serum and testicular testosterone and luteinizing hormones were estimated. Superoxide dismutase, reduced glutathione, lipid peroxidation, catalase and lactate dehydrogenase activities were measured. Spermatozoa count, morphology, motility and fertility were evaluated. Expression patterns of steroidogenic acute regulatory protein (StAR) and cytochrome P450 side chain cleavage proteins (CYP11A1) were assessed by Western blotting. Salinomycin treatment was lethal to few mice and retarded body growth in others with decreased weight of testes and seminal vesicles in a dose dependent manner. Seminiferous tubules in testes were disrupted and the epithelium of epididymis showed frequent occurrence of vacuolization and necrosis. Leydig cells showed hypertrophied cytoplasm with shrunken nuclei, condensed mitochondria, proliferated endoplasmic reticulum and increased number of lipid droplets. Salinomycin decreased motility and spermatozoa count with increased number of abnormal spermatozoa leading to infertility. The testosterone and luteinizing hormone levels were decreased in testis but increased in serum at higher doses. Depletion of superoxide dismutase and reduced glutathione with increased lipid peroxidation in both testis and epididymis indicated generation of oxidative stress. Suppressed expression of StAR and CYP11A1 proteins indicates inhibition of steroidogenesis

  20. Soft Perches in an Aviary System Reduce Incidence of Keel Bone Damage in Laying Hens

    PubMed Central

    Stratmann, Ariane; Fröhlich, Ernst K. F.; Harlander-Matauschek, Alexandra; Schrader, Lars; Toscano, Michael J.; Würbel, Hanno; Gebhardt-Henrich, Sabine G.

    2015-01-01

    Keel bone fractures and deviations are one of the major welfare and health issues in commercial laying hens. In non-cage housing systems like aviaries, falls and collisions with perches and other parts of the housing system are assumed to be one of the main causes for the high incidence of keel bone damage. The objectives of this study were to investigate the effectiveness of a soft perch material to reduce keel bone fractures and deviations in white (Dekalb White) and brown laying hens (ISA Brown) kept in an aviary system under commercial conditions. In half of 20 pens, all hard, metal perches were covered with a soft polyurethane material. Palpation of 20 hens per pen was conducted at 18, 21, 23, 30, 38, 44 and 64 weeks of age. Production data including egg laying rate, floor eggs, mortality and feed consumption were collected over the whole laying period. Feather condition and body mass was assessed twice per laying period. The results revealed that pens with soft perches had a reduced number of keel bone fractures and deviations. Also, an interaction between hybrid and age indicated that the ISA hybrid had more fractured keel bones and fewer non-damaged keel bones compared with the DW hybrid at 18 weeks of age, a response that was reversed at the end of the experiment. This is the first study providing evidence for the effectiveness of a soft perch material within a commercial setting. Due to its compressible material soft perches are likely to absorb kinetic energy occurring during collisions and increase the spread of pressure on the keel bone during perching, providing a mechanism to reduce keel bone fractures and deviations, respectively. In combination with genetic selection for more resilient bones and new housing design, perch material is a promising tool to reduce keel bone damage in commercial systems. PMID:25811980

  1. Dose-dependent protective effect of nicotine in a murine model of viral myocarditis induced by coxsackievirus B3

    PubMed Central

    Li-Sha, Ge; Jing-Lin, Zhao; Guang-Yi, Chen; Li, Liu; De-Pu, Zhou; Yue-Chun, Li

    2015-01-01

    The alpha 7 nicotinic acetylcholine receptor (alpha7 nAChR) was recently described as an anti-inflammatory target in various inflammatory diseases. The aim of this study was to investigate the dose-related effects of nicotine, an alpha7 nAChR agonist, in murine model of viral myocarditis. BALB/C mice were infected by an intraperitoneally injection with coxsackievirus B3. Nicotine was administered at doses of 0.1, 0.2 or 0.4 mg/kg three times per day for 7 or 14 consecutive days. The effects of nicotine on survival, myocardial histopathological changes, cardiac function, and cytokine levels were studied. The survival rate on day 14 increased in a dose-dependent fashion and was markedly higher in the 0.2 and 0.4 mg/kg nicotine groups than in the infected untreated group. Treatment with high-dose nicotine reduced the myocardial inflammation and improved the impaired left ventricular function in infected mice. The mRNA expressions and protein levels of TNF-α, IL-1β, IL-6, and IL-17A were significantly downregulated in dose-dependent manners in the nicotine treatment groups compared to the infected untreated group. Nicotine dose-dependently reduced the severity of viral myocarditis through inhibiting the production of proinflammatory cytokines. The findings suggest that alpha7 nAChR agonists may be a promising new strategy for patients with viral myocarditis. PMID:26507386

  2. Dose-dependent protective effect of nicotine in a murine model of viral myocarditis induced by coxsackievirus B3.

    PubMed

    Li-Sha, Ge; Jing-Lin, Zhao; Guang-Yi, Chen; Li, Liu; De-Pu, Zhou; Yue-Chun, Li

    2015-10-28

    The alpha 7 nicotinic acetylcholine receptor (alpha7 nAChR) was recently described as an anti-inflammatory target in various inflammatory diseases. The aim of this study was to investigate the dose-related effects of nicotine, an alpha7 nAChR agonist, in murine model of viral myocarditis. BALB/C mice were infected by an intraperitoneally injection with coxsackievirus B3. Nicotine was administered at doses of 0.1, 0.2 or 0.4 mg/kg three times per day for 7 or 14 consecutive days. The effects of nicotine on survival, myocardial histopathological changes, cardiac function, and cytokine levels were studied. The survival rate on day 14 increased in a dose-dependent fashion and was markedly higher in the 0.2 and 0.4 mg/kg nicotine groups than in the infected untreated group. Treatment with high-dose nicotine reduced the myocardial inflammation and improved the impaired left ventricular function in infected mice. The mRNA expressions and protein levels of TNF-α, IL-1β, IL-6, and IL-17A were significantly downregulated in dose-dependent manners in the nicotine treatment groups compared to the infected untreated group. Nicotine dose-dependently reduced the severity of viral myocarditis through inhibiting the production of proinflammatory cytokines. The findings suggest that alpha7 nAChR agonists may be a promising new strategy for patients with viral myocarditis.

  3. Dose-Dependent Effects of Radiation Therapy on Cerebral Blood Flow, Metabolism, and Neurocognitive Dysfunction

    SciTech Connect

    Hahn, Carol A. Zhou Sumin; Raynor, Renee; Tisch, Andrea; Light, Kim; Shafman, Timothy; Kirkpatrick, John; Turkington, Timothy; Hollis, Donna; Marks, Lawrence B.

    2009-03-15

    Purpose: A prospective study was performed to formally relate dose-dependent radiologically defined changes in normal brain induced by radiotherapy (RT) to neurocognitive dysfunction in subjects with primary brain tumors. Methods and Materials: Adult patients receiving three-dimensional RT for central nervous system (CNS) tumors were enrolled. Positron emission tomography (PET) scanning and neuropsychological testing were performed before RT and 3 weeks and 6 months after treatment. Analyses were performed for correlations between changes in 2-deoxy-2-[{sup 18}F]-fluoro-D-glucose (FDG)-PET (metabolism), {sup 15}O-PET (relative blood flow), regional radiation dose, follow-up time, and neuropsychological test scores. Results: Eleven subjects were enrolled and 6 completed follow-up studies. The PET data showed reduced FDG uptake, with average decreases of 2-6% in regions of the brain receiving greater than 40 Gy at 3 weeks' and 6 months' follow-up. The {sup 15}O-H{sub 2}O PET showed increases (<10%) at 3 weeks in relative regional blood flow in brain receiving greater than 30 Gy, but less at the 6-month follow-up studies. There were significant correlations between decreases in FDG uptake and increased scores from the Symptom Checklist-90-R, with an average increase in T score of 2 (p < 0.0001). The Wisconsin Card Sorting Test showed a significant correlation of decreased FDG uptake with increased errors and perseveration in test performance, with an average decrease in T score of 11 (p = 0.037). Conclusions: A dose-dependent response of CNS tissue was detected using FDG PET in this small number of patients. Decreases in CNS metabolism correlated with decreased performance on neuropsychological tests for problem solving, cognitive flexibility, and global measures of psychopathology. Additional research is needed to verify and define these findings.

  4. Psilocybin dose-dependently causes delayed, transient headaches in healthy volunteers

    PubMed Central

    Johnson, Matthew W.; Sewell, R. Andrew; Griffiths, Roland R.

    2011-01-01

    Background Psilocybin is a well-characterized classic hallucinogen (psychedelic) with a long history of religious use by indigenous cultures, and nonmedical use in modern societies. Although psilocybin is structurally related to migraine medications, and case studies suggest that psilocybin may be efficacious in treatment of cluster headache, little is known about the relationship between psilocybin and headache. Methods This double-blind study examined a broad range of psilocybin doses (0, 5, 10, 20, and 30 mg/70 kg) on headache in 18 healthy participants. Results Psilocybin frequently caused headache, the incidence, duration, and severity of which increased in a dose-dependent manner. All headaches had delayed onset, were transient, and lasted no more than a day after psilocybin administration. Conclusions Possible mechanisms for these observations are discussed, and include induction of delayed headache through nitric oxide release. These data suggest that headache is an adverse event to be expected with the nonmedical use of psilocybin-containing mushrooms as well as the administration of psilocybin in human research. Headaches were neither severe nor disabling, and should not present a barrier to future psilocybin research. PMID:22129843

  5. [The Acapulco Declaration: a proposal to reduce incidence of diabetes in México].

    PubMed

    Aguilar-Salinas, Carlos Alberto; Gómez-Pérez, Francisco Javier

    2006-01-01

    Type 2 diabetes is the main health problem in Mexico. The growing number of cases, the high percentage of individuals with chronic complications and the treatment's cost are among the explanations for the inability in the control of this disease. Diabetes prevention is most likely to reduce the rate of growth of this diabetes burden on our health system. At- risk individuals can be identified and several interventions have proved to be effective in decreasing diabetes incidence. Diabetes prevention related interventions can become a reality with the active participation of the government and society. Thus, a joint collaboration between the medical community, the government and society is needed to phase out the diabetes epidemic. Published diabetes prevention programs were reviewed and interventions feasible for Mexico were summarized in a document called "Declaración de Acapulco". This paper was reviewed and approved by the Sociedad Mexicana de Nutrición y Endocrinología; additional endorsement was obtained from several Mexican and international societies and institutions. The manuscript describes several initiatives, which can be applied in schools, work places, primary health services and by the government. Some of these are focused on the general population; others are applicable to at-risk individuals. The "Declaración de Acapulco" is a-call-for-action position directed towards the whole society and designed to achieve effective diabetes prevention.

  6. Early Treatment of NOD Mice With B7-H4 Reduces the Incidence of Autoimmune Diabetes

    PubMed Central

    Wang, Xiaojie; Hao, Jianqiang; Metzger, Daniel L.; Mui, Alice; Ao, Ziliang; Akhoundsadegh, Noushin; Langermann, Solomon; Liu, Linda; Chen, Lieping; Ou, Dawei; Verchere, C. Bruce

    2011-01-01

    OBJECTIVE Autoimmune diabetes is a T cell–mediated disease in which insulin-producing β-cells are destroyed. Autoreactive T cells play a central role in mediating β-cell destruction. B7-H4 is a negative cosignaling molecule that downregulates T-cell responses. In this study, we aim to determine the role of B7-H4 on regulation of β-cell–specific autoimmune responses. RESEARCH DESIGN AND METHODS Prediabetic (aged 3 weeks) female NOD mice (group 1, n = 21) were treated with intraperitoneal injections of B7-H4.Ig at 7.5 mg/kg, with the same amount of mouse IgG (group 2, n = 24), or with no protein injections (group 3, n = 24), every 3 days for 12 weeks. RESULTS B7-H4.Ig reduced the incidence of autoimmune diabetes, compared with the control groups (diabetic mice 28.6% of group 1, 66.7% of group 2 [P = 0.0081], and 70.8% of group 3 [group 1 vs. 3, P = 0.0035]). Histological analysis revealed that B7-H4 treatment did not block islet infiltration but rather suppressed further infiltrates after 9 weeks of treatment (group 1 vs. 2, P = 0.0003). B7-H4 treatment also reduced T-cell proliferation in response to GAD65 stimulation ex vivo. The reduction of diabetes is not due to inhibition of activated T cells in the periphery but rather to a transient increase of Foxp3+ CD4+ T-cell population at one week posttreatment (12.88 ± 1.29 vs. 11.58 ± 1.46%; n = 8; P = 0.03). CONCLUSIONS Our data demonstrate the protective role of B7-H4 in the development of autoimmune diabetes, suggesting a potential means of preventing type 1 diabetes by targeting the B7-H4 pathway. PMID:21984581

  7. Dose-dependent role of the cohesin complex in normal and malignant hematopoiesis

    PubMed Central

    Viny, Aaron D.; Ott, Christopher J.; Spitzer, Barbara; Rivas, Martin; Meydan, Cem; Papalexi, Efthymia; Yelin, Dana; Shank, Kaitlyn; Reyes, Jaime; Chiu, April; Romin, Yevgeniy; Boyko, Vitaly; Thota, Swapna; Maciejewski, Jaroslaw P.; Melnick, Ari

    2015-01-01

    Cohesin complex members have recently been identified as putative tumor suppressors in hematologic and epithelial malignancies. The cohesin complex guides chromosome segregation; however, cohesin mutant leukemias do not show genomic instability. We hypothesized that reduced cohesin function alters chromatin structure and disrupts cis-regulatory architecture of hematopoietic progenitors. We investigated the consequences of Smc3 deletion in normal and malignant hematopoiesis. Biallelic Smc3 loss induced bone marrow aplasia with premature sister chromatid separation and revealed an absolute requirement for cohesin in hematopoietic stem cell (HSC) function. In contrast, Smc3 haploinsufficiency increased self-renewal in vitro and in vivo, including competitive transplantation. Smc3 haploinsufficiency reduced coordinated transcriptional output, including reduced expression of transcription factors and other genes associated with lineage commitment. Smc3 haploinsufficiency cooperated with Flt3-ITD to induce acute leukemia in vivo, with potentiated Stat5 signaling and altered nucleolar topology. These data establish a dose dependency for cohesin in regulating chromatin structure and HSC function. PMID:26438361

  8. Shock-absorbing insoles reduce the incidence of lower limb overuse injuries sustained during Royal Marine training.

    PubMed

    House, Carol; Reece, Allyson; Roiz de Sa, Dan

    2013-06-01

    This study was undertaken to determine whether the incidence of lower limb overuse injuries (LLOIs) sustained during Royal Marine training could be reduced by issuing the recruits with shock-absorbing insoles (SAIs) to wear in their military boots. This was a retrospective longitudinal trial conducted in two phases. Injury data from 1,416 recruits issued with standard Saran insoles and 1,338 recruits issued with SAI were compared. The recruits in the two groups were of similar height, body mass, and aerobic fitness and followed the same training course. The incidence of LLOI sustained by the recruits was lower (p < 0.05) in the SAI Group (19.0%) compared to the Saran Insole Group (31.7%). The incidences of lower limb stress fractures, tibial periostitis, tenosynovitis of foot, achilles tendonopathy, other tendonopathy and anterior knee pain were lower (p < 0.05) in the SAI Group. Tibial stress fracture incidence was lower (p < 0.05) in the SAI Group but metatarsal and femoral stress fracture incidences were the same for the two insole groups. Thus, issuing SAIs to military recruits undertaking a sustained, arduous physical training program with a high incidence of LLOI would provide a beneficial reduction in the incidence of LLOI.

  9. Reducing the underreporting of percutaneous exposure incidents: A single-center experience.

    PubMed

    Fritzsche, Carlos; Heine, Markus; Loebermann, Micha; Klammt, Sebastian; Podbielski, Andreas; Mittlmeier, Thomas; Reisinger, Emil C

    2016-08-01

    Although risk reduction strategies have been implemented throughout the world, underreporting of percutaneous exposure incidents (PEIs) is common among exposed health care workers. The aim of this study was to determine the incidence rate of reported PEIs before and after implementation of an intensified reporting management policy. The introduction of an intensified reporting system led to significantly increased reporting after a PEI has occurred. However, continuous education needs to be provided to improve awareness. PMID:27125915

  10. Colchicine Significantly Reduces Incident Cancer in Gout Male Patients: A 12-Year Cohort Study.

    PubMed

    Kuo, Ming-Chun; Chang, Shun-Jen; Hsieh, Ming-Chia

    2015-12-01

    Patients with gout are more likely to develop most cancers than subjects without gout. Colchicine has been used for the treatment and prevention of gouty arthritis and has been reported to have an anticancer effect in vitro. However, to date no study has evaluated the relationship between colchicine use and incident cancers in patients with gout. This study enrolled male patients with gout identified in Taiwan's National Health Insurance Database for the years 1998 to 2011. Each gout patient was matched with 4 male controls by age and by month and year of first diagnosis, and was followed up until 2011. The study excluded those who were diagnosed with diabetes or any type of cancer within the year following enrollment. We calculated hazard ratio (HR), aged-adjusted standardized incidence ratio, and incidence of 1000 person-years analyses to evaluate cancer risk. A total of 24,050 male patients with gout and 76,129 male nongout controls were included. Patients with gout had a higher rate of incident all-cause cancers than controls (6.68% vs 6.43%, P = 0.006). A total of 13,679 patients with gout were defined as having been ever-users of colchicine and 10,371 patients with gout were defined as being never-users of colchicine. Ever-users of colchicine had a significantly lower HR of incident all-cause cancers than never-users of colchicine after adjustment for age (HR = 0.85, 95% CI = 0.77-0.94; P = 0.001). In conclusion, colchicine use was associated with a decreased risk of incident all-cause cancers in male Taiwanese patients with gout.

  11. Altering Transplantation Time to Avoid Periods of High Temperature Can Efficiently Reduce Bacterial Wilt Disease Incidence with Tomato.

    PubMed

    Wei, Zhong; Huang, Jian-Feng; Hu, Jie; Gu, Yi-An; Yang, Chun-Lan; Mei, Xin-Lan; Shen, Qi-Rong; Xu, Yang-Chun; Friman, Ville-Petri

    2015-01-01

    Tomato bacterial wilt caused by Ralstonia solanacearum bacterium is a severe problem in Southern China, where relatively high environmental temperatures commonly prevails during the crop seasons. Previous research has indicated that bacterial wilt disease incidence generally increases during the warm months of summer leading to reduced tomato yield. Moreover, the efficacy of bio-organic fertilizers (BOFs)-organic compost fortified with pathogen-suppressive bacteria-is often lost during the periods of high environmental temperatures. Here we studied if the disease incidence could be reduced and the BOF performance enhanced by simply preponing and postponing the traditional seedling transplantation times to avoid tomato plant development during periods of high environmental temperature. To this end, a continuous, two-year field experiment was conducted to evaluate the performance of BOF in two traditional (late-spring [LS] and early-autumn [EA]) and two alternative (early-spring [ES] and late-autumn [LA]) crop seasons. We found that changing the transplantation times reduced the mean disease incidence from 33.9% (LS) and 54.7% (EA) to 11.1% (ES) and 7.1% (LA), respectively. Reduction in disease incidence correlated with the reduction in R. Solanacearum pathogen density in the tomato plant rhizosphere and stem base. Applying BOF during alternative transplantation treatments improved biocontrol efficiency from 43.4% (LS) and 3.1% (EA) to 67.4% (ES) and 64.8% (LA). On average, the mean maximum air temperatures were positively correlated with the disease incidence, and negatively correlated with the BOF biocontrol efficacy over the crop seasons. Crucially, even though preponing the transplantation time reduced the tomato yield in general, it was still economically more profitable compared to LS season due to reduced crop losses and relatively higher market prices. Preponing and postponing traditional tomato transplantation times to cooler periods could thus offer simple

  12. Altering Transplantation Time to Avoid Periods of High Temperature Can Efficiently Reduce Bacterial Wilt Disease Incidence with Tomato

    PubMed Central

    Wei, Zhong; Huang, Jian-Feng; Hu, Jie; Gu, Yi-An; Yang, Chun-Lan; Mei, Xin-Lan; Shen, Qi-Rong; Xu, Yang-Chun; Friman, Ville-Petri

    2015-01-01

    Tomato bacterial wilt caused by Ralstonia solanacearum bacterium is a severe problem in Southern China, where relatively high environmental temperatures commonly prevails during the crop seasons. Previous research has indicated that bacterial wilt disease incidence generally increases during the warm months of summer leading to reduced tomato yield. Moreover, the efficacy of bio-organic fertilizers (BOFs)–organic compost fortified with pathogen-suppressive bacteria—is often lost during the periods of high environmental temperatures. Here we studied if the disease incidence could be reduced and the BOF performance enhanced by simply preponing and postponing the traditional seedling transplantation times to avoid tomato plant development during periods of high environmental temperature. To this end, a continuous, two-year field experiment was conducted to evaluate the performance of BOF in two traditional (late-spring [LS] and early-autumn [EA]) and two alternative (early-spring [ES] and late-autumn [LA]) crop seasons. We found that changing the transplantation times reduced the mean disease incidence from 33.9% (LS) and 54.7% (EA) to 11.1% (ES) and 7.1% (LA), respectively. Reduction in disease incidence correlated with the reduction in R. Solanacearum pathogen density in the tomato plant rhizosphere and stem base. Applying BOF during alternative transplantation treatments improved biocontrol efficiency from 43.4% (LS) and 3.1% (EA) to 67.4% (ES) and 64.8% (LA). On average, the mean maximum air temperatures were positively correlated with the disease incidence, and negatively correlated with the BOF biocontrol efficacy over the crop seasons. Crucially, even though preponing the transplantation time reduced the tomato yield in general, it was still economically more profitable compared to LS season due to reduced crop losses and relatively higher market prices. Preponing and postponing traditional tomato transplantation times to cooler periods could thus offer

  13. Dose dependency of outcomes of intrapleural fibrinolytic therapy in new rabbit empyema models.

    PubMed

    Komissarov, Andrey A; Florova, Galina; Azghani, Ali O; Buchanan, Ann; Boren, Jake; Allen, Timothy; Rahman, Najib M; Koenig, Kathleen; Chamiso, Mignote; Karandashova, Sophia; Henry, James; Idell, Steven

    2016-08-01

    The incidence of empyema (EMP) is increasing worldwide; EMP generally occurs with pleural loculation and impaired drainage is often treated with intrapleural fibrinolytic therapy (IPFT) or surgery. A number of IPFT options are used clinically with empiric dosing and variable outcomes in adults. To evaluate mechanisms governing intrapleural fibrinolysis and disease outcomes, models of Pasteurella multocida and Streptococcus pneumoniae were generated in rabbits and the animals were treated with either human tissue (tPA) plasminogen activator or prourokinase (scuPA). Rabbit EMP was characterized by the development of pleural adhesions detectable by chest ultrasonography and fibrinous coating of the pleura. Similar to human EMP, rabbits with EMP accumulated sizable, 20- to 40-ml fibrinopurulent pleural effusions associated with extensive intrapleural organization, significantly increased pleural thickness, suppression of fibrinolytic and plasminogen-activating activities, and accumulation of high levels of plasminogen activator inhibitor 1, plasminogen, and extracellular DNA. IPFT with tPA (0.145 mg/kg) or scuPA (0.5 mg/kg) was ineffective in rabbit EMP (n = 9 and 3 for P. multocida and S. pneumoniae, respectively); 2 mg/kg tPA or scuPA IPFT (n = 5) effectively cleared S. pneumoniae-induced EMP collections in 24 h with no bleeding observed. Although intrapleural fibrinolytic activity for up to 40 min after IPFT was similar for effective and ineffective doses of fibrinolysin, it was lower for tPA than for scuPA treatments. These results demonstrate similarities between rabbit and human EMP, the importance of pleural fluid PAI-1 activity, and levels of plasminogen in the regulation of intrapleural fibrinolysis and illustrate the dose dependency of IPFT outcomes in EMP. PMID:27343192

  14. Dose dependency of outcomes of intrapleural fibrinolytic therapy in new rabbit empyema models.

    PubMed

    Komissarov, Andrey A; Florova, Galina; Azghani, Ali O; Buchanan, Ann; Boren, Jake; Allen, Timothy; Rahman, Najib M; Koenig, Kathleen; Chamiso, Mignote; Karandashova, Sophia; Henry, James; Idell, Steven

    2016-08-01

    The incidence of empyema (EMP) is increasing worldwide; EMP generally occurs with pleural loculation and impaired drainage is often treated with intrapleural fibrinolytic therapy (IPFT) or surgery. A number of IPFT options are used clinically with empiric dosing and variable outcomes in adults. To evaluate mechanisms governing intrapleural fibrinolysis and disease outcomes, models of Pasteurella multocida and Streptococcus pneumoniae were generated in rabbits and the animals were treated with either human tissue (tPA) plasminogen activator or prourokinase (scuPA). Rabbit EMP was characterized by the development of pleural adhesions detectable by chest ultrasonography and fibrinous coating of the pleura. Similar to human EMP, rabbits with EMP accumulated sizable, 20- to 40-ml fibrinopurulent pleural effusions associated with extensive intrapleural organization, significantly increased pleural thickness, suppression of fibrinolytic and plasminogen-activating activities, and accumulation of high levels of plasminogen activator inhibitor 1, plasminogen, and extracellular DNA. IPFT with tPA (0.145 mg/kg) or scuPA (0.5 mg/kg) was ineffective in rabbit EMP (n = 9 and 3 for P. multocida and S. pneumoniae, respectively); 2 mg/kg tPA or scuPA IPFT (n = 5) effectively cleared S. pneumoniae-induced EMP collections in 24 h with no bleeding observed. Although intrapleural fibrinolytic activity for up to 40 min after IPFT was similar for effective and ineffective doses of fibrinolysin, it was lower for tPA than for scuPA treatments. These results demonstrate similarities between rabbit and human EMP, the importance of pleural fluid PAI-1 activity, and levels of plasminogen in the regulation of intrapleural fibrinolysis and illustrate the dose dependency of IPFT outcomes in EMP.

  15. Creating Socially Fit Heroes and Reducing the Incidence of Bullying in Elementary Physical Education

    ERIC Educational Resources Information Center

    Wenos, Jeanne; Trick, Teri; Williams, Jacqueline A.

    2014-01-01

    Physical educators are not immune to incidents of bullying since confrontations are likely to occur in the settings in which they teach. Children do not recognize themselves as bullies because they often benefit from mistreating others, they don't suffer serious consequences along the way, and their victims don't know how to respond to…

  16. Pharmacokinetic Modeling of Manganese I. Dose-Dependencies of Uptake and Elimination

    SciTech Connect

    Teeguarden, Justin G.; Dorman, David C.; Covington, Tammie R.; Clewell, III, H. J.; Andersen, Melvin E.

    2007-01-01

    ABSTRACT Homeostatic mechanisms controlling uptake, storage, and elimination of dietary manganese (Mn) afford protection against fluctuations in tissue manganese (Mn) levels. Homeostatic control of inhaled Mn is less well understood, but important in assessing likely risks of Mn inhalation. We have used two compartmental kinetic models to characterize the influence of Mn exposure level and route (oral, inhalation) on uptake, elimination and transport of Mn. The models were fitted to or used to interpret data from five whole body Mn elimination studies, from one dietary Mn balance study, and from two biliary elimination studies, one acute and one chronic. As dietary Mn concentrations increased from low-sufficiency (1.5 ppm) to sufficiency (20 ppm), control of Mn uptake shifts from the intestine (principally), to more proportional control by both intestinal tissues and the liver. Using a 2-compartment distribution model, the increased elimination of 54Mn tracer doses in response to increases in dietary (rats and mice) or inhaled Mn (rats) resulted from increases in Mn elimination rate constants rather than changes in intercompartmental transfer rate constants between a central compartment and deep compartment. The PK analysis also indicated differential control of absorption in single gavage oral dose studies versus continuous high oral doses in the feed. The gavage study indicated increased elimination rate constants and the chronic study had reduced rate constants for absorption. These dose-dependencies in uptake and elimination are necessary inputs for comprehensive PK models guiding human health risk assessments with Mn.

  17. Impact of acquired immunity and dose-dependent probability of illness on quantitative microbial risk assessment.

    PubMed

    Havelaar, A H; Swart, A N

    2014-10-01

    Dose-response models in microbial risk assessment consider two steps in the process ultimately leading to illness: from exposure to (asymptomatic) infection, and from infection to (symptomatic) illness. Most data and theoretical approaches are available for the exposure-infection step; the infection-illness step has received less attention. Furthermore, current microbial risk assessment models do not account for acquired immunity. These limitations may lead to biased risk estimates. We consider effects of both dose dependency of the conditional probability of illness given infection, and acquired immunity to risk estimates, and demonstrate their effects in a case study on exposure to Campylobacter jejuni. To account for acquired immunity in risk estimates, an inflation factor is proposed. The inflation factor depends on the relative rates of loss of protection over exposure. The conditional probability of illness given infection is based on a previously published model, accounting for the within-host dynamics of illness. We find that at low (average) doses, the infection-illness model has the greatest impact on risk estimates, whereas at higher (average) doses and/or increased exposure frequencies, the acquired immunity model has the greatest impact. The proposed models are strongly nonlinear, and reducing exposure is not expected to lead to a proportional decrease in risk and, under certain conditions, may even lead to an increase in risk. The impact of different dose-response models on risk estimates is particularly pronounced when introducing heterogeneity in the population exposure distribution.

  18. Raised temperature reduces the incidence of diabetes in the NOD mouse.

    PubMed

    Williams, A J; Krug, J; Lampeter, E F; Mansfield, K; Beales, P E; Signore, A; Gale, E A; Pozzilli, P

    1990-10-01

    An association between the incidence of childhood Type 1 (insulin-dependent) diabetes mellitus and the average yearly temperature in different countries has been reported, the incidence being higher in countries with a lower mean temperature. We have studied the effect of environmental temperature on the incidence of diabetes in an animal model of Type 1 diabetes, the non-obese diabetic (NOD) mouse. Female NOD mice were divided at weaning, with one group placed at a higher temperature (mean 23.7 +/- 1.7 degrees C) and the other at a lower temperature (21.0 +/- 1.8 degrees C). At 20 weeks of age 6 of 16 mice at lower temperature and 1 of 17 mice at higher temperature had developed diabetes (p less than 0.02); at 30 weeks 10 of 16 and 5 of 17 mice had developed diabetes (p less than 0.05). Non-diabetic animals in the low temperature group had a higher food intake than those in the high temperature group between 13-15 weeks of age (28.0 +/- 1.2 g/week vs 24.8 +/- 0.7 g/week, p less than 0.05). In a parallel experiment, histological examination showed that there were similar degrees of insulitis in the high and low temperature groups at seven weeks of age. We conclude that environmental temperature can affect the incidence of diabetes in the NOD mouse and that this may be related to alterations in food intake. PMID:2258003

  19. Association of Family History of ESRD, Prevalent Albuminuria, and Reduced GFR With Incident ESRD

    PubMed Central

    McClellan, William M.; Warnock, David G.; Judd, Suzanne; Muntner, Paul; Patzer, Rachel E.; Bradbury, Brian D.; McClure, Leslie A.; Newsome, Britt B.; Howard, George

    2013-01-01

    Background The contribution of albuminuria to the increased risk of incident end-stage renal disease (ESRD) in individuals with a family history of ESRD has not been well studied. Study Design Prospective cohort study. Study Setting & Participants We analyzed data for family history of ESRD collected from 19,409 participants of the Renal REGARDS (Reasons for Geographic and Racial Differences in Stroke) cohort study. Predictor Family history of ESRD was ascertained by asking “Has anyone in your immediate family ever been told that he or she had kidney failure? This would be someone who is on or had been on dialysis or someone who had a kidney transplant.” Study Outcomes Incidence rate for ESRD. Measurements Morning urine albumin-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR). Incident cases of ESRD were identified through the US Renal Data System. Results A family history of ESRD was reported by 11.1% of participants. Mean eGFRs for those with and without a family history of ESRD were 87.5 ± 22.2 (SD) and 86.5 ± 19.3 mL/min/1.73 m2, respectively (P = 0.05) and the respective geometric mean ACRs were 12.2 and 9.7 mg/g (P < 0.001). ESRD incidence rates for those with and without a family history of ESRD were 244.3 and 106.1/100,000 person-years, respectively. After adjusting for age, sex, and race, the ESRD HR for those with versus those without a family history of ESRD was 2.13 (95% CI, 1.18-3.83). Adjustment for comorbid conditions and socioeconomic status attenuated this association (HR, 1.82; 95% CI, 1.00-3.28), and further adjustment for baseline eGFR and ACR completely attenuated the association between family history of ESRD and incident ESRD (HR, 1.12; 95% CI, 0.69-1.80). Limitations The report of a family history of ESRD was not validated. Conclusion Family history of ESRD is common in older Americans and the increased risk of ESRD associated with a family history reflects lower GFR, higher albuminuria, and comorbid conditions

  20. The effectiveness of a twice-daily skin-moisturising regimen for reducing the incidence of skin tears.

    PubMed

    Carville, Keryln; Leslie, Gavin; Osseiran-Moisson, Rebecca; Newall, Nelly; Lewin, Gill

    2014-08-01

    A cluster randomised controlled trial was conducted to evaluate the effectiveness of a twice-daily moisturising regimen as compared to 'usual' skin care for reducing skin tear incidence. Aged care residents from 14 Western Australian facilities (980 beds) were invited to participate. The facilities were sorted into pairs and matched in terms of bed numbers and whether they provided high or low care. One facility from each matched pair was randomised to the intervention group. Consenting residents in an intervention facility received a twice-daily application of a commercially available, standardised pH neutral, perfume-free moisturiser on their extremities. Residents in the control facilities received ad hoc or no standardised skin-moisturising regimen. Participant numbers were sufficient to detect a 5% difference in incidence rate between the two groups with 80% power and a significance level of P = 0·05, and the inter-cluster correlation coefficient was 0·034. Data were collected over 6 months. A total of 1396 skin tears on 424 residents were recorded during the study. In the intervention group, the average monthly incidence rate was 5·76 per 1000 occupied bed days as compared to 10·57 in the control group. The application of moisturiser twice daily reduced the incidence of skin tears by almost 50% in residents living in aged care facilities.

  1. Preischemic Administration of Sevoflurane Does not Exert Dose-dependent Effects on the Outcome of Severe Forebrain Ischemia in Rats.

    PubMed

    Miura, Yoshihide; Kanazawa, Kaoru; Nasu, Ikuko

    2015-07-01

    We previously showed that preischemic administration of high-dose isoflurane worsened the outcome from severe forebrain ischemia in rats. Conversely, high doses of sevoflurane have been reported to improve the outcome from forebrain ischemia when the insult is moderate. To clarify the dose-dependent effects of sevoflurane on severe forebrain ischemia, we performed an outcome study using an identical protocol to that in our previous study with isoflurane. Fasting male Sprague-Dawley rats underwent surgical preparation for forebrain ischemia under halothane anesthesia. Anesthesia was changed to fentanyl/nitrous oxide to eliminate the halothane, after which 30 minutes of 0.5, 1.0, 1.5, 2.0, or 2.5 minimum alveolar concentration sevoflurane was administered. Ten minutes of ischemia was induced by bilateral carotid occlusion plus systemic hypotension, in which cessation of electroencephalographic activity was confirmed. Sevoflurane was discontinued and anesthesia continued with fentanyl/nitrous oxide for an additional 100 minutes. Outcome evaluation at 5 days postischemia included seizure incidence, mortality rate, neuromotor score, and histologic injuries to the cerebral cortex and hippocampal CA1 and CA3. Different doses of sevoflurane did not statistically affect seizure incidence (10.0% to 18.2%), mortality rate (20.0% to 46.7%), cortical damage (mild to moderate degree), or hippocampal CA1 damage (93.7% to 96.7% neuronal necrosis) or CA3 damage (36.3% to 41.7%). Dose-dependent effects of sevoflurane were not observed for any of the outcome variables assessed in this rat model of severe forebrain ischemia. PMID:25390656

  2. Acyclovir Prophylaxis Reduces the Incidence of Herpes Zoster Among HIV-Infected Individuals: Results of a Randomized Clinical Trial.

    PubMed

    Barnabas, Ruanne V; Baeten, Jared M; Lingappa, Jairam R; Thomas, Katherine K; Hughes, James P; Mugo, Nelly R; Delany-Moretlwe, Sinead; Gray, Glenda; Rees, Helen; Mujugira, Andrew; Ronald, Allan; Stevens, Wendy; Kapiga, Saidi; Wald, Anna; Celum, Connie

    2016-02-15

    Human immunodeficiency virus (HIV)-infected persons have higher rates of herpes zoster than HIV-uninfected individuals. We assessed whether twice daily treatment with 400 mg of oral acyclovir reduces the incidence of herpes zoster in a randomized, double-blind, placebo-controlled trial among 3408 persons coinfected with HIV and herpes simplex virus type 2. During 5175 person-years of follow-up, 26 cases of herpes zoster occurred among those assigned acyclovir, compared with 69 cases among those assigned placebo (rates, 1.00 and 2.68/100 person-years, respectively), a relative decrease of 62% (hazard ratio, 0.38; 95% confidence interval, .24-.67; P < .001). Daily acyclovir prophylaxis significantly reduced herpes zoster incidence among HIV-infected persons.

  3. Delayed Initiation but Not Gradual Advancement of Enteral Formula Feeding Reduces the Incidence of Necrotizing Enterocolitis (NEC) in Preterm Pigs

    PubMed Central

    Ghoneim, Nada; Bauchart-Thevret, Caroline; Oosterloo, Berthe; Stoll, Barbara; Kulkarni, Madhulika; de Pipaon, Miguel Saenz; Zamora, Irving J.; Olutoye, Oluyinka O.; Berg, Brian; Wittke, Anja; Burrin, Douglas G.

    2014-01-01

    Enteral formula feeding is a risk factor for necrotizing enterocolitis (NEC) in premature infants, yet studies are conflicting regarding the safest timing for introduction and advancement of feeds. Our aim was to test the effects of early vs. late initiation and abrupt vs. gradual advancement of enteral feeding of an intact vs. hydrolyzed protein formula on NEC incidence and severity in preterm pigs. In Experiment 1, preterm pigs received total parenteral nutrition (TPN) at birth with abrupt initiation of enteral formula feeds (50% full intake) on d of life (DOL) 2 (EA) or 5 (LA) while PN continued. Pigs were also fed formula containing either intact or hydrolyzed protein. In Experiment 2, preterm pigs received TPN at birth with enteral, hydrolyzed-protein formula feeds introduced on DOL 2 either abruptly (EA; 50% full feeds) or gradually (EG; 10–50% full feeds over 5 d) while PN continued. NEC incidence and severity were assessed based on macroscopic and histological scoring. In Experiment 1, NEC incidence (41% vs. 70%, P<0.05) and severity were reduced in LA vs. EA groups and LA was associated with a higher survival rate, daily weight gain and jejunum villus height. Piglets fed hydrolyzed vs. intact protein formula had lower stomach content weights and similar NEC incidence. In Experiment 2, NEC incidence and severity were not different between pigs the EG vs. EA group. Proinflammatory gene expression (IL-1β, IL-6 and S100A9) in the ileum was lower in both LA and EG vs. EA groups. In conclusion, delayed initiation but not gradual advancement of enteral feeding is protective against NEC in preterm pigs. Feeding hydrolyzed vs. intact protein formula improved gastric transit without affecting the NEC incidence. PMID:25238061

  4. Dose-dependent effects of homologous seminal plasma on motility and kinematic characteristics of post-thaw stallion epididymal spermatozoa.

    PubMed

    Neuhauser, S; Dörfel, S; Handler, J

    2015-05-01

    Preservation of epididymal spermatozoa is important to save genetic material of endangered species and breeds, or in case of unexpected injury, which will end the breeding career of valuable sires. Seminal plasma (SP) influences sperm quality in a dose-dependent manner and its addition to preserved semen immediately before insemination may be beneficial for sperm fertility. Increased plasma membrane stability of epididymal spermatozoa reduces freezing injury of cells, and the addition of SP after freezing and thawing might have activating and protecting effects on spermatozoa within the female genital tract. In this study, epididymal spermatozoa were harvested by retrograde flush of the epididymal cauda immediately after routine castration and frozen. Seminal plasma was collected from other six stallions. Homologous SP (SP from the same species, but from a different animal) was added to frozen-thawed epididymal spermatozoa at concentrations of 0, 5, 20, 50 and 80% SP. Addition of SP increased sperm motility and influenced kinematic values in a dose-dependent manner (p < 0.05). Motility improved at concentrations of 20 and 50% SP, but did not further increase at 80% SP. There was no difference in sperm motility among SP from six different donor stallions regardless of the concentrations of SP (p > 0.05). Total and progressive motility of ten frozen-thawed epididymal spermatozoa samples collected from different stallions after dilution with extender and 5, 20, 50 or 80% SP differed significantly (p < 0.05). In conclusion, addition of homologous SP to frozen-thawed stallion epididymal spermatozoa immediately improved motility in a dose-dependent manner regardless of semen quality of SP donor stallions. This might positively influence fertility when SP is added before insemination. Moreover, there seems to be a threshold level of SP concentration for optimal improvement of sperm motility. PMID:25755119

  5. Dose-dependent effects of homologous seminal plasma on motility and kinematic characteristics of post-thaw stallion epididymal spermatozoa.

    PubMed

    Neuhauser, S; Dörfel, S; Handler, J

    2015-05-01

    Preservation of epididymal spermatozoa is important to save genetic material of endangered species and breeds, or in case of unexpected injury, which will end the breeding career of valuable sires. Seminal plasma (SP) influences sperm quality in a dose-dependent manner and its addition to preserved semen immediately before insemination may be beneficial for sperm fertility. Increased plasma membrane stability of epididymal spermatozoa reduces freezing injury of cells, and the addition of SP after freezing and thawing might have activating and protecting effects on spermatozoa within the female genital tract. In this study, epididymal spermatozoa were harvested by retrograde flush of the epididymal cauda immediately after routine castration and frozen. Seminal plasma was collected from other six stallions. Homologous SP (SP from the same species, but from a different animal) was added to frozen-thawed epididymal spermatozoa at concentrations of 0, 5, 20, 50 and 80% SP. Addition of SP increased sperm motility and influenced kinematic values in a dose-dependent manner (p < 0.05). Motility improved at concentrations of 20 and 50% SP, but did not further increase at 80% SP. There was no difference in sperm motility among SP from six different donor stallions regardless of the concentrations of SP (p > 0.05). Total and progressive motility of ten frozen-thawed epididymal spermatozoa samples collected from different stallions after dilution with extender and 5, 20, 50 or 80% SP differed significantly (p < 0.05). In conclusion, addition of homologous SP to frozen-thawed stallion epididymal spermatozoa immediately improved motility in a dose-dependent manner regardless of semen quality of SP donor stallions. This might positively influence fertility when SP is added before insemination. Moreover, there seems to be a threshold level of SP concentration for optimal improvement of sperm motility.

  6. Household Water Chlorination Reduces Incidence of Diarrhea among Under-Five Children in Rural Ethiopia: A Cluster Randomized Controlled Trial

    PubMed Central

    Mengistie, Bezatu; Berhane, Yemane; Worku, Alemayehu

    2013-01-01

    Background Household water treatment has been advocated as a means of decreasing the burden of diarrheal diseases among young children in areas where piped and treated water is not available. However, its effect size, the target population that benefit from the intervention, and its acceptability especially in rural population is yet to be determined. The objective of the study was to assess the effectiveness of household water chlorination in reducing incidence of diarrhea among children under-five years of age. Method A cluster randomized community trial was conducted in 36 rural neighborhoods of Eastern Ethiopia. Households with at least one child under-five years of age were included in the study. The study compared diarrhea incidence among children who received sodium hypochlorite (liquid bleach) for household water treatment and children who did not receive the water treatment. Generalized Estimation Equation model was used to compute adjusted incidence rate ratio and the corresponding 95% confidence interval. Result In this study, the incidence of diarrhea was 4.5 episodes/100 person week observations in the intervention arm compared to 10.4 episodes/100 person week observations in the control arm. A statistically significant reduction in incidence of diarrhea was observed in the intervention group compared to the control (Adjusted IRR = 0.42, 95% CI 0.36–0.48). Conclusion Expanding access to household water chlorination can help to substantially reduce child morbidity and achieve millennium development goal until reliable access to safe water is achieved. Trial Registration ClinicalTrials.gov NCT01376440 PMID:24194899

  7. Febuxostat exerts dose-dependent renoprotection in rats with cisplatin-induced acute renal injury.

    PubMed

    Fahmi, Alaa N A; Shehatou, George S G; Shebl, Abdelhadi M; Salem, Hatem A

    2016-08-01

    The aim of the present study was to investigate possible renoprotective effects of febuxostat, a highly potent xanthine oxidase inhibitor, against cisplatin (CIS)-induced acute kidney injury in rats. Male Sprague Dawley rats were randomly assigned into four groups of six rats each, as follows: normal control; CIS, received a single intraperitoneal injection of CIS (7.5 mg/kg); [febuxostat 10 + CIS] and [febuxostat 15 + CIS], received febuxostat (10 and 15 mg/kg/day, respectively, orally) for 14 days, starting 7 days before CIS injection. At the end of experiment, 24-h urine output was collected and serum was separated for biochemical assessments. Kidney tissue homogenate was prepared for determination of oxidative stress-related parameters, nitric oxide (NO), and tumor necrosis factor-α (TNF-α). Moreover, histological alterations of kidney tissues were evaluated. Serum creatinine, blood urea, and urinary total protein were significantly elevated, while serum albumin and creatinine clearance were significantly reduced, in CIS-intoxicated rats, indicating depressed renal function. CIS administration also elicited renal oxidative stress, evidenced by increased malondialdehyde content and depleted levels of reduced glutathione and superoxide dismutase activity. Moreover, enhancement of renal levels of the pro-inflammatory TNF-α indicated renal inflammation. CIS-administered rats also showed increased serum lactate dehydrogenase activity and reduced renal NO bioavailability. Febuxostat dose-dependently improved or restored these changes to near-normal (e.g., mean ± SD of serum creatinine levels in control, CIS, [febuxostat 10 + CIS] and [febuxostat 15 + CIS] groups were 0.78 ± 0.19, 3.28 ± 2.0 (P < 0.01 versus control group), 1.03 ± 0.36 (P < 0.01 versus CIS group), and 0.93 ± 0.21 (P < 0.01 versus CIS group) mg/dl, respectively, and blood urea levels for the different groups were 36.80 ± 4.36, 236.10 ± 89.19 (P < 0

  8. Efficacy of Anti-Interleukin-2 Receptor Antibody (Daclizumab) in Reducing the Incidence of Acute Rejection After Renal Transplantation

    PubMed Central

    Saghafi, Hossein; Rahbar, Khosrow; Nobakht Haghighi, Ali; Qoreishi, Mohammad; Safdari, Farshad

    2012-01-01

    Background Acute rejection remains a major problem in renal transplantation and represents one of the most important causes of chronic allograft dysfunction and late graft loss. Daclizumab is a genetically engineered human IgG1 monoclonal antibody that binds specifically to the α chain of the interleukin-2 receptor, and may thus reduce the risk of rejection after renal transplantation. Objectives The aim of this study was to examine the effect of daclizumab induction therapy combined with a triple immunosuppressive protocol including prednisolone,cyclosporine microemulsion (CsA), and mycophenolate mofetil (MMF), in reducing the incidence of acute rejection in recipients of living unrelated donor kidneys. Patients and Methods In this historical cohort study, 43 adult recipients of their first kidney allograft received daclizumab (three 1 mg/kg doses administered every 2 weeks) with triple immunosuppressive therapy (steroids, CsA, and MMF). This group was compared to 43 first-time graft recipients who received maintenance triple immunosuppressive therapy comprising steroids, CsA, and MMF. The end point was the incidence of biopsy confirmed acute rejection within 6 months after transplantation. Results At 6 months, 5 (11.6%) of the patients in the daclizumab group had biopsy-proven rejections, as compared to 14 (32.5%) in the control group (P = 0.017). The sex and the age of recipients had no impact on the incidence of acute rejection episodes in the two groups. Conclusions Adding interleukin-2 receptor antibody (daclizumab) to maintenance triple immunosuppressive therapy (prednisolone, CsA, and MMF) reduces the incidence of acute rejection episodes at 6 months in first-time transplant recipients of living unrelated donor. PMID:23573470

  9. GATA-3 dose-dependent checkpoints in early T cell commitment1

    PubMed Central

    Scripture-Adams, Deirdre D.; Damle, Sagar S.; Li, Long; Elihu, Koorosh J.; Qin, Shuyang; Arias, Alexandra M.; Butler, Robert R.; Champhekar, Ameya; Zhang, Jingli A.; Rothenberg, Ellen V.

    2014-01-01

    GATA-3 expression is crucial for T cell development and peaks during commitment to the T-cell lineage, midway through the CD4−CD8− (DN) 1-3 stages. We used RNA interference and conditional deletion to reduce GATA-3 protein acutely at specific points during T-cell differentiation in vitro. Even moderate GATA-3 reduction killed DN1 cells, delayed progression to DN2 stage, skewed DN2 gene regulation, and blocked appearance of DN3 phenotype. Although a Bcl-2 transgene rescued DN1 survival and improved DN2 cell generation, it did not restore DN3 differentiation. Gene expression analyses (qPCR, RNA-seq) showed that GATA-3-deficient DN2 cells quickly upregulated genes including Spi1 (PU.1) and Bcl11a and downregulated genes including Cpa3, Ets1, Zfpm1, Bcl11b, Il9r and Il17rb, with gene-specific kinetics and dose-dependencies. These targets could mediate two distinct roles played by GATA-3 in lineage commitment, as revealed by removing wildtype or GATA-3-deficient early T-lineage cells from environmental Notch signals. GATA-3 worked as a potent repressor of B-cell potential even at low expression levels, so that only full deletion of GATA-3 enabled pro-T cells to reveal B-cell potential. The ability of GATA-3 to block B-cell development did not require T-lineage commitment factor Bcl11b. In prethymic multipotent precursors, however, titration of GATA-3 activity using tamoxifen-inducible GATA-3 showed that GATA-3 inhibits B and myeloid developmental alternatives at different threshold doses. Furthermore, differential impacts of a GATA-3 obligate repressor construct imply that B and myeloid development are inhibited through distinct transcriptional mechanisms. Thus, the pattern of GATA-3 expression sequentially produces B-lineage exclusion, T-lineage progression, and myeloid-lineage exclusion for commitment. PMID:25172496

  10. Random drug testing to reduce the incidence of addiction in anesthesia residents: preliminary results from one program.

    PubMed

    Fitzsimons, Michael G; Baker, Keith H; Lowenstein, Edward; Zapol, Warren M

    2008-08-01

    Substance abuse occurs in approximately 1%-2% of anesthesia residents and nearly 80% of programs have had one or more resident (s) with such a problem. Education and control efforts have failed to reduce the frequency of substance abuse. Anesthesia providers have a professional obligation to be drug-free for the well being of their patients. We have instituted a program of preplacement and random urine testing of residents in anesthesiology in an attempt to decrease the incidence of substance abuse. We demonstrate that such a program is feasible, despite logistic and cultural obstacles. Larger multi-institutional studies will be required to determine whether instituting a program of random urine testing decreases the incidence of substance abuse in anesthesiology residents. PMID:18633044

  11. Brassinolide Increases Potato Root Growth In Vitro in a Dose-Dependent Way and Alleviates Salinity Stress

    PubMed Central

    Xia, Shitou; Su, Yi; Wang, Huiqun; Luo, Weigui; Su, Shengying

    2016-01-01

    Brassinosteroids (BRs) are steroidal phytohormones that regulate various physiological processes, such as root development and stress tolerance. In the present study, we showed that brassinolide (BL) affects potato root in vitro growth in a dose-dependent manner. Low BL concentrations (0.1 and 0.01 μg/L) promoted root elongation and lateral root development, whereas high BL concentrations (1–100 μg/L) inhibited root elongation. There was a significant (P < 0.05) positive correlation between root activity and BL concentrations within a range from 0.01 to 100 μg/L, with the peak activity of 8.238 mg TTC·g−1 FW·h−1 at a BL concentration of 100 μg/L. Furthermore, plants treated with 50 μg/L BL showed enhanced salt stress tolerance through in vitro growth. Under this scenario, BL treatment enhanced the proline content and antioxidant enzymes' (superoxide dismutase, peroxidase, and catalase) activity and reduced malondialdehyde content in potato shoots. Application of BL maintain K+ and Na+ homeostasis by improving tissue K+/Na+ ratio. Therefore, we suggested that the effects of BL on root development from stem fragments explants as well as on primary root development are dose-dependent and that BL application alleviates salt stress on potato by improving root activity, root/shoot ratio, and antioxidative capacity in shoots and maintaining K+/Na+ homeostasis in potato shoots and roots. PMID:27803931

  12. Do Regular Ultrasound Scans Reduce the Incidence of Stillbirth in Women with Apparently Normal Pregnancies?

    PubMed Central

    Toner, Brenda; Mone, Fionnuala

    2015-01-01

    Objective To determine the incidence of stillbirth in women who have regular ante-natal ultrasound compared to those that have infrequent scans in a low risk population. Study Design A retrospective observational study was performed in a tertiary center with 5,700 deliveries per annum. Data on all deliveries was collected via the Northern Ireland Maternity System Database. Only women with an apparently low risk pregnancy were included. Women who had private antenatal care often had frequent scans in the third trimester. Women who did not have private antenatal care often had scans infrequently. The still birth rate was calculated for both groups of women from 2007 to 2011 and compared using a Chi-squared analysis Results Our study included 23,519 ‘low-risk’ deliveries spanning 2007-2011. This included 2,088 (9%) patients who had frequent ultrasound surveillance and delivery at term and 21,431 (91%) patients who did not. The overall stillbirth rate was 0.34% and 0.20% respectively which was not statistically different (p=0.31). Conclusion There is no difference in the rate of stillbirth between patients who have more frequent ante-natal ultrasound surveillance compared with those who do not in a low risk population. PMID:26170484

  13. AN EXTRACT OF PENICILLIUM CHRYSOGENUM INDUCES DOSE-DEPENDENT ALLERGIC ASTHMA RESPONSES IN MICE

    EPA Science Inventory

    Rationale: Penicillium chrysogenum, a common indoor mold, is known to have several allergens and can induce allergic responses in a mouse model of allergic penicilliosis. Our hypothesis is that soluble components of P. chrysogenum (PCE) can dose-dependently induce responses typ...

  14. Marijuana’s Dose-Dependent Effects in Daily Marijuana Smokers

    PubMed Central

    Ramesh, Divya; Haney, Margaret; Cooper, Ziva D.

    2015-01-01

    Active marijuana produces significant subjective, psychomotor, and physiological effects relative to inactive marijuana, yet demonstrating that these effects are dose-dependent has proven difficult. This within-subject, double-blind study was designed to develop a smoking procedure to obtain a marijuana dose–response function. In four outpatient laboratory sessions, daily marijuana smokers (N = 17 males, 1 female) smoked six 5-s puffs from 3 marijuana cigarettes (2 puffs/cigarette). The number of puffs from active (≥5.5% Δ9-tetrahydrocannabinol/THC) and inactive (0.0% THC) marijuana varied according to condition (0, 2, 4, or 6 active puffs); active puffs were always smoked before inactive puffs. Subjective, physiological, and performance effects were assessed prior to and at set time points after marijuana administration. Active marijuana dose-dependently increased heart rate and decreased marijuana craving, despite evidence (carbon monoxide expiration, weight of marijuana cigarettes post-smoking) that participants inhaled less of each active marijuana cigarette than inactive cigarettes. Subjective ratings of marijuana “strength,” “high,” “liking,” “good effect,” and “take again” were increased by active marijuana compared with inactive marijuana, but these effects were not dose-dependent. Active marijuana also produced modest, non-dose-dependent deficits in attention, psychomotor function, and recall relative to the inactive condition. In summary, although changes in inhalation patterns as a function of marijuana strength likely minimized the difference between dose conditions, dose-dependent differences in marijuana’s cardiovascular effects and ratings of craving were observed, whereas subjective ratings of marijuana effects did not significantly vary as a function of dose. PMID:23937597

  15. Strontium Ranelate Reduces the Fracture Incidence in a Growing Mouse Model of Osteogenesis Imperfecta.

    PubMed

    Shi, Changgui; Hu, Bo; Guo, Lei; Cao, Peng; Tian, Ye; Ma, Jun; Chen, Yuanyuan; Wu, Huiqiao; Hu, Jinquan; Deng, Lianfu; Zhang, Ying; Yuan, Wen

    2016-05-01

    Osteogenesis imperfecta (OI) is a genetic bone dysplasia characterized by brittle bones with increased fracture risk. Although current treatment options to improve bone strength in OI focus on antiresorptive bisphosphonates, controlled clinical trials suggest they have an equivocal effect on reducing fracture risk. Strontium ranelate (SrR) is a promising therapy with a dual mode of action that is capable of simultaneously maintaining bone formation and reducing bone resorption, and may be beneficial for the treatment of OI. In this study, SrR therapy was investigated to assess its effects on fracture frequency and bone mass and strength in an animal model of OI, the oim/oim mouse. Three-week-old oim/oim and wt/wt mice were treated with either SrR or vehicle (Veh) for 11 weeks. After treatment, the average number of fractures sustained by SrR-treated oim/oim mice was significantly reduced compared to Veh-treated oim/oim mice. Micro-computed tomographic (μCT) analyses of femurs showed that both trabecular and cortical bone mass were significantly improved with SrR treatment in both genotypes. SrR significantly inhibited bone resorption, whereas bone formation indices were maintained. Biomechanical testing revealed improved bone structural properties in both oim/oim and wild-type (wt/wt) mice under the treatment, whereas no significant effects on bone brittleness and material quality were observed. In conclusion, SrR was able to effectively reduce fractures in oim/oim mice by improving bone mass and strength and thus represents a potential therapy for the treatment of pediatric OI. © 2015 American Society for Bone and Mineral Research. PMID:26679066

  16. High frequency of IL-4 producing helper T lymphocytes associated with a reduced incidence of heart allograft rejection.

    PubMed

    Van Hoffen, E; Polen, E; Robertus-Teunissen, M; De Jonge, N; Lahpor, J R; Gmelig-Meyling, F H; De Weger, R A

    2000-01-01

    The reduction in the frequency of rejection episodes several months after heart transplantation (HTX) correlates with the development of donor-specific nonresponsiveness. This is reflected in a reduced frequency of donor-specific cytotoxic T cells (CTL) in the peripheral blood. We investigated whether the reduced CTL frequency and the incidence of rejection episodes coincided with a change in the frequency of either IL-2- or IL-4-producing helper T lymphocytes (HTL). We measured the frequency of HTL before and at several time points after HTX in the blood of ten recipients, using limiting dilution analysis for IL-2 and IL-4. In most patients, HTL frequencies dropped immediately after transplantation, but returned to pre-HTX values later after transplantation. No consistent decrease or increase in frequencies was observed long after HTX. In contrast to IL-2, the HTL frequencies for IL-4 before transplantation were significantly higher in patients without post-HTX rejection episodes requiring treatment than in patients with such episodes. This phenomenon was observed for the in vitro responses towards both donor and third-party cells. In conclusion, relatively high frequencies of IL-4-producing T cells may have a beneficial effect on the outcome of human heart transplantation, because they are associated with a reduced incidence of rejection episodes after transplantation. PMID:11111999

  17. Oral vaccination reduces the incidence of tuberculosis in free-living brushtail possums

    PubMed Central

    Tompkins, D. M.; Ramsey, D. S. L.; Cross, M. L.; Aldwell, F. E.; de Lisle, G. W.; Buddle, B. M.

    2009-01-01

    Bovine tuberculosis (Tb) caused by Mycobacterium bovis has proved refractory to eradication from domestic livestock in countries with wildlife disease reservoirs. Vaccination of wild hosts offers a way of controlling Tb in livestock without wildlife culling. This study was conducted in a Tb-endemic region of New Zealand, where the introduced Australian brushtail possum (Trichosurus vulpecula) is the main wildlife reservoir of Tb. Possums were trapped and vaccinated using a prototype oral-delivery system to deliver the Tb vaccine bacille Calmette–Guerin. Vaccinated and control possums were matched according to age, sex and location, re-trapped bimonthly and assessed for Tb status by palpation and lesion aspiration; the site was depopulated after 2 years and post-mortem examinations were conducted to further identify clinical Tb cases and subclinical infection. Significantly fewer culture-confirmed Tb cases were recorded in vaccinated possums (1/51) compared with control animals (12/71); the transition probability from susceptible to infected was significantly reduced in both males and females by vaccination. Vaccine efficacy was estimated at 95 per cent (87–100%) for females and 96 per cent (82–99%) for males. Hence, this trial demonstrates that orally delivered live bacterial vaccines can significantly protect wildlife against natural disease exposure, indicating that wildlife vaccination, along with existing control methods, could be used to eradicate Tb from domestic animals. PMID:19493904

  18. Reduced incidence of bone metastases in irradiated areas after external radiation therapy of prostatic carcinoma

    SciTech Connect

    Jacobsson, H.; Naeslund, I. )

    1991-06-01

    Fourteen males, out of 380 patients, treated with radiation to the central pelvis and lumbar spine for poorly differentiated prostatic carcinoma were analyzed in retrospect. The dose of radiation to the bones of the target area was 5,000 cGy. The patients showed no signs of metastases at bone scintigraphy performed in connection with the treatment. In an average of 34 months after finishing radiotherapy, the patients developed metastases at bone scintigraphy. The pattern was similar in all patients. The treated target area appeared as a cold zone surrounded by more or less homogenously and strongly increased activity of the axial skeleton, characteristic of bone metastases. Radiography, which was performed in 11 patients, confirmed widespread metastatic disease sparing the target area. This was interpretated as bone metastasis being precluded by the irradiation. The most probable explanation of this finding is eradication in situ of distant micrometastases already present in the bone marrow at the time of treatment. An alternate explanation is a reduced implantation of later seeded blood-born metastases as an effect of the irradiation. The characteristic pattern of this phenomenon must be recognized at bone scintigraphy.

  19. Low cost antiviral activity of Plodia interpunctella haemolymph in vivo demonstrated by dose dependent infection.

    PubMed

    Saejeng, A; Siva-Jothy, M T; Boots, M

    2011-02-01

    Given the ubiquity of infectious disease it is important to understand the way in which hosts defend themselves and any costs that they may pay for this defence. Despite this, we know relatively little about insect immune responses to viruses when compared to their well-characterized responses to other pathogens. In particular it is unclear whether there is significant haemocoelic response to viral infection. Here we directly examine this question by examining whether there is a dose-dependency in infection risk when a DNA virus is injected directly into the haemocoel. Infection from direct injection into the haemocoel showed a clear dose dependency that is indicative of an active intrahaemocoelic immune response to DNA viruses in insects. In contrast to the natural oral infection route, we found no measurable sublethal effects in the survivors from direct injection. This suggests that the immune responses in the haemocoel are less costly than those that occur earlier.

  20. Dose-dependent on reversible effects of lead on rat dopaminergic system

    SciTech Connect

    Memo, M.; Lucchi, L.; Spano, P.F.; Trabucchi, M.

    1981-02-16

    It has been suggested that hyperactivity and mental retardation, the most serious clinical aspects observed in children during lead intoxication, may occur as consequence of specific alterations of neurotransmitter functions. In our experiments we indicate that the behavioural patterns observed in chronically lead exposed rats may be correlated with an impairment of the dopaminergic system. Performing our study at two different levels of lead exposure, we found a dose-dependent change in dopamine turnover. Moreover, 30 days after the last assumption of lead we observed a complete disappearance of these neurochemical variations. Our findings suggest that lead affects dopamine function in different brain areas in reversible manner, inducing effects which are dose-dependent.

  1. Dose-dependent model of caffeine effects on human vigilance during total sleep deprivation.

    PubMed

    Ramakrishnan, Sridhar; Laxminarayan, Srinivas; Wesensten, Nancy J; Kamimori, Gary H; Balkin, Thomas J; Reifman, Jaques

    2014-10-01

    Caffeine is the most widely consumed stimulant to counter sleep-loss effects. While the pharmacokinetics of caffeine in the body is well-understood, its alertness-restoring effects are still not well characterized. In fact, mathematical models capable of predicting the effects of varying doses of caffeine on objective measures of vigilance are not available. In this paper, we describe a phenomenological model of the dose-dependent effects of caffeine on psychomotor vigilance task (PVT) performance of sleep-deprived subjects. We used the two-process model of sleep regulation to quantify performance during sleep loss in the absence of caffeine and a dose-dependent multiplier factor derived from the Hill equation to model the effects of single and repeated caffeine doses. We developed and validated the model fits and predictions on PVT lapse (number of reaction times exceeding 500 ms) data from two separate laboratory studies. At the population-average level, the model captured the effects of a range of caffeine doses (50-300 mg), yielding up to a 90% improvement over the two-process model. Individual-specific caffeine models, on average, predicted the effects up to 23% better than population-average caffeine models. The proposed model serves as a useful tool for predicting the dose-dependent effects of caffeine on the PVT performance of sleep-deprived subjects and, therefore, can be used for determining caffeine doses that optimize the timing and duration of peak performance.

  2. Dose-dependent model of caffeine effects on human vigilance during total sleep deprivation.

    PubMed

    Ramakrishnan, Sridhar; Laxminarayan, Srinivas; Wesensten, Nancy J; Kamimori, Gary H; Balkin, Thomas J; Reifman, Jaques

    2014-10-01

    Caffeine is the most widely consumed stimulant to counter sleep-loss effects. While the pharmacokinetics of caffeine in the body is well-understood, its alertness-restoring effects are still not well characterized. In fact, mathematical models capable of predicting the effects of varying doses of caffeine on objective measures of vigilance are not available. In this paper, we describe a phenomenological model of the dose-dependent effects of caffeine on psychomotor vigilance task (PVT) performance of sleep-deprived subjects. We used the two-process model of sleep regulation to quantify performance during sleep loss in the absence of caffeine and a dose-dependent multiplier factor derived from the Hill equation to model the effects of single and repeated caffeine doses. We developed and validated the model fits and predictions on PVT lapse (number of reaction times exceeding 500 ms) data from two separate laboratory studies. At the population-average level, the model captured the effects of a range of caffeine doses (50-300 mg), yielding up to a 90% improvement over the two-process model. Individual-specific caffeine models, on average, predicted the effects up to 23% better than population-average caffeine models. The proposed model serves as a useful tool for predicting the dose-dependent effects of caffeine on the PVT performance of sleep-deprived subjects and, therefore, can be used for determining caffeine doses that optimize the timing and duration of peak performance. PMID:24859426

  3. Modelling Gaucher disease progression: long-term enzyme replacement therapy reduces the incidence of splenectomy and bone complications

    PubMed Central

    2014-01-01

    Long-term complications and associated conditions of type 1 Gaucher Disease (GD) can include splenectomy, bone complications, pulmonary hypertension, Parkinson disease and malignancies. Enzyme replacement therapy (ERT) reverses cytopenia and reduces organomegaly. To study the effects of ERT on long-term complications and associated conditions, the course of Gaucher disease was modelled. The cohort consisted of all diagnosed GD patients in the Netherlands. Mutually exclusive disease states were defined as ‘asymptomatic’, ‘signs/symptoms’, ‘recovery’, ‘splenectomy’, ‘bone complication’, ‘multiple complications’ and ‘malignancy’. A natural history (NH) cohort was delineated based upon historical data on Dutch patients before ERT was available. Cumulative incidence curves were composed for progression from each disease state to the next. Two scenarios were applied for the ERT cohort: time to complications was calculated from A. start of ERT; B. entering the previous disease state. Median time for the development of signs and/or symptoms was 30.1 years (N = 73). In the NH cohort (N = 42), 9% had developed a bone complication after 10 years in the signs/symptoms phase, while 21% had undergone a splenectomy. In the ERT cohort (N = 29 (A), N = 28 (B)), 12% (A) or 4% (B) had developed a bone complication after 10 years in this phase and no patient was splenectomized. No patients in the NH cohort recovered, compared to 50% in the ERT cohort after 3.6 years (N = 28 (A)) or 22.4 years (N = 27 (B)) of treatment. Median time from a first to a second complication was 11 years in the NH cohort (N = 31), whereas 16 respectively 14 percent had developed a second complication after 10 years in the ERT cohort (N = 17, scenario A/B). Fourteen percent (scenario A/B) developed an associated malignancy after 10 years in the phase ‘multiple complications’ (N = 23). Associated malignancies occurred almost exclusively in advanced disease stages, therefore it

  4. A rubber-covered ceramic weapon reduces the incidence of dental trauma in recruits during combat basic training.

    PubMed

    Becker, Talia; Ashkenazi, Malka

    2011-10-01

    The effect of a rubber-covered ceramic weapon was assessed on the incidence of dental trauma during basic training, since soldiers are more at risk of impact from a personal weapon. Dental files of soldiers (n = 4,542), who completed 8 months of training during 2008, were analyzed for incidence and type of dental trauma from a personal weapon. A rubber-covered ceramic weapon (n = 2,972) or a conventional one (n = 1,570, control) was used. Dental trauma was 0.4% per 8 months (0.6% per year) from the ceramic weapon and 1.5% per 8 months (2.3% per year) from the conventional one (p<0.001). The most prevalent type of injury was a simple/noncomplicated crown fracture (82% in study group, 75% in control group). The ceramic weapon significantly reduced dental trauma by diminishing the impact while in direct contact with the teeth or by absorbing and/or distributing the impact force. In conclusion, when possible a rubber-covered ceramic weapon should be preferred for basic combat training.

  5. [Experience of using bacteriophages and bitsillin-5 to reduce the incidence of respiratory diseases of bacterial ethiology in military personnel].

    PubMed

    Akimkin, V G; Kalmykov, A A; Aminev, R M; Polyakov, V S; Artebyakin, S V

    2016-02-01

    The authors defined epidemiological efficacy and safety of the use of bacteriophages(streptococcal, staphylococcal, piobakferiophage multipartial) and bitsillin-5 to reduce tonsillitis morbidityand other respiratory diseases with bacterial etiology in groups of servicemen during their formationagainst increase of seasonal morbidity. The results of the use of these preventive agents were evaluatedby a comparative analysis of this disease in experimental and control groups. In total 510 healthy conscriptswere involved into the study. The effectiveness of prophylactic use of bacteriophages and bitsillin-5, whichprovided a reduction in the incidence of respiratory infections of bacterial ethiology, tonsillitis, and otherrespiratory diseases is showed. Recommendations on the choice of drugsfor the prevention of these infections,methods and organization of their application in organized groups are given. PMID:27263210

  6. [Experience of using bacteriophages and bitsillin-5 to reduce the incidence of respiratory diseases of bacterial ethiology in military personnel].

    PubMed

    Akimkin, V G; Kalmykov, A A; Aminev, R M; Polyakov, V S; Artebyakin, S V

    2016-02-01

    The authors defined epidemiological efficacy and safety of the use of bacteriophages(streptococcal, staphylococcal, piobakferiophage multipartial) and bitsillin-5 to reduce tonsillitis morbidityand other respiratory diseases with bacterial etiology in groups of servicemen during their formationagainst increase of seasonal morbidity. The results of the use of these preventive agents were evaluatedby a comparative analysis of this disease in experimental and control groups. In total 510 healthy conscriptswere involved into the study. The effectiveness of prophylactic use of bacteriophages and bitsillin-5, whichprovided a reduction in the incidence of respiratory infections of bacterial ethiology, tonsillitis, and otherrespiratory diseases is showed. Recommendations on the choice of drugsfor the prevention of these infections,methods and organization of their application in organized groups are given.

  7. High interindividual variability in dose-dependent reduction in speed of movement after exposing C. elegans to shock waves.

    PubMed

    Angstman, Nicholas B; Kiessling, Maren C; Frank, Hans-Georg; Schmitz, Christoph

    2015-01-01

    In blast-related mild traumatic brain injury (br-mTBI) little is known about the connections between initial trauma and expression of individual clinical symptoms. Partly due to limitations of current in vitro and in vivo models of br-mTBI, reliable prediction of individual short- and long-term symptoms based on known blast input has not yet been possible. Here we demonstrate a dose-dependent effect of shock wave exposure on C. elegans using shock waves that share physical characteristics with those hypothesized to induce br-mTBI in humans. Increased exposure to shock waves resulted in decreased mean speed of movement while increasing the proportion of worms rendered paralyzed. Recovery of these two behavioral symptoms was observed during increasing post-traumatic waiting periods. Although effects were observed on a population-wide basis, large interindividual variability was present between organisms exposed to the same highly controlled conditions. Reduction of cavitation by exposing worms to shock waves in polyvinyl alcohol resulted in reduced effect, implicating primary blast effects as damaging components in shock wave induced trauma. Growing worms on NGM agar plates led to the same general results in initial shock wave effect in a standard medium, namely dose-dependence and high interindividual variability, as raising worms in liquid cultures. Taken together, these data indicate that reliable prediction of individual clinical symptoms based on known blast input as well as drawing conclusions on blast input from individual clinical symptoms is not feasible in br-mTBI. PMID:25705183

  8. Leptin Within the Subphysiological to Physiological Range Dose Dependently Improves Male Reproductive Function in an Obesity Mouse Model.

    PubMed

    Hoffmann, Annett; Manjowk, Gloria-Maria; Wagner, Isabel Viola; Klöting, Nora; Ebert, Thomas; Jessnitzer, Beate; Lössner, Ulrike; Stukenborg, Jan-Bernd; Blüher, Matthias; Stumvoll, Michael; Söder, Olle; Svechnikov, Konstantin; Fasshauer, Mathias; Kralisch, Susan

    2016-06-01

    Obesity has recently been linked with reduced fertility, and the mechanisms underpinning this effect are currently unknown. The adipokine leptin is dysregulated in obesity and affects reproductive tracts; therefore, we investigated the dose-dependent effects of leptin on Leydig cell function and spermatogenesis. Eight-week-old leptin-deficient obese (ob/ob) male mice were treated with subphysiological (0.1- or 0.5-mg/kg body weight [BW]/d) or physiological (3.0-mg/kg BW/d) doses of leptin or saline for 12 weeks (chronic treatment) or 72 hours (acute treatment). We then evaluated male reproductive function markers. Mean testis weight increased significantly in the 0.1- and 3.0-mg/kg BW/d groups compared with saline controls (both P < .05). Intratesticular testosterone levels relative to testis weight significantly increased in the 0.5-mg/kg BW/d group compared with saline controls (P < .05). FSH levels increased in a dose-dependent manner with leptin treatment, whereas LH levels did not change. Leptin treatment significantly up-regulated both mRNA and protein expression of the steroidogenic enzyme cytochrome P450 17A1. Spermatogenesis improved in leptin-treated animals. Significantly more seminiferous tubules were observed in stages I-VIII (P < .01), and there were fewer abnormal seminiferous tubule structures (P < .01). Acute treatment with physiological leptin doses partially improved male reproductive markers without changing BW. Administration of subphysiological to physiological doses of leptin improves Leydig cell function and spermatogenesis.

  9. High interindividual variability in dose-dependent reduction in speed of movement after exposing C. elegans to shock waves

    PubMed Central

    Angstman, Nicholas B.; Kiessling, Maren C.; Frank, Hans-Georg; Schmitz, Christoph

    2015-01-01

    In blast-related mild traumatic brain injury (br-mTBI) little is known about the connections between initial trauma and expression of individual clinical symptoms. Partly due to limitations of current in vitro and in vivo models of br-mTBI, reliable prediction of individual short- and long-term symptoms based on known blast input has not yet been possible. Here we demonstrate a dose-dependent effect of shock wave exposure on C. elegans using shock waves that share physical characteristics with those hypothesized to induce br-mTBI in humans. Increased exposure to shock waves resulted in decreased mean speed of movement while increasing the proportion of worms rendered paralyzed. Recovery of these two behavioral symptoms was observed during increasing post-traumatic waiting periods. Although effects were observed on a population-wide basis, large interindividual variability was present between organisms exposed to the same highly controlled conditions. Reduction of cavitation by exposing worms to shock waves in polyvinyl alcohol resulted in reduced effect, implicating primary blast effects as damaging components in shock wave induced trauma. Growing worms on NGM agar plates led to the same general results in initial shock wave effect in a standard medium, namely dose-dependence and high interindividual variability, as raising worms in liquid cultures. Taken together, these data indicate that reliable prediction of individual clinical symptoms based on known blast input as well as drawing conclusions on blast input from individual clinical symptoms is not feasible in br-mTBI. PMID:25705183

  10. Dose-dependent, protective effect of FK506 against white matter changes in the rat brain after chronic cerebral ischemia.

    PubMed

    Wakita, H; Tomimoto, H; Akiguchi, I; Kimura, J

    1998-05-01

    Neuroprotective effects of immunosuppressive agents have been shown in cerebral ischemia. To investigate the role of immunosuppressive agents in chronic cerebral ischemia and to design a drug protocol with safe therapeutic windows, we examined the effects of FK506, a potent immunosuppressive agent, on chronic cerebral ischemia. Both common carotid arteries were ligated in 73 male Wistar rats. Fifty-eight of these rats received a chronic injection of FK506 (0.2, 0.5, 1.0 mg/kg) and the remaining 15 received a vehicle solution injection. Microglia/macrophage was investigated with immunohistochemistry for leukocyte common antigen and major histocompatibility complex, and astroglia was examined with glial fibrillary acidic protein as markers. White matter rarefaction and the number of immunopositive glial cells were assessed from 7 to 30 days after the ligation. In the vehicle-treated animals, there was persistent and extensive activation of the microglia/macrophages and astroglia in the white matter, including the optic nerve, optic tract, corpus callosum, internal capsule, anterior commissure and traversing fiber bundles of the caudoputamen. In the FK506-treated rats, the number of activated microglia/macrophages was significantly reduced in a dose-dependent manner (p<0.01) as compared to the vehicle-treated rats. Rarefaction of the white matter was also inhibited by FK506 in a dose-dependent manner (p<0. 01). Thus, a clinically-relevant dosage of FK506 attenuated both glial activation and white matter changes in chronic cerebral ischemia in the rat. These results indicate a potential use for FK506 in cerebrovascular diseases.

  11. Leveraging management strategies for seedborne plant diseases to reduce Salmonella enterica Serovar Typhimurium incidence on tomato seed and seedlings.

    PubMed

    Lewis Ivey, Melanie L; Xu, Xiulan; Miller, Sally A

    2014-03-01

    Tomatoes have been linked to many outbreaks of salmonellosis over the last decade, but the routes of contamination have yet to be discerned. Many phytopathogens of tomato are seedborne and are effectively managed using seed sanitizers. Seed sanitizers effective against bacterial phytopathogens were evaluated for their efficacy in killing bioluminescent Salmonella enterica serovar Typhimurium strain SeT-A14 on tomato seed infested with moderately high and high levels of pathogen. SeT-A14 incidence on seedlings produced from contaminated seed following sanitation was also determined. At a moderately high infestation rate (40%), SeT-A14 was eradicated on seed sanitized with 1.2% sodium hypochlorite (NaClO) mixed with 0.03% surfactant for 2 min, hydrochloric acid (HCl) for 30 min, and trichloromelamine for 2 min. At a higher infestation rate (94%), only NaClO and HCl were effective in eradicating SeT-A14 from the seed. At both infestation rates, 2% Virkon-S for 15 min significantly reduced SeT-A14 incidence compared with the nontreated infested controls but did not eradicate the pathogen. Hot water, a commonly used sanitizer for managing seedborne bacterial plant diseases, significantly reduced SeT-A14 on heavily infested seed, but incidence was still moderate at 17.5%. On seedlings produced from moderately highly infested seed, SeT-A14 was not detected using RapidChek Salmonella test strips. Using heavily infested seed, SeT-A14 was detected with the test strips in one of four pooled samples of 14-day-old seedlings produced from nonsanitized seed and from seed sanitized with hot water and trichloromelamine. However, bioluminescence was not observed on 14-day-old seedlings. To our knowledge, this is the first report that provides evidence that S. enterica serovar Typhimurium can be seed transmitted and can lead to the contamination of tomato seedlings. In addition to eliminating important bacterial phytopathogens from tomato seed, NaClO or HCl may mitigate the risk of

  12. Short term cadmium administration dose dependently elicits immediate biochemical, neurochemical and neurobehavioral dysfunction in male rats.

    PubMed

    Haider, Saida; Anis, Lubna; Batool, Zehra; Sajid, Irfan; Naqvi, Fizza; Khaliq, Saima; Ahmed, Shoaib

    2015-02-01

    Cadmium is a toxic environmental and industrial pollutant. Cadmium toxicity has been reported to produce biochemical and behavioral dysfunction that may cause adverse effects on several organs including the central nervous system. The present study was designed to investigate the neurotoxic effects of Cadmium Chloride (CdCl2) at three different doses by using different behavioral models. Lipid peroxidation (LPO), superoxide dismutase (SOD) and acetylcholinesterase (AChE) activities were also monitored following acute intraperitoneal injection of cadmium. Twenty four adult locally bred Albino Wistar rats were divided into control and 3 test groups (n = 6). Control rats were injected intraperitoneally with saline (0.9% NaCl) and test groups were injected with CdCl2 (1 mg/kg, 2 mg/kg and 3 mg/kg) dissolved in physiological solution. Behavioral activities of rats were monitored after 1 h of cadmium injection. Locomotor activity and depression-like symptoms were measured by Open Field Test (OFT) and Forced Swimming Test (FST) respectively. Anxiety like behavior was monitored using Light-dark Transition (LDT) test and memory functions of rats were assessed by Morris Water Maze test (MWM). In the present study acute cadmium administration dose dependently increased anxiety in rats as compared to control rats. A significant increase in depression-like symptoms was also exhibited by cadmium treated rats. These behavioral dysfunctions may be attributed to the decreased superoxide dismutase (SOD) activity and simultaneously increased brain lipid peroxidation (LPO). Moreover learning and memory assessed by MWM showed dose dependent impairment in memory function in cadmium treated rats as compared to control rats. Acetylcholinesterase (AChE) activity was also decreased in brains of cadmium administered rats. It is suggested in this study that behavioral, biochemical and neurochemical dysfunctions caused by acute cadmium administration occur in a dose dependent manner.

  13. Dose-dependent effect of antipsychotic drugs on autonomic nervous system activity in schizophrenia

    PubMed Central

    2012-01-01

    Background Antipsychotic drugs are considered a trigger factor for autonomic dysregulation, which has been shown to predict potentially fatal arrhythmias in schizophrenia. However, the dose-dependent effect of antipsychotic drugs and other psychotropic drugs on autonomic nervous system (ANS) activity remain unclear. The purpose of this study was to investigate the dose-dependent effect of antipsychotic drugs and other clinical factors on ANS activity in an adequate sample size of patients with schizophrenia. Methods A total of 211 Japanese patients with schizophrenia and 44 healthy subjects participated in this study. ANS activity was assessed by means of heart rate variability (HRV) power spectral analysis. Antipsychotic drug treatment and various clinical factors were investigated for each participant. The patient group was categorized into three subgroups according to daily dose of antipsychotic drug, and HRV was compared between groups. Results The results showed significantly decreased low-frequency and high-frequency components of HRV in the patient group compared to the control group. The high-dose group showed a significantly lower HRV than the medium-dose group and an even lower HRV than the low-dose group. In addition, a significant association between HRV and antipsychotic drug dose was identified by multiple regression analysis. HRV was not associated with age, sex, body mass index, duration of illness, or daily dose of other psychotropic drugs. Conclusion These results suggest that antipsychotic drugs exert a significant dose-dependent effect on the extent of decline in ANS activity, and that optimal antipsychotic medication is required to avoid possible cardiovascular adverse events in patients with schizophrenia. PMID:23151241

  14. PEGylated cholecystokinin prolongs satiation in rats: dose dependency and receptor involvement

    PubMed Central

    Verbaeys, I; León-Tamariz, F; Buyse, J; De Cuyper, M; Pottel, H; Van Boven, M; Cokelaere, M

    2007-01-01

    Background and purpose: Acute intraperitoneal (i.p.) administration of cholecystokinin (CCK) is known to induce a significant, but short-lasting, reduction in food intake, followed by recovery within hours. Therefore, we had covalently coupled CCK to a 10 kDa polyethylene glycol and showed that this conjugate, PEG-CCK9, produced a significantly longer anorectic effect than unmodified CCK9. The present study assessed the dose–dependency of this response and the effect of two selective CCK1 receptor antagonists, with different abilities to cross the blood-brain barrier (BBB), on PEG-CCK9-induced anorexia. Experimental approach: Food intake was measured, for up to 23 h, after i.p. administration of different doses (2, 4, 8, 16 and 32 μg kg−1) of CCK9 or PEG-CCK9 in male Wistar rats. Devazepide (100 μg kg−1), which penetrates the BBB or 2-NAP (3 mg kg−1), which does not cross the BBB, were coadministered i.p. with PEG-CCK9 (6 μg kg−1) and food intake was monitored. Key results: In PEG-CCK9-treated rats, a clear dose-dependency was seen for both the duration and initial intensity of the anorexia whereas, for CCK9, only the initial intensity was dose-dependent. Intraperitoneal administration of devazepide or 2-NAP, injected immediately prior to PEG-CCK9, completely abolished the anorectic effect of PEG-CCK9. Conclusions and implications: The duration of the anorexia for PEG-CCK9 was dose-dependent, suggesting that PEGylation of CCK9 increases its circulation time. Both devazepide and 2-NAP completely abolished the anorectic effect of i.p. PEG-CCK9 indicating that its anorectic effect was solely due to stimulation of peripheral CCK1 receptors. PMID:17618299

  15. Dose-dependent inhibition of gastric injury by hydrogen in alkaline electrolyzed drinking water

    PubMed Central

    2014-01-01

    Background Hydrogen has been reported to relieve damage in many disease models, and is a potential additive in drinking water to provide protective effects for patients as several clinical studies revealed. However, the absence of a dose–response relationship in the application of hydrogen is puzzling. We attempted to identify the dose–response relationship of hydrogen in alkaline electrolyzed drinking water through the aspirin induced gastric injury model. Methods In this study, hydrogen-rich alkaline water was obtained by adding H2 to electrolyzed water at one atmosphere pressure. After 2 weeks of drinking, we detected the gastric mucosal damage together with MPO, MDA and 8-OHdG in rat aspirin induced gastric injury model. Results Hydrogen-dose dependent inhibition was observed in stomach mucosal. Under pH 8.5, 0.07, 0.22 and 0.84 ppm hydrogen exhibited a high correlation with inhibitory effects showed by erosion area, MPO activity and MDA content in the stomach. Gastric histology also demonstrated the inhibition of damage by hydrogen-rich alkaline water. However, 8-OHdG level in serum did not have significant hydrogen-dose dependent effect. pH 9.5 showed higher but not significant inhibitory response compared with pH 8.5. Conclusions Hydrogen is effective in relieving the gastric injury induced by aspirin-HCl, and the inhibitory effect is dose-dependent. The reason behind this may be that hydrogen-rich water directly interacted with the target tissue, while the hydrogen concentration in blood was buffered by liver glycogen, evoking a suppressed dose–response effect. Drinking hydrogen-rich water may protect healthy individuals from gastric damage caused by oxidative stress. PMID:24589018

  16. Dietary garlic and onion reduce the incidence of atherogenic diet-induced cholesterol gallstones in experimental mice.

    PubMed

    Vidyashankar, Satyakumar; Sambaiah, Kari; Srinivasan, Krishnapura

    2009-06-01

    Mice fed with diet containing 0.5 % cholesterol for 10 weeks resulted in cholesterol supersaturation in gallbladder bile which promoted the formation of cholesterol gallstones (CGS). In this study, dietary hypocholesterolaemic spices, garlic and onion (both raw or heat-processed) were examined for their antilithogenic potential by including at 0.6 and 2.0 % level, respectively, along with lithogenic (LG) diet for 10 weeks. Dietary garlic and onion reduced the CGS incidence by 15-39 %, the effect being maximum in the heat-processed onion group. Dietary garlic and onion markedly reduced biliary cholesterol. The cholesterol:phospholipid ratio which was 1.58 in the LG diet group was reduced to 0.73-0.96 in the garlic and onion groups. The biliary cholesterol saturation index was 0.92, 1.25, 1.09 and 0.86, respectively, in the heat-processed onion, raw garlic, heat-processed garlic and raw onion groups, while it was 1.9 in the LG group. The hydrophobicity index of bile was - 0.08, - 0.079, - 0.032 and - 0.073, respectively, in the heat-processed onion, raw garlic, heat-processed garlic and raw onion groups, while it was +0.054 in the LG group. Hepatic hydroxymethyl glutaryl-CoA reductase activity was lowered in the LG diet-fed group, while dietary garlic or onion countered this alteration and also increased the activities of hepatic cholesterol 7 alpha-hydroxylase and sterol 27-hydroxylase. Serum and liver cholesterol were decreased by feeding garlic or onion compared to the LG diet. Thus, dietary Allium spices exerted antilithogenic influence by decreasing the cholesterol hyper-secretion into bile and increasing the bile acid output thus decreasing the formation of lithogenic bile in experimental mice.

  17. Reduced energy intake and moderate exercise reduce mammary tumor incidence in virgin female BALB/c mice treated with 7,12-dimethylbenz(a)anthracene

    NASA Technical Reports Server (NTRS)

    Lane, Helen W.; Teer, Patricia; Keith, Robert E.; White, Marguerite T.; Strahan, Susan

    1991-01-01

    The concurrent effects of diet (standard AIN-76A, restricted AIN-76A and high-fat diet) and moderate rotating-drum treadmill exercise on the incidence of 7,12-dimethylbenz(a)anthracene-induced mammary carcinomas in virgin female BALB/cMed mice free of murine mammary tumor virus are evaluated. Analyses show that, although energy intake was related to mammary tumor incidence, neither body weight nor dietary fat predicted tumor incidence.

  18. Use of a laser beam with an oblique angle of incidence to measure the reduced scattering coefficient of a turbid medium

    NASA Astrophysics Data System (ADS)

    Wang, Lihong; Jacques, Steven L.

    1995-05-01

    A simple and quick approach is used to measure the reduced scattering coefficient ( mu s `) of a semi-infinite turbid medium having a much smaller absorption coefficient than mu s`. A laser beam with an oblique angle of incidence to the medium causes the center of the diffuse reflectance that is several transport mean-free paths away from the incident point to shift away from the point of incidence by an amount Delta x. This amount is used to compute mu s` by mu s` = sin( alpha i)/(n Delta x), where n is the refractive index of the turbid medium divided by that of the incident medium and alpha i is the angle of incidence measured from the surface normal. For a turbid medium having an absorption coefficient comparable with mu s `, a revision to the above formula is made. This method is tested theoretically by Monte Carlo simulations and experimentally by a video reflectometer.

  19. The variation of sonic plesio-velocity in dose dependent lathyritic rabbit femurs.

    PubMed

    Lees, S; Barnard, S M; Churchill, D

    1987-01-01

    It has been hypothesized that the origin of the increased elastic modulus of mineralized bone compared with the demineralized bone matrix is in the higher crosslinking density of the collagen in bone. Osteolathyrism is ascribed to an inhibition of crosslinking of the collagen by the lathyrogen and should be accompanied by a decrease in the elastic modulus of the bone. Dose dependent osteolathyrism was induced by varying the amount of BAPN ingested per day by young New Zealand white rabbits until they were mature. The femurs exhibited dose dependent properties, including wet bone density and sonic plesio-velocity in the radial direction. It was found that there is no minimum critical dose. Even though no overt osteolathyritic stigmata could be observed, both the sonic properties and the wet bone density could be affected at any dose level. The sonic plesio-velocity and the longitudinal elastic modulus decreased with BAPN dose level, most rapidly at the lower dose levels and then less so at higher dosages. Since BAPN acts to inhibit the crosslinking density, it appears that the elastic moduli of bone are dependent on the crosslinking density.

  20. Dose dependence of strength after low-temperature irradiation in metallic materials

    SciTech Connect

    Byun, Thak Sang; Li, Meimei; Farrell, Kenneth

    2013-01-01

    This study intends to review and characterize the low-temperature (< 200 oC) irradiation hardening behaviors in metallic materials and to propose new interpretations on the dose dependence of strength, particularly in the pre-hardening and saturation regimes. The analysis results of yield stress-dose curves indicate that four dose-dependence regimes exist: the pre-hardening, main hardening, saturation, and embrittlement regimes. The semi-log plots of yield stress versus dose data revealed that the pre-hardening regime displaying zero-hardening or softening was common at least for the alloys with low dose data available. It was observed that the dose range of the pre-hardening regime increased with the strength of material, which indicates that slower initiation in irradiation hardening is expected when strength is higher. For the majority of the metallic materials analyzed, it was reconfirmed that the exponent of the power-law hardening function was evaluated to be about 0.5 in the main hardening regime and about 0.1 in the saturation regime. In these positive hardening regimes the low strength pure metals such as Fe, Ta, Cu, and Zr displayed lower hardening exponents. The minimum dose to the saturation of irradiation hardening was in the range of 0.003 0.08 dpa, depending on the category of materials. It was also reaffirmed that there exists a strong relationship between the saturation in irradiation hardening and the occurrence of plastic instability at yield.

  1. Analysis of tensile deformation and failure in austenitic stainless steels: Part II - Irradiation dose dependence

    NASA Astrophysics Data System (ADS)

    Kim, Jin Weon; Byun, Thak Sang

    2010-01-01

    Irradiation effects on the stable and unstable deformation and fracture behavior of austenitic stainless steels (SSs) have been studied in detail based on the equivalent true stress versus true strain curves. An iterative finite element simulation technique was used to obtain the equivalent true stress-true strain data from experimental tensile curves. The simulation result showed that the austenitic stainless steels retained high strain hardening rate during unstable deformation even after significant irradiation. The strain hardening rate was independent of irradiation dose up to the initiation of a localized necking. Similarly, the equivalent fracture stress was nearly independent of dose before the damage (embrittlement) mechanism changed. The fracture strain and tensile fracture energy decreased with dose mostly in the low dose range <˜2 dpa and reached nearly saturation values at higher doses. It was also found that the fracture properties for EC316LN SS were less sensitive to irradiation than those for 316 SS, although their uniform tensile properties showed almost the same dose dependencies. It was confirmed that the dose dependence of tensile fracture properties evaluated by the linear approximation model for nominal stress was accurate enough for practical use without elaborate calculations.

  2. Deferasirox at therapeutic doses is associated with dose-dependent hypercalciuria.

    PubMed

    Wong, Phillip; Polkinghorne, Kevan; Kerr, Peter G; Doery, James C G; Gillespie, Matthew T; Larmour, I; Fuller, Peter J; Bowden, Donald K; Milat, Frances

    2016-04-01

    Deferasirox is an oral iron chelator used widely in the treatment of thalassemia major and other transfusion-dependent hemoglobinopathies. Whilst initial long-term studies established the renal safety of deferasirox, there are now increasing reports of hypercalciuria and renal tubular dysfunction. In addition, urolithiasis with rapid loss of bone density in patients with β thalassemia major has been reported. We conducted a cross-sectional cohort study enrolling 152 adult patients comprising of β thalassemia major (81.5%), sickle cell disease (8%), thalassemia intermedia (2%), HbH disease (6.5%) and E/β thalassemia (2%). Cases were matched with normal control subjects on age, gender and serum creatinine. Iron chelator use was documented and urine calcium to creatinine ratios measured. At the time of analysis, 88.8% of patients were receiving deferasirox and 11.2% were on deferoxamine. Hypercalciuria was present in 91.9% of subjects on deferasirox in a positive dose-dependent relationship. This was not seen with subjects receiving deferoxamine. At a mean dose of 30.2±8.8mg/kg/day, deferasirox was associated with an almost 4 fold increase in urine calcium to creatinine ratio (UCa/Cr). Hypercalciuria was present at therapeutic doses of deferasirox in a dose-dependent manner and warrants further investigation and vigilance for osteoporosis, urolithiasis and other markers of renal dysfunction. PMID:26802257

  3. Dose Dependence of Strength After Low-Temperature Irradiation in Metallic Materials

    NASA Astrophysics Data System (ADS)

    Byun, Thak Sang; Li, Meimei; Farrell, Kenneth

    2013-01-01

    This study intends to review and characterize the low-temperature (<473 K [200 °C]) irradiation-hardening behaviors in metallic materials and to propose new interpretations on the dose dependence of strength, particularly in the prehardening and saturation regimes. The analysis of results of yield stress-dose curves indicate that four dose-dependence regimes exist: the prehardening, main hardening, saturation, and embrittlement regimes. The semilog plots of yield stress vs dose data revealed that the prehardening regime displaying zero hardening or softening was common at least for the alloys with low-dose data available. It was observed that the dose range of the prehardening regime increased with the strength of material, which indicates that slower initiation in irradiation hardening is expected when strength is higher. For the majority of the metallic materials analyzed, it was reconfirmed that the exponent of the power-law hardening function was evaluated to be about 0.5 in the main hardening regime and about 0.1 in the saturation regime. In these positive hardening regimes, the low strength pure metals such as Fe, Ta, Cu, and Zr displayed lower hardening exponents. The minimum dose to the saturation of irradiation hardening was in the range of 0.003 to 0.08 dpa, depending on the category of materials. It was also reaffirmed that there exists a strong relationship between the saturation in irradiation hardening and the occurrence of plastic instability at yield.

  4. The P-element-induced silencing effect of KP transposons is dose dependent in Drosophila melanogaster.

    PubMed

    Sameny, Alireza; Locke, John

    2011-09-01

    Transposable elements are found in the genomes of all eukaryotes and play a critical role in altering gene expression and genome organization. In Drosophila melanogaster, transposable P elements are responsible for the phenomenon of hybrid dysgenesis. KP elements, a deletion-derivative of the complete P element, can suppress this mutagenic effect. KP elements can also silence the expression of certain other P-element-mediated transgenes in a process called P-element-dependent silencing (PDS), which is thought to involve the recruitment of heterochromatin proteins. To explore the mechanism of this silencing, we have mobilized KP elements to create a series of strains that contain single, well-defined KP insertions that show PDS. To understand the quantitative role of KP elements in PDS, these single inserts were combined in a series of crosses to obtain genotypes with zero, one, or two KP elements, from which we could examine the effect of KP gene dose. The extent of PDS in these genotypes was shown to be dose dependent in a logarithmic rather than linear fashion. A logarithmic dose dependency is consistent with the KP products interacting with heterochromatic proteins in a concentration-dependent manner such that two molecules are needed to induce gene silencing. PMID:21888571

  5. Case Study: Nutritional and Lifestyle Support to Reduce Infection Incidence in an International-Standard Premier League Soccer Player.

    PubMed

    Ranchordas, Mayur K; Bannock, Laurent; Robinson, Scott L

    2016-04-01

    Professional soccer players are exposed to large amounts of physiological and psychological stress, which can increase infection risk and threaten availability for training and competition. Accordingly, it is important for practitioners to implement strategies that support player well-being and prevent illness. This case study demonstrates how a scientifically supported and practically applicable nutrition and lifestyle strategy can reduce infection incidence in an illness-prone professional soccer player. In the 3 months before the intervention, the player had 3 upper-respiratory tract infections (URTIs) and subsequently missed 3 competitive matches and 2 weeks' training. He routinely commenced morning training sessions in the fasted state and was estimated to be in a large daily energy deficit. Throughout the 12-week intervention, the amount, composition, and timing of energy intake was altered, quercetin and vitamin D were supplemented, and the player was provided with a daily sleep and hygiene protocol. There was a positive increase in serum vitamin D 25(OH) concentration from baseline to Week 12 (53 n·mol-1 to 120 n·mol-1) and salivary immunoglobulin-A (98 mg·dl-1 to 135 mg·dl-1), as well as a decline in the number of URTI symptoms (1.8 ± 2.0 vs. 0.25 ± 0.5 for Weeks 0-4 and Weeks 8-12, respectively). More important, he maintained availability for all training and matches over the 12-week period. We offer this case study as a real-world applied example for other players and practitioners seeking to deploy nutrition and lifestyle strategies to reduce risk of illness and maximize player availability. PMID:26479983

  6. Expression of the human PAC1 receptor leads to dose-dependent hydrocephalus-related abnormalities in mice

    PubMed Central

    Lang, Bing; Song, Bing; Davidson, Wendy; MacKenzie, Alastair; Smith, Norman; McCaig, Colin D.; Harmar, Anthony J.; Shen, Sanbing

    2006-01-01

    Hydrocephalus is a common and potentially devastating birth defect affecting the CNS, and its relationship with G protein–coupled receptors (GPCRs) is unknown. We have expressed 2, 4, or 6 copies of a GPCR — the human PAC1 receptor with a 130-kb transgene in the mouse nervous system in a pattern closely resembling that of the endogenous gene. Consistent with PAC1 actions, PKA and PKC activity were elevated in the brains of Tg mice. Remarkably, Tg mice developed dose-dependent hydrocephalus-like characteristics, including enlarged third and lateral ventricles and reduced cerebral cortex, corpus callosum, and subcommissural organ (SCO). Neuronal proliferation and apoptosis were implicated in hydrocephalus, and we observed significantly reduced neuronal proliferation and massively increased neuronal apoptosis in the developing cortex and SCO of Tg embryos, while neurite outgrowth and neuronal migration in vitro remain uncompromised. Ventricular ependymal cilia are crucial for directing cerebrospinal fluid flow, and ependyma of Tg mice exhibited disrupted cilia with increased phospho-CREB immunoreactivity. These data demonstrate that altered neuronal proliferation/apoptosis and disrupted ependymal cilia are the main factors contributing to hydrocephalus in PAC1-overexpressing mice. This is the first report to our knowledge demonstrating that misregulation of GPCRs can be involved in hydrocephalus-related neurodevelopmental disorders. PMID:16823490

  7. Argon Inhalation Attenuates Retinal Apoptosis after Ischemia/Reperfusion Injury in a Time- and Dose-Dependent Manner in Rats

    PubMed Central

    Ulbrich, Felix; Schallner, Nils; Coburn, Mark; Loop, Torsten; Lagrèze, Wolf Alexander; Biermann, Julia; Goebel, Ulrich

    2014-01-01

    Purpose Retinal ischemia and reperfusion injuries (IRI) permanently affect neuronal tissue and function by apoptosis and inflammation due to the limited regenerative potential of neurons. Recently, evidence emerged that the noble gas Argon exerts protective properties, while lacking any detrimental or adverse effects. We hypothesized that Argon inhalation after IRI would exert antiapoptotic effects in the retina, thereby protecting retinal ganglion cells (RGC) of the rat's eye. Methods IRI was performed on the left eyes of rats (n = 8) with or without inhaled Argon postconditioning (25, 50 and 75 Vol%) for 1 hour immediately or delayed after ischemia (i.e. 1.5 and 3 hours). Retinal tissue was harvested after 24 hours to analyze mRNA and protein expression of Bcl-2, Bax and Caspase-3, NF-κB. Densities of fluorogold-prelabeled RGCs were analyzed 7 days after injury in whole-mounts. Histological tissue samples were prepared for immunohistochemistry and blood was analyzed regarding systemic effects of Argon or IRI. Statistics were performed using One-Way ANOVA. Results IRI induced RGC loss was reduced by Argon 75 Vol% inhalation and was dose-dependently attenuated by lower concentrations, or by delayed Argon inhalation (1504±300 vs. 2761±257; p<0.001). Moreover, Argon inhibited Bax and Bcl-2 mRNA expression significantly (Bax: 1.64±0.30 vs. 0.78±0.29 and Bcl-2: 2.07±0.29 vs. 0.99±0.22; both p<0.01), as well as caspase-3 cleavage (1.91±0.46 vs. 1.05±0.36; p<0.001). Expression of NF-κB was attenuated significantly. Immunohistochemistry revealed an affection of Müller cells and astrocytes. In addition, IRI induced leukocytosis was reduced significantly after Argon inhalation at 75 Vol%. Conclusion Immediate and delayed Argon postconditioning protects IRI induced apoptotic loss of RGC in a time- and dose-dependent manner, possibly mediated by the inhibition of NF-κB. Further studies need to evaluate Argon's possible role as a therapeutic option. PMID

  8. Consumption of sweetened, dried cranberries may reduce urinary tract infection incidence in susceptible women – a modified observational study

    PubMed Central

    2013-01-01

    Background Urinary tract infections (UTIs) are one of the most common bacterial infections, and over 50% of women will have a UTI during their lifetimes. Antibiotics are used for prophylaxis of recurrent UTIs but can lead to emergence of drug-resistant bacteria. Therefore, it is reasonable to investigate nutritional strategies for prevention of UTIs. Cranberry juices and supplements have been used for UTI prophylaxis, but with variable efficacy. Because dried cranberries may contain a different spectrum of polyphenolics than juice, consuming berries may or may not be more beneficial than juice in decreasing the incidence of UTIs in susceptible women. The primary objectives of this study were to determine if consumption of sweetened, dried cranberries (SDC) decreases recurrent UTIs and whether this intervention would alter the heterogeneity, virulence factor (VF) profiles, or numbers of intestinal E. coli. Methods Twenty women with recurrent UTIs were enrolled in the trial and consumed one serving of SDC daily for two weeks. Clinical efficacy was determined by two criteria, a decrease in the six-month UTI rates pre- and post-consumption and increased time until the first UTI since beginning the study. Strain heterogeneity and virulence factor profiles of intestinal E. coli isolated from rectal swabs were determined by DNA fingerprinting and muliplex PCR, respectively. The numbers of intestinal E. coli eluted from rectal swabs pre- and post-consumption were also quantified. Results Over one-half of the patients did not experience a UTI within six months of SDC consumption, and the mean UTI rate per six months decreased significantly. Kaplan-Meier analysis of infection incidence in women consuming SDC compared to patients in a previous control group showed a significant reduction in time until first UTI within six months. The heterogeneity, VF profiles, and prevalence of intestinal E. coli strains were not significantly different after cranberry consumption

  9. Dose-dependent Nodal/Smad signals pattern the early mouse embryo.

    PubMed

    Robertson, Elizabeth J

    2014-08-01

    Nodal signals in the early post-implantation stage embryo are essential to establish initial proximal-distal (P-D) polarity and generate the final anterior-posterior (A-P) body axis. Nodal signaling in the epiblast results in the phosphorylation of Smad2 in the overlying visceral endoderm necessary to induce the AVE, in part via Smad2-dependent activation of the T-box gene Eomesodermin. Slightly later following mesoderm induction a continuum of dose-dependent Nodal signaling during the process of gastrulation underlies specification of mesodermal and definitive endoderm progenitors. Dynamic Nodal expression during the critical 72 h time window immediately following implantation, accomplished by a series of feed-back and feed-forward mechanisms serves to provide key positional cues required for establishment of the body plan and controls cell fate decisions in the early mammalian embryo. PMID:24704361

  10. Dose-dependent mesothelioma induction by intraperitoneal administration of multi-wall carbon nanotubes in p53 heterozygous mice.

    PubMed

    Takagi, Atsuya; Hirose, Akihiko; Futakuchi, Mitsuru; Tsuda, Hiroyuki; Kanno, Jun

    2012-08-01

    Among various types of multi-wall carbon nanotubes (MWCNT) are those containing fibrous particles longer than 5 μm with an aspect ratio of more than three (i.e. dimensions similar to mesotheliomagenic asbestos). A previous study showed that micrometer-sized MWCNT (μm-MWCNT) administered intraperitoneally at a dose of 3000 μg/mouse corresponding to 1 × 10(9) fibers per mouse induced mesotheliomas in p53 heterozygous mice. Here, we report a dose-response study; three groups of p53 heterozygous mice (n = 20) were given a single intraperitoneal injection of 300 μg/mouse of μm-MWCNT (corresponding to 1 × 10(8) fibers), 30 μg/mouse (1 × 10(7)) or 3 μg/mouse (1 × 10(6)), respectively, and observed for up to 1 year. The cumulative incidence of mesotheliomas was 19/20, 17/20 and 5/20, respectively. The severity of peritoneal adhesion and granuloma formation were dose-dependent and minimal in the lowest dose group. However, the time of tumor onset was apparently independent of the dose. All mice in the lowest dose group that survived until the terminal kill had microscopic atypical mesothelial hyperplasia considered as a precursor lesion of mesothelioma. Right beneath was a mononuclear cell accumulation consisting of CD45- or CD3-positive lymphocytes and CD45/CD3-negative F4/80 faintly positive macrophages; some of the macrophages contained singular MWCNT in their cytoplasm. The lesions were devoid of epithelioid cell granuloma and fibrosis. These findings were in favor of the widely proposed mode of action of fiber carcinogenesis, that is, frustrated phagocytosis where the mesotheliomagenic microenvironment on the peritoneal surface is neither qualitatively altered by the density of the fibers per area nor by the formation of granulomas against agglomerates.

  11. The Abuela Project: safe cheese workshops to reduce the incidence of Salmonella typhimurium from consumption of raw-milk fresh cheese.

    PubMed Central

    Bell, R A; Hillers, V N; Thomas, T A

    1999-01-01

    OBJECTIVES: A multiagency intervention was implemented in Yakima County, Wash, to reduce the incidence of Salmonella serotype Typhimurium infections resulting from eating queso fresco (fresh cheese) made from raw milk, a traditional food in the Hispanic diet. METHODS: A pasteurized-milk queso fresco recipe with taste and texture acceptable to the Hispanic community was developed. Trained Hispanic volunteers conducted safe cheese workshops, which were attended by more than 225 persons. RESULTS: Workshop participants' acceptance of the new recipe was excellent and positive behavior changes were maintained over 6 months. CONCLUSIONS: Educational interventions in Hispanic communities can reduce the incidence of Salmonella Typhimurium associated with eating queso fresco. PMID:10474564

  12. Ozone inhalation leads to a dose-dependent increase of cytogenetic damage in human lymphocytes.

    PubMed

    Holland, Nina; Davé, Veronica; Venkat, Subha; Wong, Hofer; Donde, Aneesh; Balmes, John R; Arjomandi, Mehrdad

    2015-05-01

    Ozone is an important constituent of ambient air pollution and represents a major public health concern. Oxidative injury due to ozone inhalation causes the generation of reactive oxygen species and can be genotoxic. To determine whether ozone exposure causes genetic damage in peripheral blood lymphocytes, we used a well-validated cytokinesis-block micronucleus Cytome assay. Frequencies of micronuclei (MN) and nucleoplasmic bridges (NB) were used as indicators of cytogenetic damage. Samples were obtained from 22 non-smoking healthy subjects immediately before and 24-hr after controlled 4-hr exposures to filtered air, 100 ppb, and 200 ppb ozone while exercising in a repeated-measure study design. Inhalation of ozone at different exposure levels was associated with a significant dose-dependent increase in MN frequency (P < 0.0001) and in the number of cells with more than one MN per cell (P <  .0005). Inhalation of ozone also caused an increase in the number of apoptotic cells (P = 0.002). Airway neutrophilia was associated with an increase in MN frequency (P = 0.033) independent of the direct effects of ozone exposure (P < 0.0001). We also observed significant increases in both MN and NB frequencies after exercise in filtered air, suggesting that physical activity is also an important inducer of oxidative stress. These results corroborate our previous findings that cytogenetic damage is associated with ozone exposure, and show that damage is dose-dependent. Further study of ozone-induced cytogenetic damage in airway epithelial cells could provide evidence for the role of oxidative injury in lung carcinogenesis, and help to address the potential public health implications of exposures to oxidant environments.

  13. Ozone Inhalation Leads to a Dose-Dependent Increase of Cytogenetic Damage in Human Lymphocytes

    PubMed Central

    Holland, Nina; Davé, Veronica; Venkat, Subha; Wong, Hofer; Donde, Aneesh; Balmes, John R; Arjomandi, Mehrdad

    2014-01-01

    Ozone is an important constituent of ambient air pollution and represents a major public health concern. Oxidative injury due to ozone inhalation causes the generation of reactive oxygen species and can be genotoxic. To determine whether ozone exposure causes genetic damage in peripheral blood lymphocytes, we employed a well-validated cytokinesis-block micronucleus Cytome assay. Frequencies of micronuclei (MN) and nucleoplasmic bridges (NB) were used as indicators of cytogenetic damage. Samples were obtained from 22 non-smoking healthy subjects immediately before and 24-hr after controlled 4-hr exposures to filtered air, 100 ppb, and 200 ppb ozone while exercising in a repeated-measure study design. Inhalation of ozone at different exposure levels was associated with a significant dose-dependent increase in MN frequency (P < 0.0001) and in the number of cells with more than 1 MN per cell (P < 0.0005). Inhalation of ozone also caused an increase in the number of apoptotic cells (P = 0.002). Airway neutrophilia was associated with an increase in MN frequency (P = 0.033) independent of the direct effects of ozone exposure (P < 0.0001). We also observed significant increases in both MN and NB frequencies after exercise in filtered air, suggesting that physical activity is also an important inducer of oxidative stress. These results corroborate our previous findings that cytogenetic damage is associated with ozone exposure, and show that damage is dose-dependent. Further study of ozone-induced cytogenetic damage in airway epithelial cells could provide evidence for the role of oxidative injury in lung carcinogenesis, and help to address the potential public health implications of exposures to oxidant environments. PMID:25451016

  14. Dose-Dependent Onset of Regenerative Program in Neutron Irradiated Mouse Skin

    PubMed Central

    Artibani, Mara; Kobos, Katarzyna; Colautti, Paolo; Negri, Rodolfo; Amendola, Roberto

    2011-01-01

    Background Tissue response to irradiation is not easily recapitulated by cell culture studies. The objective of this investigation was to characterize, the transcriptional response and the onset of regenerative processes in mouse skin irradiated with different doses of fast neutrons. Methodology/Principal Findings To monitor general response to irradiation and individual animal to animal variation, we performed gene and protein expression analysis with both pooled and individual mouse samples. A high-throughput gene expression analysis, by DNA oligonucleotide microarray was done with three months old C57Bl/6 mice irradiated with 0.2 and 1 Gy of mono-energetic 14 MeV neutron compared to sham irradiated controls. The results on 440 irradiation modulated genes, partially validated by quantitative real time RT-PCR, showed a dose-dependent up-regulation of a sub-class of keratin and keratin associated proteins, and members of the S100 family of Ca2+-binding proteins. Immunohistochemistry confirmed mRNA expression data enabled mapping of protein expression. Interestingly, proteins up-regulated in thickening epidermis: keratin 6 and S100A8 showed the most significant up-regulation and the least mouse-to-mouse variation following 0.2 Gy irradiation, in a concerted effort toward skin tissue regeneration. Conversely, mice irradiated at 1 Gy showed most evidence of apoptosis (Caspase-3 and TUNEL staining) and most 8-oxo-G accumulation at 24 h post-irradiation. Moreover, no cell proliferation accompanied 1 Gy exposure as shown by Ki67 immunohistochemistry. Conclusions/Significance The dose-dependent differential gene expression at the tissue level following in vivo exposure to neutron radiation is reminiscent of the onset of re-epithelialization and wound healing and depends on the proportion of cells carrying multiple chromosomal lesions in the entire tissue. Thus, this study presents in vivo evidence of a skin regenerative program exerted independently from DNA repair

  15. The administration of Sheng Hua Tang immediately after delivery to reduce the incidence of retained placenta in Holstein dairy cows.

    PubMed

    Cui, Dongan; Wang, Xuezhi; Wang, Lei; Wang, Xurong; Zhang, Jingyan; Qin, Zhe; Li, Jianxi; Yang, Zhiqiang

    2014-03-15

    Sheng Hua Tang, a classical herbal formula consisting of Radix Angelicae sinensis, Ligustici rhizoma, Semen persicae, Zingiberis rhizoma, and Radix glycyrrhizae, is known to be beneficial in alleviating postpartum diseases and facilitating a return to normal reproductive function. This study investigated whether the administration of Sheng Hua Tang within 2 to 4 hours after delivery was effective as a preventive treatment for reducing the risk of retained placenta in Holstein dairy cows. A total of 357 cows, each of which had delivered its calf spontaneously, were randomly allocated to one of two groups. In the treatment group, the cows (n = 175) received Sheng Hua Tang with an oral dose of 0.36 g crude herb per kg·body weight once daily for three consecutive days. The controls (n = 182) received no treatment. The placental retention proportion was 4.0% and 17.0% within 12 hours after delivery in the treated and control animals, respectively (P < 0.01). We found decreases in the calving-to-first-service interval (73.2 ± 25.1 vs. 81.9 ± 32.8 days; P < 0.01), calving-to-conception interval (93.4 ± 38.8 vs. 114.6 ± 42.9 days; P < 0.01), and service per conception (1.5 ± 0.8 vs. 1.9 ± 1.0 days; P < 0.01) in the treatment group compared with the control group. The first artificial insemination conception proportion was higher in the treatment group than in the control group (60.4% vs. 41.1%; P = 0.01). Moreover, the between-group difference in the proportion of cows that were pregnant within 180 days postpartum approached statistical significance (88.2% vs. 80.6%; P = 0.07). Sheng Hua Tang showed beneficial effects in reducing the incidence of retained placenta and improving subsequent reproductive performance in cows. This preventive treatment strategy would be effective in improving the management of puerperal health. The potential benefits of Sheng Hua Tang warrant further investigation to determine whether this preventive treatment strategy can be endorsed as

  16. Dose-dependent effects of dietary Pb and Zn on feeding and growth rates of the landsnail Helix engaddensis.

    PubMed

    Swaileh, K M; Ezzughayyar, A

    2001-09-01

    Dose-dependent effects of dietary lead and zinc on feeding and growth rates of adult Helix engaddensis snails were studied over a 1-month period followed by a 2-week recovery period. Snails were fed on an artificial diet containing the following lead or zinc concentrations= 0, 20, 100, 500, 2500, and 12,500 microg/g dry food. At the end of the 6 weeks, mortality rate among snails fed on Pb-contaminated diet was 18.3% (11/60) and the respective value for Zn-contaminated diet was 50% (30/60). Both metals significantly reduced growth and feeding rates. Snails were found to be sensitive to zinc but tolerant to lead. During the recovery period, snails fed on Zn-contaminated diet failed completely to feed or grow normally, whereas snails fed on Pb-contaminated diet showed signs of slow improvement in terms of feeding and growth rates. The NOEC and LOEC for lead were 100 and 500 microg/g (-1), respectively, while the respective concentrations for zinc were 20 and 100 microg/g (-1).

  17. SHOEBOX Modulates Root Meristem Size in Rice through Dose-Dependent Effects of Gibberellins on Cell Elongation and Proliferation

    PubMed Central

    Li, Jintao; Zhao, Yu; Chu, Huangwei; Wang, Likai; Fu, Yanru; Liu, Ping; Upadhyaya, Narayana; Chen, Chunli; Mou, Tongmin; Feng, Yuqi; Kumar, Prakash; Xu, Jian

    2015-01-01

    Little is known about how the size of meristem cells is regulated and whether it participates in the control of meristem size in plants. Here, we report our findings on shoebox (shb), a mild gibberellin (GA) deficient rice mutant that has a short root meristem size. Quantitative analysis of cortical cell length and number indicates that shb has shorter, rather than fewer, cells in the root meristem until around the fifth day after sowing, from which the number of cortical cells is also reduced. These defects can be either corrected by exogenous application of bioactive GA or induced in wild-type roots by a dose-dependent inhibitory effect of paclobutrazol on GA biosynthesis, suggesting that GA deficiency is the primary cause of shb mutant phenotypes. SHB encodes an AP2/ERF transcription factor that directly activates transcription of the GA biosynthesis gene KS1. Thus, root meristem size in rice is modulated by SHB-mediated GA biosynthesis that regulates the elongation and proliferation of meristem cells in a developmental stage-specific manner. PMID:26275148

  18. SHOEBOX Modulates Root Meristem Size in Rice through Dose-Dependent Effects of Gibberellins on Cell Elongation and Proliferation.

    PubMed

    Li, Jintao; Zhao, Yu; Chu, Huangwei; Wang, Likai; Fu, Yanru; Liu, Ping; Upadhyaya, Narayana; Chen, Chunli; Mou, Tongmin; Feng, Yuqi; Kumar, Prakash; Xu, Jian

    2015-08-01

    Little is known about how the size of meristem cells is regulated and whether it participates in the control of meristem size in plants. Here, we report our findings on shoebox (shb), a mild gibberellin (GA) deficient rice mutant that has a short root meristem size. Quantitative analysis of cortical cell length and number indicates that shb has shorter, rather than fewer, cells in the root meristem until around the fifth day after sowing, from which the number of cortical cells is also reduced. These defects can be either corrected by exogenous application of bioactive GA or induced in wild-type roots by a dose-dependent inhibitory effect of paclobutrazol on GA biosynthesis, suggesting that GA deficiency is the primary cause of shb mutant phenotypes. SHB encodes an AP2/ERF transcription factor that directly activates transcription of the GA biosynthesis gene KS1. Thus, root meristem size in rice is modulated by SHB-mediated GA biosynthesis that regulates the elongation and proliferation of meristem cells in a developmental stage-specific manner.

  19. Dose-dependent reduction of replication elongation rate by (p)ppGpp in Escherichia coli and Bacillus subtilis.

    PubMed

    Denapoli, Jessica; Tehranchi, Ashley K; Wang, Jue D

    2013-04-01

    DNA replication is regulated in response to environmental constraints such as nutrient availability. While much is known about regulation of replication during initiation, little is known about regulation of replication during elongation. In the bacterium Bacillus subtilis, replication elongation is paused upon sudden amino acid starvation by the starvation-inducible nucleotide (p)ppGpp. However, in many bacteria including Escherichia coli, replication elongation is thought to be unregulated by nutritional availability. Here we reveal that the replication elongation rate in E. coli is modestly but significantly reduced upon strong amino acid starvation. This reduction requires (p)ppGpp and is exacerbated in a gppA mutant with increased pppGpp levels. Importantly, high levels of (p)ppGpp, independent of amino acid starvation, are sufficient to inhibit replication elongation even in the absence of transcription. Finally, in both E. coli and B. subtilis, (p)ppGpp inhibits replication elongation in a dose-dependent manner rather than via a switch-like mechanism, although this inhibition is much stronger in B. subtilis. This supports a model where replication elongation rates are regulated by (p)ppGpp to allow rapid and tunable response to multiple abrupt stresses in evolutionarily diverse bacteria.

  20. Dose-Dependent Suppression of Cytokine production from T cells by a Novel Phosphoinositide 3-Kinase Delta Inhibitor

    PubMed Central

    Way, Emily E.; Trevejo-Nunez, Giraldina; Kane, Lawrence P.; Steiner, Bart H.; Puri, Kamal D.; Kolls, Jay K.; Chen, Kong

    2016-01-01

    There remains a significant need for development of effective small molecules that can inhibit cytokine-mediated inflammation. Phosphoinositide 3 kinase (PI3K) is a direct upstream activator of AKT, and plays a critical role in multiple cell signaling pathways, cell cycle progression, and cell growth, and PI3K inhibitors have been approved or are in clinical development. We examined novel PI3Kdelta inhibitors, which are highly selective for the p110delta isoform of in CD3/CD28 stimulated T-cell cytokine production. In vitro generated CD4+ T effector cells stimulated in the presence of a PI3Kdelta inhibitor demonstrated a dose-dependent suppression of cytokines produced by Th1, Th2, and Th17 cells. This effect was T-cell intrinsic, and we observed similar effects on human PBMCs. Th17 cells expressing a constitutively activated form of AKT were resistant to PI3Kdelta inhibition, suggesting that the inhibitor is acting through AKT signaling pathways. Additionally, PI3Kdelta inhibition decreased IL-17 production in vivo and decreased neutrophil recruitment to the lung in a murine model of acute pulmonary inflammation. These experiments show that targeting PI3Kdelta activity can modulate T-cell cytokine production and reduce inflammation in vivo, suggesting that PI3Kdelta inhibition could have therapeutic potential in treating inflammatory diseases. PMID:27461849

  1. Green tea consumption is associated with reduced incident CHD and improved CHD-related biomarkers in the Dongfeng-Tongji cohort

    PubMed Central

    Tian, Chong; Huang, Qiao; Yang, Liangle; Légaré, Sébastien; Angileri, Francesca; Yang, Handong; Li, Xiulou; Min, Xinwen; Zhang, Ce; Xu, Chengwei; Yuan, Jing; Miao, Xiaoping; He, Mei-an; Wu, Tangchun; Zhang, Xiaomin

    2016-01-01

    Prospective studies on the association of green tea with risk of coronary heart disease (CHD) incidence were scarce. This study examined whether green tea can reduce CHD incidence and have a beneficial effect on CHD-related risk markers in middle-aged and older Chinese population. We included 19 471 participants who were free of CHD, stroke or cancer at baseline from September 2008 to June 2010, and were followed until October 2013. Cox proportional hazard models were used to examine the hazard ratios (HR) of CHD incidence in relation to green tea consumption. Linear regression models were used to evaluate the effect of green tea on 5-year changes of CHD-related biomarkers. Compared with non-green tea consumers, the multivariable-adjusted HR for CHD was 0.89 (95% CI, 0.81-0.98) in green tea consumers. Particularly, the reduced risk of CHD incidence with green tea consumption was more evident among participants who were male, more than 60 years old, overweight, or with diabetes mellitus. In addition, green tea consumption improved multiple CHD-related risk markers including total cholesterol, HDL-cholesterol, triglycerides, mean platelet volume, and uric acid. In conclusion, green tea consumption was associated with a reduced risk of CHD incidence in the middle-aged and older Chinese populations, and the association might be partly due to altered CHD-related biomarkers. PMID:27072746

  2. Green tea consumption is associated with reduced incident CHD and improved CHD-related biomarkers in the Dongfeng-Tongji cohort.

    PubMed

    Tian, Chong; Huang, Qiao; Yang, Liangle; Légaré, Sébastien; Angileri, Francesca; Yang, Handong; Li, Xiulou; Min, Xinwen; Zhang, Ce; Xu, Chengwei; Yuan, Jing; Miao, Xiaoping; He, Mei-an; Wu, Tangchun; Zhang, Xiaomin

    2016-04-13

    Prospective studies on the association of green tea with risk of coronary heart disease (CHD) incidence were scarce. This study examined whether green tea can reduce CHD incidence and have a beneficial effect on CHD-related risk markers in middle-aged and older Chinese population. We included 19,471 participants who were free of CHD, stroke or cancer at baseline from September 2008 to June 2010, and were followed until October 2013. Cox proportional hazard models were used to examine the hazard ratios (HR) of CHD incidence in relation to green tea consumption. Linear regression models were used to evaluate the effect of green tea on 5-year changes of CHD-related biomarkers. Compared with non-green tea consumers, the multivariable-adjusted HR for CHD was 0.89 (95% CI, 0.81-0.98) in green tea consumers. Particularly, the reduced risk of CHD incidence with green tea consumption was more evident among participants who were male, more than 60 years old, overweight, or with diabetes mellitus. In addition, green tea consumption improved multiple CHD-related risk markers including total cholesterol, HDL-cholesterol, triglycerides, mean platelet volume, and uric acid. In conclusion, green tea consumption was associated with a reduced risk of CHD incidence in the middle-aged and older Chinese populations, and the association might be partly due to altered CHD-related biomarkers.

  3. Preconditioning cortical lesions reduce the incidence of peri-infarct depolarizations during focal ischemia in the Spontaneously Hypertensive Rat: interaction with prior anesthesia and the impact of hyperglycemia

    PubMed Central

    Zhao, Liang; Nowak Jr, Thaddeus S

    2015-01-01

    The relationship between peri-infarct depolarizations (PIDs) and infarction was investigated in a model of preconditioning by cortical freeze lesions (cryogenic lesions, CL) in the Spontaneously Hypertensive Rat. Small (< 5 mm3) lesions produced 24 hours before permanent focal ischemia were protective, without impacting baseline cerebral blood flow (CBF) and metabolism. Prior CL reduced infarct volume, associated with improved penumbral CBF as previously showed for ischemic preconditioning. The brief initial procedure avoided sham effects on infarct volume after subsequent occlusion under brief anesthesia. However, under prolonged isoflurane anesthesia for perfusion monitoring both sham and CL rats showed reduced PID incidence relative to naive animals. This anesthesia effect could be eliminated by using α-chloralose during perfusion imaging. As an additional methodological concern, blood glucose was frequently elevated at the time of the second surgery, reflecting buprenorphine-induced pica and other undefined mechanisms. Even modest hyperglycemia (>10 mmol/L) reduced PID incidence. In normoglycemic animals CL preconditioning reduced PID number by 50%, demonstrating associated effects on PID incidence, penumbral perfusion, and infarct progression. Hyperglycemia suppressed PIDs without affecting the relationship between CBF and infarction. This suggests that the primary effect of preconditioning is to improve penumbral perfusion, which in turn impacts PID incidence and infarct size. PMID:25757750

  4. Preconditioning cortical lesions reduce the incidence of peri-infarct depolarizations during focal ischemia in the Spontaneously Hypertensive Rat: interaction with prior anesthesia and the impact of hyperglycemia.

    PubMed

    Zhao, Liang; Nowak, Thaddeus S

    2015-07-01

    The relationship between peri-infarct depolarizations (PIDs) and infarction was investigated in a model of preconditioning by cortical freeze lesions (cryogenic lesions, CL) in the Spontaneously Hypertensive Rat. Small (< 5 mm(3)) lesions produced 24 hours before permanent focal ischemia were protective, without impacting baseline cerebral blood flow (CBF) and metabolism. Prior CL reduced infarct volume, associated with improved penumbral CBF as previously showed for ischemic preconditioning. The brief initial procedure avoided sham effects on infarct volume after subsequent occlusion under brief anesthesia. However, under prolonged isoflurane anesthesia for perfusion monitoring both sham and CL rats showed reduced PID incidence relative to naive animals. This anesthesia effect could be eliminated by using α-chloralose during perfusion imaging. As an additional methodological concern, blood glucose was frequently elevated at the time of the second surgery, reflecting buprenorphine-induced pica and other undefined mechanisms. Even modest hyperglycemia (>10 mmol/L) reduced PID incidence. In normoglycemic animals CL preconditioning reduced PID number by 50%, demonstrating associated effects on PID incidence, penumbral perfusion, and infarct progression. Hyperglycemia suppressed PIDs without affecting the relationship between CBF and infarction. This suggests that the primary effect of preconditioning is to improve penumbral perfusion, which in turn impacts PID incidence and infarct size. PMID:25757750

  5. An evaluation of early countermeasures to reduce the risk of internal radiation exposure after the Fukushima nuclear incident in Japan.

    PubMed

    Nomura, Shuhei; Tsubokura, Masaharu; Gilmour, Stuart; Hayano, Ryugo S; Watanabe, Yuni N; Kami, Masahiro; Kanazawa, Yukio; Oikawa, Tomoyoshi

    2016-05-01

    After a radiation-release incident, intake of radionuclides in the initial stage immediately following the incident may be the major contributor to total internal radiation exposure for individuals in affected areas. However, evaluation of early internal contamination risk is greatly lacking. This study assessed the relationship between initial stage evacuation/indoor sheltering and internal radiation contamination levels 4 months after the 2011 Fukushima nuclear incident in Japan and estimated potential pathways of the contamination. The study population comprised 525 participants in the internal radiation screening program at Minamisoma Municipal General Hospital, 23 km north of the Fukushima nuclear plant. The analysed dataset included the results of a screening performed in July 2011, 4 months after the incident, and of a questionnaire on early-incident response behaviours, such as sheltering indoors and evacuations, completed by participants. Association between such early countermeasures and internal contamination levels of cesium-134 were assessed using Tobit multiple regression analyses. Our study shows that individuals who evacuated to areas outside Fukushima Prefecture had similar contamination levels of cesium-134 to individuals who stayed in Fukushima (relative risk: 0.86; 95% confidence interval: 0.74-0.99). Time spent outdoors had no significant relationship with contamination levels. The effects of inhalation from radiological plumes released from the nuclear plant on total internal radiation contamination might be so low as to be undetectable by the whole-body counting unit used to examine participants. Given the apparent limited effectiveness of evacuation and indoor sheltering on internal contamination, the decision to implement such early responses to a radiation-release incident should be made by carefully balancing their potential benefits and health risks.

  6. Combined use of alcohol hand rub and gloves reduces the incidence of late onset infection in very low birthweight infants

    PubMed Central

    Ng, P; Wong, H; Lyon, D; So, K; Liu, F; Lam, R; Wong, E; Cheng, A; Fok, T

    2004-01-01

    Objective: To assess the incidence of late onset (> 72 hours) infection and necrotising enterocolitis (NEC) in very low birthweight (VLBW) infants in two 36 month periods using two hand hygiene protocols: conventional handwashing (HW; first 36 month period); an alcohol hand rub and gloves technique (HR; second 36 month period). Method: VLBW infants admitted to the neonatal intensive care unit during the period December 1993–November 1999 were eligible. A new hand hygiene protocol using alcohol handrub and gloves was introduced in December 1996. Each patient's case record was reviewed retrospectively by two independent investigators using a standard data collection form. The incidence of NEC and systemic infections, including bacterial or fungal septicaemia, meningitis, and peritonitis, in the two periods were compared. Results: The HW and HR groups contained 161 and 176 VLBW infants respectively. The incidence of late onset systemic infection decreased from 13.5 to 4.8 episodes (including NEC)/1000 patient days after introduction of the HR regimen, representing a 2.8-fold reduction. Similarly, the incidence of Gram positive, Gram negative, and fungal infections decreased 2.5-fold, 2.6-fold, and 7-fold respectively. There was also a significant reduction in the incidence of NEC in the HR group (p < 0.0001). Subgroup analysis revealed that the incidence of methicillin resistant Staphylococcus aureus (MRSA) septicaemia was significantly decreased in the second 36 month period (p  =  0.048). The clinical data suggest that infants in the HW group had significantly earlier onset of sepsis (p < 0.05) and required oxygen supplementation for longer (p < 0.05) than those in the HR group. Significantly more VLBW infants were discharged from the neonatal intensive care unit without ever being infected (p < 0.0001), and also significantly fewer infants had more than one episode of infection in the HR group (p < 0.0001). Conclusion: The introduction of the HR

  7. Single-dose oral guanidinoacetic acid exhibits dose-dependent pharmacokinetics in healthy volunteers.

    PubMed

    Ostojic, Sergej M; Vojvodic-Ostojic, Aleksandra

    2015-03-01

    Guanidinoacetic acid (GAA), the natural precursor of creatine, has potential as a dietary supplement for human nutrition, yet no data are available regarding its dose-dependent pharmacokinetic (PK) behavior. We hypothesized that a single dose of orally administered GAA exhibited dose-dependent PK behavior in healthy volunteers. Forty-eight young adults were enrolled in a randomized, placebo-controlled, double-blind, parallel-group trial to receive single oral doses of GAA (1.2, 2.4, and 4.8 g) or a placebo. Pharmacokinetic metrics for plasma GAA and creatine were assessed immediately before (0 hours) and at 1, 2, 4, 6, 8, 12, and 24 hours after GAA ingestion. The lag time appeared to be similar after the bolus ingestion of GAA (0.14 ± 0.17 hours for low-dose GAA, 0.31 ± 0.18 hours for medium-dose GAA, and 0.38 ± 0.32 hours for high-dose GAA; P = .05). An increase in the area under the concentration-time curve for plasma GAA was found for the dose range tested, with 2.4- and 9.3-fold increases in the area under the concentration-time curve for every 2-fold increase in the GAA dose (P < .0001). No differences were found for elimination half-time between the low-dose and medium-dose groups (<1.75 hours), whereas the elimination half-time was significantly longer (>2.1 hours) for the high-dose GAA regimen (P = .001). The volume of distribution was affected by the dosage of GAA applied (102.6 ± 17.3 L for low-dose GAA, 97.5 ± 15.7 L for medium-dose GAA, and 61.1 ± 12.7 L for high-dose GAA; P < .0001). Ingestion of GAA elevated plasma creatine by 80%, 116%, and 293% compared with the placebo for the 1.2, 2.4, and 4.8 g doses, respectively (P < .0001). Guanidinoacetic acid single-dose PK metrics were nonlinear with respect to dose size. Across the dose range of 1.2 to 4.8 g, systemic exposure to GAA increased in a greater than dose-proportional manner. PMID:25622538

  8. Dose-dependent effect of Lactobacillus rhamnosus on quantitative reduction of faecal rotavirus shedding in children.

    PubMed

    Fang, Shiuh-Bin; Lee, Hung-Chang; Hu, Jen-Jan; Hou, Shao-Yi; Liu, Hsuan-Liang; Fang, Hsu-Wei

    2009-10-01

    Beneficial effects of probiotics in acute infectious diarrhoea in children are mainly seen in watery diarrhoea and viral gastroenteritis. Lactobacillus rhamnosus, one the most extensively studied probiotic strains, is effective in shortening courses of acute diarrhoea in children. However, the dose-dependent effect of Lactobacillus upon quantification of faecal rotavirus shedding in humans remains little known. Thus, an open-label randomized trial in 23 children with acute rotaviral gastroenteritis was undertaken by randomly allocating patients to receive one of the three regimens for 3 days: daily Lactobacillus rhamnosus 35 (Lcr35) with 0 CFU/day to six patients in the control group, 2 x 10(8) CFU/day to nine patients in the low-dose group, and 6 x 10(8) CFU/day to eight patients in the high-dose group. Faecal samples were collected before and after the 3-day regimen for measurements of rotavirus concentrations by ELISA. There was no statistically significant change in faecal rotavirus concentrations in either the control group (119.2 x 10(5) particles/ml vs. 23.7 x 10(5) particles/ml, p = 0.075) or the low-dose group (36.1 x 10(5) particles/ml vs. 73.5 x 10(5) particles/ml, p = 0.859). However, the high-dose group had a significant reduction of faecal rotavirus concentration (64.2 x 10(5) particles/ml vs. 9.0 x 10(5) particles/ml, p = 0.012). Without any exception, the faecal rotavirus concentrations of all eight patients in the high-dose Lcr35 group declined by 86% after 3 days when compared with those before Lcr35 administration. In conclusion, this is the first report to provide quantitative evidence of the dose-dependent effect of Lactobacillus rhamnosus, a minimal effective dose of 6 x 10(8) CFU for 3 days, upon the faecal rotavirus shedding in paediatric patients.

  9. Testing Dose-Dependent Effects of the Nectar Alkaloid Anabasine on Trypanosome Parasite Loads in Adult Bumble Bees

    PubMed Central

    Anthony, Winston E.; Palmer-Young, Evan C.; Leonard, Anne S.; Irwin, Rebecca E.; Adler, Lynn S.

    2015-01-01

    The impact of consuming biologically active compounds is often dose-dependent, where small quantities can be medicinal while larger doses are toxic. The consumption of plant secondary compounds can be toxic to herbivores in large doses, but can also improve survival in parasitized herbivores. In addition, recent studies have found that consuming nectar secondary compounds may decrease parasite loads in pollinators. However, the effect of compound dose on bee survival and parasite loads has not been assessed. To determine how secondary compound consumption affects survival and pathogen load in Bombus impatiens, we manipulated the presence of a common gut parasite, Crithidia bombi, and dietary concentration of anabasine, a nectar alkaloid produced by Nicotiana spp. using four concentrations naturally observed in floral nectar. We hypothesized that increased consumption of secondary compounds at concentrations found in nature would decrease survival of uninfected bees, but improve survival and ameliorate parasite loads in infected bees. We found medicinal effects of anabasine in infected bees; the high-anabasine diet decreased parasite loads and increased the probability of clearing the infection entirely. However, survival time was not affected by any level of anabasine concentration, or by interactive effects of anabasine concentration and infection. Crithidia infection reduced survival time by more than two days, but this effect was not significant. Our results support a medicinal role for anabasine at the highest concentration; moreover, we found no evidence for a survival-related cost of anabasine consumption across the concentration range found in nectar. Our results suggest that consuming anabasine at the higher levels of the natural range could reduce or clear pathogen loads without incurring costs for healthy bees. PMID:26545106

  10. Testing Dose-Dependent Effects of the Nectar Alkaloid Anabasine on Trypanosome Parasite Loads in Adult Bumble Bees.

    PubMed

    Anthony, Winston E; Palmer-Young, Evan C; Leonard, Anne S; Irwin, Rebecca E; Adler, Lynn S

    2015-01-01

    The impact of consuming biologically active compounds is often dose-dependent, where small quantities can be medicinal while larger doses are toxic. The consumption of plant secondary compounds can be toxic to herbivores in large doses, but can also improve survival in parasitized herbivores. In addition, recent studies have found that consuming nectar secondary compounds may decrease parasite loads in pollinators. However, the effect of compound dose on bee survival and parasite loads has not been assessed. To determine how secondary compound consumption affects survival and pathogen load in Bombus impatiens, we manipulated the presence of a common gut parasite, Crithidia bombi, and dietary concentration of anabasine, a nectar alkaloid produced by Nicotiana spp. using four concentrations naturally observed in floral nectar. We hypothesized that increased consumption of secondary compounds at concentrations found in nature would decrease survival of uninfected bees, but improve survival and ameliorate parasite loads in infected bees. We found medicinal effects of anabasine in infected bees; the high-anabasine diet decreased parasite loads and increased the probability of clearing the infection entirely. However, survival time was not affected by any level of anabasine concentration, or by interactive effects of anabasine concentration and infection. Crithidia infection reduced survival time by more than two days, but this effect was not significant. Our results support a medicinal role for anabasine at the highest concentration; moreover, we found no evidence for a survival-related cost of anabasine consumption across the concentration range found in nectar. Our results suggest that consuming anabasine at the higher levels of the natural range could reduce or clear pathogen loads without incurring costs for healthy bees.

  11. In vitro and in vivo evaluation of a dry powder endotracheal insufflator device for use in dose-dependent preclinical studies in mice.

    PubMed

    Duret, Christophe; Wauthoz, Nathalie; Merlos, Romain; Goole, Jonathan; Maris, Calliope; Roland, Isabelle; Sebti, Thami; Vanderbist, Francis; Amighi, Karim

    2012-08-01

    The aim of this study was to evaluate the ability of the Penn-Century Dry Powder Insufflator for mice (DP-4M) to reproducibly, uniformly, and deeply deliver dry powders for inhalation in the mouse lung. Itraconazole-based dry powder formulations produced by spray-drying were different in terms of composition (different ratios of drug and mannitol, with or without phospholipids), but relatively similar in terms of particle size and mass median aerodynamic diameter. The ability of the dry powder insufflator to disaggregate each formulation was the same, indicated by the absence of a statistically significant difference between the particle size distribution parameters, as measured by laser scattering. The emitted fraction varied in vivo compared to the in vitro condition. Fluorescent particle distribution in the lungs was uniform and reached the alveolar spaces, as visualized by fluorescent microscopy. In terms of drug recovery in lung tissue, a minimum administered powder mass (in this case ∼1 mg) was necessary to recover at least 30% of the emitted dose in the lung and to obtain reproducible pulmonary concentrations. To reduce the dose administered in the lung, it was preferable to dilute the active ingredient within the carrier instead of reducing the dry powder mass inserted in the sampling chamber. Dry powder insufflators are devices usable in dose-dependent preclinical trials but have critical parameters to efficiently deliver reproducible doses depending on the type of formulation. PMID:22538097

  12. Dose-Dependent Flux of Buprenorphine Following Transdermal Administration in Healthy Subjects.

    PubMed

    Wang, Yi; Cipriano, Alessandra; Munera, Catherine; Harris, Stephen C

    2016-10-01

    Buprenorphine transdermal delivery system (BTDS) applied once every 7 days is indicated for the management of pain that is severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. The 7-day flux of buprenorphine from BTDS to systemic circulation was investigated in a phase 1, 2-period crossover study with 3 randomized groups of healthy subjects receiving BTDS containing buprenorphine 5, 10, or 20 mg for 7 days preceded or followed by intravenous buprenorphine infusion (25 μg/h for 24 hours). Residual and absolute bioavailability methods were used to estimate 7-day flux of buprenorphine. Following BTDS administration, mean area under the curve of buprenorphine increased proportionally (12.6, 24.3, and 51.1 ng/[mL · h]), maximum mean plasma concentration rose with increasing dose (176, 191, and 471 pg/mL), and absolute bioavailability was 14% to 16%. Mean residual amount of buprenorphine in the BTDS after 7-day application was 4.50, 8.57, and 17.1 mg. Flux of buprenorphine was approximately 5, 10, and 20 μg/h for BTDS containing 5, 10, and 20 mg buprenorphine, respectively. BTDS was safe and well tolerated following a single 7-day application in healthy subjects. The results of this study demonstrated dose-dependent flux of buprenorphine delivered via transdermal system. PMID:26865472

  13. Dose-dependent fluoxetine effects on boldness in male Siamese fighting fish.

    PubMed

    Dzieweczynski, Teresa L; Campbell, Brennah A; Kane, Jessica L

    2016-03-01

    As the use of pharmaceuticals and personal care products (PPCPs) continues to rise, these compounds enter the environment in increasing frequency. One such PPCP, fluoxetine, has been found in detectable amounts in aquatic ecosystems worldwide, where it may interfere with the behavior of exposed organisms. Fluoxetine exposure has been found to influence boldness and exploration in a range of fish species; however, how it might alter behavior in multiple contexts or over time is rarely examined. To this end, the effects of fluoxetine on boldness over time were studied in male Siamese fighting fish. Three different groups of males (0, 0.5 and 5 µg l(-1) fluoxetine) were tested in multiple boldness assays (empty tank, novel environment and shoal) once a week for 3 weeks to collect baseline measures and then at three different time points post-exposure. The effects of these varying exposure amounts on behavior were then examined for overall response, consistency and across-context correlations. Unexposed males were bolder in all contexts, were more consistent within a context, and had stronger between-context correlations than exposed males. Fluoxetine had dose-dependent effects on behavior, as males that received the higher dose exhibited greater behavioral effects. This study stresses the potential fitness consequences of fluoxetine exposure and suggests that examining behavioral effects of PPCPs under different dosing regimens and in multiple contexts is important to gain an increased understanding of how exposure affects behavior. PMID:26985051

  14. Dose-dependent nuclear β-catenin response segregates endomesoderm along the sea star primary axis.

    PubMed

    McCauley, Brenna S; Akyar, Eda; Saad, H Rosa; Hinman, Veronica F

    2015-01-01

    In many invertebrates, the nuclearization of β-catenin at one pole of the embryo initiates endomesoderm specification. An intriguing possibility is that a gradient of nuclear β-catenin (nβ-catenin), similar to that operating in vertebrate neural tube patterning, functions to distinguish cell fates in invertebrates. To test this hypothesis, we determined the function of nβ-catenin during the early development of the sea star, which undergoes a basal deuterostomal mode of embryogenesis. We show that low levels of nβ-catenin activity initiate bra, which is expressed in the future posterior endoderm-fated territory; intermediate levels are required for expression of foxa and gata4/5/6, which are later restricted to the endoderm; and activation of ets1 and erg in the mesoderm-fated territory requires the highest nβ-catenin activity. Transcription factors acting downstream of high nβ-catenin segregate the endoderm/mesoderm boundary, which is further reinforced by Delta/Notch signaling. Significantly, therefore, in sea stars, endomesoderm segregation arises through transcriptional responses to levels of nβ-catenin activity. Here, we describe the first empirical evidence of a dose-dependent response to a dynamic spatiotemporal nβ-catenin activity that patterns cell fates along the primary axis in an invertebrate.

  15. A dose-dependent tug of war involving the NPM1 leukaemic mutant, nucleophosmin, and ARF.

    PubMed

    Bolli, N; De Marco, M F; Martelli, M P; Bigerna, B; Pucciarini, A; Rossi, R; Mannucci, R; Manes, N; Pettirossi, V; Pileri, S A; Nicoletti, I; Falini, B

    2009-03-01

    In acute myeloid leukaemia (AML), nucleophosmin-1 (NPM1) mutations create a nuclear export signal (NES) motif and disrupt tryptophans at NPM1 C-terminus, leading to nucleophosmin accumulation in leukaemic cell cytoplasm. We investigated how nucleophosmin NES motifs (two physiological and one created by the mutation) regulate traffic and interaction of mutated NPM1, NPM1wt and p14(ARF). Nucleophosmin export into cytoplasm was maximum when the protein contained all three NES motifs, as naturally occurs in NPM1-mutated AML. The two physiological NES motifs mediated NPM1 homo/heterodimerization, influencing subcellular distribution of NPM1wt, mutated NPM1 and p14(ARF) in a 'dose-dependent tug of war' fashion. In transfected cells, excess doses of mutant NPM1 relocated completely NPM1wt (and p14(ARF)) from the nucleoli to the cytoplasm. This distribution pattern was also observed in a proportion of NPM1-mutated AML patients. In transfected cells, excess of NPM1wt (and p14(ARF)) relocated NPM1 mutant from the cytoplasm to the nucleoli. Notably, this distribution pattern was not observed in AML patients where the mutant was consistently cytoplasmic restricted. These findings reinforce the concept that NPM1 mutants are naturally selected for most efficient cytoplasmic export, pointing to this event as critical for leukaemogenesis. Moreover, they provide a rationale basis for designing small molecules acting at the interface between mutated NPM1 and other interacting proteins. PMID:19005479

  16. Dose-dependent protective effects of apomorphine against methamphetamine-induced nigrostriatal damage.

    PubMed

    Fornai, F; Battaglia, G; Gesi, M; Orzi, F; Nicoletti, F; Ruggieri, S

    2001-04-13

    (R)-apomorphine is a non-selective dopamine (DA) agonist which is used in the treatment of Parkinson's disease. In addition to symptomatic effects, apomorphine exerts a neuroprotective activity in specific experimental models. For instance, apomorphine prevents experimental parkinsonism induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Neuroprotection obtained with apomorphine does not seem to be related to its dopamine (DA) agonist properties, instead it appears to be grounded on the antioxidant and the free radical scavenging effects of the compound. In this study, we sought to determine whether apomorphine protects against methamphetamine toxicity. We found that apomorphine (1; 5 and 10 mg/kg) dose-dependently protects against methamphetamine- (5 mg/kg X3, 2 h apart) induced striatal DA loss and reduction of tyrosine hydroxylase (TH) activity in the rat striatum. These protective effects are neither due to a decrease in the amount of striatal methamphetamine nor to hypothermia as indicated by measurement of striatal methamphetamine and body temperature at different time intervals after drug administration. The effects of apomorphine were neither opposite to, nor reversed by the DA antagonist haloperidol despite no decrease in body temperature was observed when apomorphine was given in combination with haloperidol. The present data are in line with recent studies suggesting a DA receptor-independent neuroprotective effect of apomorphine on DA neurons and call for further studies aimed at evaluating potential neuroprotective effects of apomorphine in Parkinson's disease.

  17. Dose-dependent Medicinal Effects of Thymus haussknechtii Velen Grown Wild in Turkey.

    PubMed

    Kılıçgün, Hasan; Korkmaz, Mustafa

    2016-01-01

    In this study, it was aimed to determine dose-dependent interactions between phenolic contents and antioxidant, antibacterial and antifungal effect mechanisms of the infusions of Thymus haussknechtii Velen, naturally grown in the Eastern Anatolia region of Turkey. Therefore, the infusions of Thymus haussknechtii were tested and the interactions between phenolic contents and antioxidant, antibacterial and antifungal effect mechanisms were determined by way of different antioxidant, antibacterial and antioxidant test systems. The concentrations of Thymus haussknechtii showed strong hydrogen peroxide scavenging activity and free radical scavenging activity [1,1-diphenyl-2-picryl-hydrazil (DPPH) % inhibition]. Also, it was seen that Thymus haussknechtii infusions possessed strong antibacterial and antifungal activity against different gram negative and positive bacteria and fungi. In this study, positive correlations between antioxidant, antibacterial, antifungal potency and the total phenolic content of Thymus haussknechtii were found. When the concentration differences were examined, it was seen that concentrations of 4% had the most strong antioxidant, antibacterial and antifungal activity. As a result, Thymus haussknechtii can be reliable antioxidant, antibacterial antifungal substance at concentrations of 4% when it is used as a supplement to therapeutic regimens and for medicinal purposes.

  18. Silver Nanoparticles Incite Size and Dose-Dependent Developmental Phenotypes and Nanotoxicity in Zebrafish Embryos

    PubMed Central

    Browning, Lauren M.; Lee, Kerry J.; Nallathamby, Prakash D.; Xu, Xiao-Hong Nancy

    2013-01-01

    Nanomaterials possess distinctive physicochemical properties and promise a wide range of applications, from advanced technology to leading-edge medicine. However, their effects on living organisms remain largely unknown. Here we report that the purified silver nanoparticles (Ag NPs, 97 ± 13 nm) incite specific developmental stage embryonic phenotypes and nanotoxicity in a dose-dependent manner, upon acute exposure of given-stage embryos to the NPs (0–24 pM) for only 2 h. The critical concentrations of the NPs that cause 50% of embryos develop normally for cleavage, early-gastrula, early-segmentation, late-segmentation, and hatching stage zebrafish embryos are 3.5, 4, 6, 6, and 8 pM, respectively, showing that the earlier developmental stage embryos are much more sensitive to the effects of the NPs than the later stage. Interestingly, distinctive phenotypes (head abnormality and no eyes) are observed only in cleavage and early-gastrula stage embryos treated with the NPs, showing the stage-specific effects of the NPs. By comparing with our study of the smaller Ag NPs (13.1 ± 2.5 nm), we found that the embryonic phenotypes strikingly depend upon the sizes of Ag NPs and embryonic developmental stages. These notable findings suggest that the Ag NPs are unlike any conventional chemicals or ions. They can potentially enable target specific study and therapy for early embryonic development in size, stage, dose, and exposure-duration dependent manners. PMID:24024906

  19. Chrysin, a flavonoid attenuates histological changes of hyperammonemic rats: A dose dependent study.

    PubMed

    Renuka, Mani; Vijayakumar, Natesan; Ramakrishnan, Arumugam

    2016-08-01

    Chrysin (5,7-dihydroxyflavone) is a major component of some traditional medicinal herbs present in honey, propolis and many plant extracts. The study was aimed to illuminate the effect of chrysin in the pathogenesis of ammonium chloride (NH4Cl) induced hyperammonemic rat model in a dose dependent manner. Rats were injected with NH4Cl (100mg/kg b.w.) by intraperitonially (i.p) thrice a week for 8 consecutive weeks for the induction of experimental hyperammonemia. Hyperammonemic rats were treated with chrysin by orally at a dose of 25, 50 & 100mg/kg b.w. respectively. Protective effect of chrysin against hyperammonemia was evaluated by performing biochemical estimations and morphopathological investigations of hematoxylin and eosin stained sections of liver, brain and kidney tissues. Supplementation of chrysin reinstated the levels of blood ammonia, plasma urea, uric acid, total bilirubin, creatinine, brain glutamate, glutamine, nitric oxide (NO) and the activities of Na(+)/K(+)-ATPase, and liver marker enzymes. On the other hand increased level of plasma urea was observed in chrysin treated rats as compared with hyperammonemic rats. Chrysin administration caused distortion of hepatic, brain and kidney architecture as shown by histological examination. Chrysin at a dose (100mg/kg b.w.) showed an utmost decline in the level of all biochemical estimations. Both biochemical and morphological studies clearly revealed that chrysin protects against cell injury induced by ammonia intoxication in a dose-response manner with respect to endogenous antioxidants and hypoammonemic effects. PMID:27470372

  20. Dose-Dependent Regulation of Alternative Splicing by MBNL Proteins Reveals Biomarkers for Myotonic Dystrophy

    PubMed Central

    Struck, Adam J.; Gupta, Riti; Farnsworth, Dylan R.; Mahady, Amy E.; Eichinger, Katy; Thornton, Charles A.; Wang, Eric T.; Berglund, J. Andrew

    2016-01-01

    Alternative splicing is a regulated process that results in expression of specific mRNA and protein isoforms. Alternative splicing factors determine the relative abundance of each isoform. Here we focus on MBNL1, a splicing factor misregulated in the disease myotonic dystrophy. By altering the concentration of MBNL1 in cells across a broad dynamic range, we show that different splicing events require different amounts of MBNL1 for half-maximal response, and respond more or less steeply to MBNL1. Motifs around MBNL1 exon 5 were studied to assess how cis-elements mediate the MBNL1 dose-dependent splicing response. A framework was developed to estimate MBNL concentration using splicing responses alone, validated in the cell-based model, and applied to myotonic dystrophy patient muscle. Using this framework, we evaluated the ability of individual and combinations of splicing events to predict functional MBNL concentration in human biopsies, as well as their performance as biomarkers to assay mild, moderate, and severe cases of DM. PMID:27681373

  1. Dose-dependent Medicinal Effects of Thymus haussknechtii Velen Grown Wild in Turkey.

    PubMed

    Kılıçgün, Hasan; Korkmaz, Mustafa

    2016-01-01

    In this study, it was aimed to determine dose-dependent interactions between phenolic contents and antioxidant, antibacterial and antifungal effect mechanisms of the infusions of Thymus haussknechtii Velen, naturally grown in the Eastern Anatolia region of Turkey. Therefore, the infusions of Thymus haussknechtii were tested and the interactions between phenolic contents and antioxidant, antibacterial and antifungal effect mechanisms were determined by way of different antioxidant, antibacterial and antioxidant test systems. The concentrations of Thymus haussknechtii showed strong hydrogen peroxide scavenging activity and free radical scavenging activity [1,1-diphenyl-2-picryl-hydrazil (DPPH) % inhibition]. Also, it was seen that Thymus haussknechtii infusions possessed strong antibacterial and antifungal activity against different gram negative and positive bacteria and fungi. In this study, positive correlations between antioxidant, antibacterial, antifungal potency and the total phenolic content of Thymus haussknechtii were found. When the concentration differences were examined, it was seen that concentrations of 4% had the most strong antioxidant, antibacterial and antifungal activity. As a result, Thymus haussknechtii can be reliable antioxidant, antibacterial antifungal substance at concentrations of 4% when it is used as a supplement to therapeutic regimens and for medicinal purposes. PMID:26826832

  2. Dose-Dependent Effects of Androgens on the Circadian Timing System and Its Response to Light

    PubMed Central

    Butler, Matthew P.; Karatsoreos, Ilia N.; LeSauter, Joseph

    2012-01-01

    The hypothalamic suprachiasmatic nucleus (SCN) is the locus of a master clock that regulates circadian rhythms in physiology and behavior. Gonadectomy in male mice lengthens the period of circadian rhythms and increases the day-to-day variability of activity onset time. Both of these responses are rescued by the nonaromatizable androgen dihydrotestosterone. Androgen receptors (AR) are localized in SCN neurons that receive direct retinal input. To explore how androgens affect circadian clock function and its responsiveness to photic cues, we measured wheel-running behavior and SCN AR expression in intact, gonadectomized, and testosterone-replaced mice, held under various photic conditions. Gonadectomy lengthened circadian period in constant dim light but not in constant darkness. Increasing intensities of constant light parametrically increased circadian period, and this was potentiated at all intensities by gonadectomy. In contrast, gonadectomy did not alter light-induced pupil constriction, suggesting a nonretinal locus of hormone action. In hormone-replaced animals housed in constant darkness, T concentration was positively correlated with precision of activity onset and with SCN AR expression and negatively correlated with duration of activity. We infer the existence of two androgenic mechanisms: one modulates SCN responsiveness to light, and the second modulates SCN timekeeping and locomotor activity in a dose-dependent manner. Finally, the effects of androgens on period are a result of hormonal modulation of the SCN's response to photic input rather than to a change in the inherent period of oscillators in the absence of light. PMID:22492303

  3. Simplified models to analyse time- and dose-dependent responses of populations to toxicants.

    PubMed

    Sánchez-Bayo, Francisco; Goka, Kouichi

    2007-10-01

    The basis of ecotoxicology lies currently in the dose-response of organisms to toxicants, as typically described by probit and logistic models. While recognising its merits, standard endpoints ignore the process of toxicity with time, and consequently our ability to predict direct toxic effects in environmental risk assessments is seriously curtailed. Although the response of toxicants with time has been studied before, its application in ecotoxicology remains underutilised. One reason is that no convincing mechanism has been proposed to explain the hyperbolic curves of such responses, whereas a variety of models have been used to describe them. The explanation of both time- and dose-dependent responses is found ultimately in the natural variability of receptor sites among individuals of populations exposed to a toxicant inhibitor with time. The process can be explained by the kinetics of inhibition, and is appropriately described by a simple mathematical expression like the Michaelis-Menten equation, though other asymptotic models (e.g. logistic model) can also be used. The advantage of the hyperbolic model is that median effect values (e.g. LC(50) for dose- and ET(50) for time-dependent responses) enable calculation of toxicity effects at any concentration level and/or time of exposure, thus making it especially attractive for risk assessment. PMID:17624612

  4. Dose dependent effect of GnRH analogue on pregnancy rate of repeat breeder crossbred cows.

    PubMed

    Kharche, S D; Srivastava, S K

    2007-05-01

    The aim of this study was to investigate the effect of treating repeat breeder dairy crossbred cows with different doses of GnRH analogue through i.m. at the time of artificial insemination, on pregnancy rates from their first service after treatment and overall pregnancy rates. One hundred and thirty seven crossbred dairy cows with a history of repeat breeding and eligible after 6-8 infertile services but clinically free of diseases were selected for the study. The animals were randomly divided into three groups. Group 1 (n = 55) cows were treated intramuscularly with each 20 microg Buserelin-acetate (Receptal, Hoechst Roussel Vet GmbH) at the time of artificial insemination. Group 2 (n = 40) cows were treated intramuscularly with each 10 microg Buserelin-acetate at the time of artificial insemination. Group 3 (n = 42) cows were treated intramuscularly with saline as control at the time of artificial insemination. The first service pregnancy rates in Groups 1-3 were 45, 25 and 17%, respectively. Similarly, the overall conception rates in Groups 1-3 were 87, 58 and 48%, respectively. The results indicated that the pregnancy rate in crossbred cows could be improved by the GnRH treatment. The higher dose of GnRH significantly increased (P < 0.05) the first service as well as overall pregnancy rate in a dose dependent manner in repeat breeder crossbred cow bred previously 6-8 times unsuccessfully. PMID:16787717

  5. [Dose-dependent effects of intracisternally administered insulin on rat's behavior and glucose level].

    PubMed

    Shestakova, S A; Stepanov, I I; Eliseeva, A P; Shatik, S V; Fedorova, N V; Klimenko, V M

    2007-03-01

    Rat behavior in the open field and elevated plus-maze as well as glycaemia level were analyzed in rats after intracisternal administration of 2.5, 25, 50 and 200 ng of insulin. Dose-dependent changes were found in both behavioral tests: insulin in low doses (2.5 and 25 ng) increased probability of locomotion and investigative activity in open field, while insulin in high doses (50 and 200 ng) did not alter locomotor activity and showed tendency to weakening of the investigative behavior (especially in the dose of 50 ng). Significant decrease of rat anxiety level during the first 5 minutes of testing was found after administration of 2.5 and 200 ng of insulin and during the next 5 minutes after administration of 2.5 and 25 ng of insulin in elevated plus-maze. The glucose level in rats was increased in 1-2 hours after insulin administration, though glycaemia level did not exceed normal values. Thus revealed alterations of behavior are supposed to be the result of direct insulin influence on central mechanisms of activation and/or suppression of underlying behavioral characteristics of animals. PMID:17598469

  6. Time- and dose-dependency of the effects of nitrogen pollution on lichens.

    PubMed

    Munzi, Silvana; Pisani, Tommaso; Paoli, Luca; Loppi, Stefano

    2010-10-01

    The present work aims at testing if exposure time and dose play a role in the response of lichen species to nitrogen (N) pollution. To this purpose, samples of the N-sensitive Evernia prunastri and the N-tolerant Xanthoria parietina were treated for 5 weeks either with solutions of NH(4)NO(3) 0.05 and 1 M, or (NH(4))(2)SO(4) 0.025 and 0.5 M. Photosynthetic efficiency was measured as an indicator of sample vitality. The results showed that the lowest concentrations were ineffective at the beginning, but after several supplies both compounds inhibited photosynthetic activity of E. prunastri. The highest concentrations had a deleterious effect, but with a temporal trend. For X. parietina no effect was found for the lowest concentrations, while the same trend shown by E. prunastri was instead observed following treatments with the highest concentrations. It was concluded that the response of lichens to N supply is not only species-specific, but also time- and dose-dependent. The results give a clue on field studies on the relationships between lichens and N pollution.

  7. Dose-dependent immunohistochemical and ultrastructural changes after oral methylphenidate administration in rat heart tissue.

    PubMed

    Take, G; Bahcelioglu, M; Oktem, H; Tunc, E; Gözil, R; Erdogan, D; Calguner, E; Helvacioglu, F; Giray, S G; Elmas, C

    2008-08-01

    Methylphenidate, more commonly known as Ritalin, is a piperidine derivative and is the drug most often used to treat attention deficit/hyperactivity disorder, one of the most common behavioural disorders of children and young adults. Our aims were to investigate dose-dependent immunohistochemical D2 expression and ultrastructural changes of the rat heart tissue, and to demonstrate possible toxicity of the long-term and high dose use of the methylphenidate. In this study, 27 female pre-pubertal Wistar albino rats, divided into three different dose groups (5, 10 and 20 mg/kg) and their control groups, were used. They were treated orally with methylphenidate dissolved in saline solution for 5 days/week during 3 months. At the end of the third month, after perfusion fixation, left ventricle of cardiac tissue was removed. Paraffin, semi-thin and thin sections were collected and immunohistochemical, terminal deoxynucleotidyl transferase-mediated Dig-dUTP nick end labelling assay and ultrastructural studies were performed. In conclusion, we believe that Ritalin is dose-related affecting dopaminergic system to increase heart rhythm and contraction. Thus, this drug may cause degenerative ultrastructural changes in mitochondrial path.

  8. Ferutinin dose-dependent effects on uterus and mammary gland in ovariectomized rats.

    PubMed

    Ferretti, Marzia; Cavani, Francesco; Manni, Paola; Carnevale, Gianluca; Bertoni, Laura; Zavatti, Manuela; Palumbo, Carla

    2014-08-01

    The present paper completes our recent study on the effects of phytoestrogen ferutinin in preventing osteoporosis and demonstrating the superior osteoprotective effect of a 2 mg/kg/day dose in ovariectomized (OVX) rats, compared to both estrogens and lower (0.5, 1 mg/kg/day) ferutinin doses. Morphological and morphometrical analyses were performed on the effects of different doses of ferutinin administrated for one month on uterus and on mammary gland of Sprague-Dawley OVX rats, evaluated in comparison with the results for estradiol benzoate. To verify whether ferutinin provides protection against uterine and breast cancer, estimations were made of both the amount of cell proliferation (by Ki-67), and the occurrence of apoptosis (by TUNEL), two processes that in unbalanced ratio form the basis for cancer onset. The results suggest that the effects of ferutinin are dose dependent and that a 2 mg/kg/day dose might offer a better protective action against the onset of both breast and uterine carcinoma compared to ferutinin in lower doses or estradiol benzoate, increasing cellular apoptosis in glandular epithelia. PMID:24510547

  9. Electron dose dependence of signal-to-noise ratio, atom contrast and resolution in transmission electron microscope images.

    PubMed

    Lee, Z; Rose, H; Lehtinen, O; Biskupek, J; Kaiser, U

    2014-10-01

    In order to achieve the highest resolution in aberration-corrected (AC) high-resolution transmission electron microscopy (HRTEM) images, high electron doses are required which only a few samples can withstand. In this paper we perform dose-dependent AC-HRTEM image calculations, and study the dependence of the signal-to-noise ratio, atom contrast and resolution on electron dose and sampling. We introduce dose-dependent contrast, which can be used to evaluate the visibility of objects under different dose conditions. Based on our calculations, we determine optimum samplings for high and low electron dose imaging conditions.

  10. Electron dose dependence of signal-to-noise ratio, atom contrast and resolution in transmission electron microscope images.

    PubMed

    Lee, Z; Rose, H; Lehtinen, O; Biskupek, J; Kaiser, U

    2014-10-01

    In order to achieve the highest resolution in aberration-corrected (AC) high-resolution transmission electron microscopy (HRTEM) images, high electron doses are required which only a few samples can withstand. In this paper we perform dose-dependent AC-HRTEM image calculations, and study the dependence of the signal-to-noise ratio, atom contrast and resolution on electron dose and sampling. We introduce dose-dependent contrast, which can be used to evaluate the visibility of objects under different dose conditions. Based on our calculations, we determine optimum samplings for high and low electron dose imaging conditions. PMID:24566042

  11. Household Air Pollution Causes Dose-Dependent Inflammation and Altered Phagocytosis in Human Macrophages

    PubMed Central

    Fullerton, Duncan G.; Scriven, James; Aljurayyan, Abdullah N.; Mzinza, David; Barrett, Steve; Wright, Adam K. A.; Wootton, Daniel G.; Glennie, Sarah J.; Baple, Katy; Knott, Amy; Mortimer, Kevin; Russell, David G.; Heyderman, Robert S.; Gordon, Stephen B.

    2015-01-01

    Three billion people are exposed to household air pollution from biomass fuel use. Exposure is associated with higher incidence of pneumonia, and possibly tuberculosis. Understanding mechanisms underlying these defects would improve preventive strategies. We used human alveolar macrophages obtained from healthy Malawian adults exposed naturally to household air pollution and compared them with human monocyte-derived macrophages exposed in vitro to respirable-sized particulates. Cellular inflammatory response was assessed by IL-6 and IL-8 production in response to particulate challenge; phagosomal function was tested by uptake and oxidation of fluorescence-labeled beads; ingestion and killing of Streptococcus pneumoniae and Mycobacterium tuberculosis were measured by microscopy and quantitative culture. Particulate ingestion was quantified by digital image analysis. We were able to reproduce the carbon loading of naturally exposed alveolar macrophages by in vitro exposure of monocyte-derived macrophages. Fine carbon black induced IL-8 release from monocyte-derived and alveolar macrophages (P < 0.05) with similar magnitude responses (log10 increases of 0.93 [SEM = 0.2] versus 0.74 [SEM = 0.19], respectively). Phagocytosis of pneumococci and mycobacteria was impaired with higher particulate loading. High particulate loading corresponded with a lower oxidative burst capacity (P = 0.0015). There was no overall effect on killing of M. tuberculosis. Alveolar macrophage function is altered by particulate loading. Our macrophage model is comparable morphologically to the in vivo uptake of particulates. Wood smoke–exposed cells demonstrate reduced phagocytosis, but unaffected mycobacterial killing, suggesting defects related to chronic wood smoke inhalation limited to specific innate immune functions. PMID:25254931

  12. Household air pollution causes dose-dependent inflammation and altered phagocytosis in human macrophages.

    PubMed

    Rylance, Jamie; Fullerton, Duncan G; Scriven, James; Aljurayyan, Abdullah N; Mzinza, David; Barrett, Steve; Wright, Adam K A; Wootton, Daniel G; Glennie, Sarah J; Baple, Katy; Knott, Amy; Mortimer, Kevin; Russell, David G; Heyderman, Robert S; Gordon, Stephen B

    2015-05-01

    Three billion people are exposed to household air pollution from biomass fuel use. Exposure is associated with higher incidence of pneumonia, and possibly tuberculosis. Understanding mechanisms underlying these defects would improve preventive strategies. We used human alveolar macrophages obtained from healthy Malawian adults exposed naturally to household air pollution and compared them with human monocyte-derived macrophages exposed in vitro to respirable-sized particulates. Cellular inflammatory response was assessed by IL-6 and IL-8 production in response to particulate challenge; phagosomal function was tested by uptake and oxidation of fluorescence-labeled beads; ingestion and killing of Streptococcus pneumoniae and Mycobacterium tuberculosis were measured by microscopy and quantitative culture. Particulate ingestion was quantified by digital image analysis. We were able to reproduce the carbon loading of naturally exposed alveolar macrophages by in vitro exposure of monocyte-derived macrophages. Fine carbon black induced IL-8 release from monocyte-derived and alveolar macrophages (P < 0.05) with similar magnitude responses (log10 increases of 0.93 [SEM = 0.2] versus 0.74 [SEM = 0.19], respectively). Phagocytosis of pneumococci and mycobacteria was impaired with higher particulate loading. High particulate loading corresponded with a lower oxidative burst capacity (P = 0.0015). There was no overall effect on killing of M. tuberculosis. Alveolar macrophage function is altered by particulate loading. Our macrophage model is comparable morphologically to the in vivo uptake of particulates. Wood smoke-exposed cells demonstrate reduced phagocytosis, but unaffected mycobacterial killing, suggesting defects related to chronic wood smoke inhalation limited to specific innate immune functions.

  13. Role of mouthguards in reducing mild traumatic brain injury/concussion incidence in high school football athletes.

    PubMed

    Winters, Jackson; DeMont, Richard

    2014-01-01

    There is continued speculation on the value of mouthguards (MGs) in preventing mild traumatic brain injury (MTBI)/concussion injuries. The purpose of this randomized prospective study was to compare the impact of pressure-laminated (LM), custom-made, properly fitted MGs to over-the-counter (OTC) MGs on the MTBI/concussion incidence in high school football athletes over a season of play. Four hundred twelve players from 6 high school football teams were included in the study. Twenty-four MTBI/concussion injuries (5.8%) were recorded. When examining the MTBI/concussion injury rate by MG type, there was a significant difference (P = 0.0423) with incidence rates of 3.6% and 8.3% in the LM MG and OTC MG groups, respectively.

  14. Bioactive Dietary Polyphenols Inhibit Heme Iron Absorption in A Dose-Dependent Manner in Human Intestinal Caco-2 cells

    PubMed Central

    Ma, Qianyi; Kim, Eun-Young; Lindsay, Elizabeth Ann; Han, Okhee

    2011-01-01

    Although heme iron is an important form of dietary iron, its intestinal absorption mechanism remains elusive. Our previous work revealed that (−)-epigallocatechin-3-gallate (EGCG) and grape seed extract (GSE) markedly inhibited intestinal heme iron absorption by reducing the basolateral iron export in Caco-2 cells. The aims of this study were to examine whether small amounts of EGCG, GSE and green tea extract (GT) could inhibit heme iron absorption, and to test whether the inhibitory action of polyphenols could be offset by ascorbic acid. A heme-55Fe absorption study was conducted by adding various concentrations of EGCG, GSE and GT to Caco-2 cells in the absence and presence of ascorbic acid. Polyphenolic compounds significantly inhibited heme-55Fe absorption in a dose-dependent manner. The addition of ascorbic acid did not modulate the inhibitory effect of dietary polyphenols on heme iron absorption when the cells were treated with polyphenols at a concentration of 46 mg/L. However, ascorbic acid was able to offset or reverse the inhibitory effects of polyphenolic compounds when lower concentrations of polyphenols were added (≤ 4.6 mg/L). Ascorbic acid modulated the heme iron absorption without changing the apical heme uptake, the expression of the proteins involved in heme metabolism and basolateral iron transport, and heme oxygenase activity, indicating that ascorbic acid may enhance heme iron absorption by modulating the intracellular distribution of 55Fe. These results imply that the regular consumption of dietary ascorbic acid can easily counteract the inhibitory effects of low concentrations of dietary polyphenols on heme iron absorption but cannot counteract the inhibitory actions of high concentrations of polyphenols. PMID:22417433

  15. Dose-dependent deleterious and salutary actions of the Nrf2 inducer dh404 in chronic kidney disease.

    PubMed

    Vaziri, Nosratola D; Liu, Shuman; Farzaneh, Seyed H; Nazertehrani, Sohrab; Khazaeli, Mahyar; Zhao, Ying-Yong

    2015-09-01

    Oxidative stress and inflammation play a central role in the progression and complications of chronic kidney disease (CKD) and are, in part, due to impairment of the Nrf2 system, which regulates the expression of antioxidant and detoxifying molecules. Natural Nrf2-inducing phytochemicals have been shown to ameliorate kidney disease in experimental animals. However, owing to adverse outcomes a clinical trial of a synthetic Nrf2 activator, bardoxolone methyl (BARD), in CKD patients was terminated. BARD activates Nrf2 via covalent modification of reactive cysteine residues in the Nrf2 repressor molecule, Keap1. In addition to Nrf2, Keap1 suppresses IKKB, the positive regulator of NF-κB. Treatment with a BARD analog, dh404, at 5-20mg/kg/day in diabetic obese Zucker rats exacerbates, whereas its use at 2mg/kg/day in 5/6 nephrectomized rats attenuates, CKD progression. We, therefore, hypothesized that deleterious effects of high-dose BARD are mediated by the activation of NF-κB. CKD (5/6 nephrectomized) rats were randomized to receive dh404 (2 or 10mg/kg/day) or vehicle for 12 weeks. The vehicle-treated group exhibited glomerulosclerosis; interstitial fibrosis and inflammation; activation of NF-κB; upregulation of oxidative, inflammatory, and fibrotic pathways; and suppression of Nrf2 activity and its key target gene products. Treatment with low-dose dh404 restored Nrf2 activity and expression of its target genes, attenuated activation of NF-κB and fibrotic pathways, and reduced glomerulosclerosis, interstitial fibrosis, and inflammation. In contrast, treatment with a high dh404 dosage intensified proteinuria, renal dysfunction, and histological abnormalities; amplified upregulation of NF-κB and fibrotic pathways; and suppressed the Nrf2 system. Thus therapy with BARD analogs exerts a dose-dependent dimorphic impact on CKD progression.

  16. A Luminal Glycoprotein Drives Dose-Dependent Diameter Expansion of the Drosophila melanogaster Hindgut Tube

    PubMed Central

    Syed, Zulfeqhar A.; Tång, Erika; Bouhin, Hervé; van Dijk-Härd, Iris F.; Uv, Anne

    2012-01-01

    An important step in epithelial organ development is size maturation of the organ lumen to attain correct dimensions. Here we show that the regulated expression of Tenectin (Tnc) is critical to shape the Drosophila melanogaster hindgut tube. Tnc is a secreted protein that fills the embryonic hindgut lumen during tube diameter expansion. Inside the lumen, Tnc contributes to detectable O-Glycans and forms a dense striated matrix. Loss of tnc causes a narrow hindgut tube, while Tnc over-expression drives tube dilation in a dose-dependent manner. Cellular analyses show that luminal accumulation of Tnc causes an increase in inner and outer tube diameter, and cell flattening within the tube wall, similar to the effects of a hydrostatic pressure in other systems. When Tnc expression is induced only in cells at one side of the tube wall, Tnc fills the lumen and equally affects all cells at the lumen perimeter, arguing that Tnc acts non-cell-autonomously. Moreover, when Tnc expression is directed to a segment of a tube, its luminal accumulation is restricted to this segment and affects the surrounding cells to promote a corresponding local diameter expansion. These findings suggest that deposition of Tnc into the lumen might contribute to expansion of the lumen volume, and thereby to stretching of the tube wall. Consistent with such an idea, ectopic expression of Tnc in different developing epithelial tubes is sufficient to cause dilation, while epidermal Tnc expression has no effect on morphology. Together, the results show that epithelial tube diameter can be modelled by regulating the levels and pattern of expression of a single luminal glycoprotein. PMID:22876194

  17. Dose-dependent functionality and toxicity of green tea polyphenols in experimental rodents.

    PubMed

    Murakami, Akira

    2014-09-01

    A large number of physiologically functional foods are comprised of plant polyphenols. Their antioxidative activities have been intensively studied for a long period and proposed to be one of the major mechanisms of action accounting for their health promotional and disease preventive effects. Green tea polyphenols (GTPs) are considered to possess marked anti-oxidative properties and versatile beneficial functions, including anti-inflammation and cancer prevention. On the other hand, some investigators, including us, have uncovered their toxicity at high doses presumably due to pro-oxidative properties. For instance, both experimental animal studies and epidemiological surveys have demonstrated that GTPs may cause hepatotoxicity. We also recently showed that diets containing high doses (0.5-1%) of a GTP deteriorated dextran sodium sulfate (DSS)-induced intestinal inflammation and carcinogenesis. In addition, colitis mode mice fed a 1% GTP exhibited symptoms of nephrotoxicity, as indicated by marked elevation of serum creatinine level. This diet also increased thiobarbituric acid-reactive substances, a reliable marker of oxidative damage, in both kidneys and livers even in normal mice, while the expression levels of antioxidant enzymes and heat shock proteins (HSPs) were diminished in colitis and normal mice. Intriguingly, GTPs at 0.01% and 0.1% showed hepato-protective activities, i.e., they significantly suppressed DSS-increased serum aspartate aminotransferase and alanine aminotransferase levels. Moreover, those diets remarkably restored DSS-down-regulated expressions of heme oxygenase-1 and HSP70 in livers and kidneys. Taken together, while low and medium doses of GTPs are beneficial in colitis model mice, unwanted side-effects occasionally emerge with high doses. This dose-dependent functionality and toxicity of GTPs are in accordance with the concept of hormesis, in which mild, but not severe, stress activates defense systems for adaptation and survival.

  18. Amphetamine Exerts Dose-Dependent Changes in Prefrontal Cortex Attractor Dynamics during Working Memory

    PubMed Central

    Balaguer-Ballester, Emili; Seamans, Jeremy K.; Phillips, Anthony G.; Durstewitz, Daniel

    2015-01-01

    Modulation of neural activity by monoamine neurotransmitters is thought to play an essential role in shaping computational neurodynamics in the neocortex, especially in prefrontal regions. Computational theories propose that monoamines may exert bidirectional (concentration-dependent) effects on cognition by altering prefrontal cortical attractor dynamics according to an inverted U-shaped function. To date, this hypothesis has not been addressed directly, in part because of the absence of appropriate statistical methods required to assess attractor-like behavior in vivo. The present study used a combination of advanced multivariate statistical, time series analysis, and machine learning methods to assess dynamic changes in network activity from multiple single-unit recordings from the medial prefrontal cortex (mPFC) of rats while the animals performed a foraging task guided by working memory after pretreatment with different doses of d-amphetamine (AMPH), which increases monoamine efflux in the mPFC. A dose-dependent, bidirectional effect of AMPH on neural dynamics in the mPFC was observed. Specifically, a 1.0 mg/kg dose of AMPH accentuated separation between task-epoch-specific population states and convergence toward these states. In contrast, a 3.3 mg/kg dose diminished separation and convergence toward task-epoch-specific population states, which was paralleled by deficits in cognitive performance. These results support the computationally derived hypothesis that moderate increases in monoamine efflux would enhance attractor stability, whereas high frontal monoamine levels would severely diminish it. Furthermore, they are consistent with the proposed inverted U-shaped and concentration-dependent modulation of cortical efficiency by monoamines. PMID:26180194

  19. Melatonin protects ram spermatozoa from cryopreservation injuries in a dose-dependent manner.

    PubMed

    Succu, Sara; Berlinguer, Fiammetta; Pasciu, Valeria; Satta, Valentina; Leoni, Giovanni G; Naitana, Salvatore

    2011-04-01

    Cryopreservation harms spermatozoa at different levels and thus impairs their fertilizing ability. The role of melatonin in protecting spermatozoa from different kind injuries has been widely reported. Thus, this study tested whether the addition of melatonin to ram semen freezing extender could exert a protective effect and ameliorate postthawing sperm function. Melatonin was added to recommended ram extender to yield five different final concentrations: 0.001, 0.01, 0.1, 1, and 10 mm. A control group without melatonin supplementation was included. Spermatozoa viability, motility parameters, and intracellular ATP concentrations were evaluated both before and after cryopreservation, while DNA integrity and in vitro fertilizing ability were evaluated only after thawing. Obtained results showed that the concentration of 1 mm melatonin led to higher viability rates, higher percentages of total motile and progressive motile spermatozoa, higher percentages of spermatozoa with average rapid and medium velocity, higher intracellular ATP concentrations, and higher DNA integrity among semen frozen in control and melatonin-supplemented extenders (P<0.05). In addition, results obtained after the IVF test showed that at 1 mm concentration, melatonin led to a faster first embryonic division and to higher total cleavage rates compared to the other experimental groups (P<0.05). No difference in embryo output was observed among the six experimental groups. In conclusion, the addition of melatonin to ram semen freezing extender protected spermatozoa during cryopreservation in a dose-dependent manner. These results are likely to be mediated by its well-known antioxidant properties, even if a direct action of the indolamine cannot be ruled out.

  20. Optimization of monoclonal antibody delivery via the lymphatics: the dose dependence

    SciTech Connect

    Steller, M.A.; Parker, R.J.; Covell, D.G.; Holton, O.D. 3d.; Keenan, A.M.; Sieber, S.M.; Weinstein, J.N.

    1986-04-01

    After interstitial injection in mice, antibody molecules enter local lymphatic vessels, flow with the lymph to regional lymph nodes, and bind to target antigens there. Compared with i.v. administration, delivery via the lymphatics provides a more efficient means for localizing antibody in lymph nodes. An IgG2a (36-7-5) directed against the murine class I major histocompatibility antigen H-2Kk has proved useful for studying the pharmacology of lymphatic delivery. At very low doses, most of the antibody remains at the injection site in Kk-positive animals. As the dose is progressively increased, most effective labeling occurs first in nodes proximal to the injection site and then in the next group of nodes along the lymphatic chain. At higher doses, antibody overflows the lymphatic system and enters the blood-stream via the thoracic duct and other lymphatic-venous connections. Once in the blood, antibody is rapidly cleared, apparently by binding to Kk-bearing cells. These findings indicate that the single-pass distribution of monoclonal antibodies in the lymphatics can be strongly dose dependent, a principle which may be of clinical significance in the improvement of immunolymphoscintigraphic imaging, especially with antibodies directed against normal and malignant lymphoid cells. Monoclonal antibodies directed against normal cell types in the lymph node may be useful for assessing the integrity of lymphatic chains by immunolymphoscintigraphy or, more speculatively, for altering the status of regional immune function. The results presented here indicate that a low or intermediate antibody dose may optimize the signal:noise ratio for imaging. In Kk-negative animals, the percentage of dose taken up in the major organs was essentially independent of the dose administered; there was no evidence for saturable sites of nonspecific binding.

  1. Field strength and dose dependence of contrast enhancement by gadolinium-based MR contrast agents.

    PubMed

    Rinck, P A; Muller, R N

    1999-01-01

    The relaxivities r1 and r2 of magnetic resonance contrast agents and the T1 relaxation time values of tissues are strongly field dependent. We present quantitative data and simulations of different gadolinium-based extracellular fluid contrast agents and the modulation of their contrast enhancement by the magnetic field to be able to answer the following questions: How are the dose and field dependences of their contrast enhancement? Is there an interrelationship between dose and field dependence? Should one increase or decrease doses at specific fields? Nuclear magnetic relaxation dispersion data were acquired for the following contrast agents: gadopentetate dimeglumine, gadoterate meglumine, gadodiamide injection, and gadoteridol injection, as well as for several normal and pathological human tissue samples. The magnetic field range stretched from 0.0002 to 4.7 T, including the entire clinical imaging range. The data acquired were then fitted with the appropriate theoretical models. The combination of the diamagnetic relaxation rates (R1 = 1/T1 and R2 = 1/T2) of tissues with the respective paramagnetic contributions of the contrast agents allowed the prediction of image contrast at any magnetic field. The results revealed a nearly identical field and dose-dependent increase of contrast enhancement induced by these contrast agents within a certain dose range. The target tissue concentration (TTC) was an important though nonlinear factor for enhancement. The currently recommended dose of 0.1 mmol/kg body weight seems to be a compromise close to the lower limits of diagnostically sufficient contrast enhancement for clinical imaging at all field strengths. At low field contrast enhancement might be insufficient. Adjustment of dose or concentration, or a new class of contrast agents with optimized relaxivity, would be a valuable contribution to a better diagnostic yield of contrast enhancement at all fields.

  2. Amphetamine Exerts Dose-Dependent Changes in Prefrontal Cortex Attractor Dynamics during Working Memory.

    PubMed

    Lapish, Christopher C; Balaguer-Ballester, Emili; Seamans, Jeremy K; Phillips, Anthony G; Durstewitz, Daniel

    2015-07-15

    Modulation of neural activity by monoamine neurotransmitters is thought to play an essential role in shaping computational neurodynamics in the neocortex, especially in prefrontal regions. Computational theories propose that monoamines may exert bidirectional (concentration-dependent) effects on cognition by altering prefrontal cortical attractor dynamics according to an inverted U-shaped function. To date, this hypothesis has not been addressed directly, in part because of the absence of appropriate statistical methods required to assess attractor-like behavior in vivo. The present study used a combination of advanced multivariate statistical, time series analysis, and machine learning methods to assess dynamic changes in network activity from multiple single-unit recordings from the medial prefrontal cortex (mPFC) of rats while the animals performed a foraging task guided by working memory after pretreatment with different doses of d-amphetamine (AMPH), which increases monoamine efflux in the mPFC. A dose-dependent, bidirectional effect of AMPH on neural dynamics in the mPFC was observed. Specifically, a 1.0 mg/kg dose of AMPH accentuated separation between task-epoch-specific population states and convergence toward these states. In contrast, a 3.3 mg/kg dose diminished separation and convergence toward task-epoch-specific population states, which was paralleled by deficits in cognitive performance. These results support the computationally derived hypothesis that moderate increases in monoamine efflux would enhance attractor stability, whereas high frontal monoamine levels would severely diminish it. Furthermore, they are consistent with the proposed inverted U-shaped and concentration-dependent modulation of cortical efficiency by monoamines. PMID:26180194

  3. Melatonin protects ram spermatozoa from cryopreservation injuries in a dose-dependent manner.

    PubMed

    Succu, Sara; Berlinguer, Fiammetta; Pasciu, Valeria; Satta, Valentina; Leoni, Giovanni G; Naitana, Salvatore

    2011-04-01

    Cryopreservation harms spermatozoa at different levels and thus impairs their fertilizing ability. The role of melatonin in protecting spermatozoa from different kind injuries has been widely reported. Thus, this study tested whether the addition of melatonin to ram semen freezing extender could exert a protective effect and ameliorate postthawing sperm function. Melatonin was added to recommended ram extender to yield five different final concentrations: 0.001, 0.01, 0.1, 1, and 10 mm. A control group without melatonin supplementation was included. Spermatozoa viability, motility parameters, and intracellular ATP concentrations were evaluated both before and after cryopreservation, while DNA integrity and in vitro fertilizing ability were evaluated only after thawing. Obtained results showed that the concentration of 1 mm melatonin led to higher viability rates, higher percentages of total motile and progressive motile spermatozoa, higher percentages of spermatozoa with average rapid and medium velocity, higher intracellular ATP concentrations, and higher DNA integrity among semen frozen in control and melatonin-supplemented extenders (P<0.05). In addition, results obtained after the IVF test showed that at 1 mm concentration, melatonin led to a faster first embryonic division and to higher total cleavage rates compared to the other experimental groups (P<0.05). No difference in embryo output was observed among the six experimental groups. In conclusion, the addition of melatonin to ram semen freezing extender protected spermatozoa during cryopreservation in a dose-dependent manner. These results are likely to be mediated by its well-known antioxidant properties, even if a direct action of the indolamine cannot be ruled out. PMID:21214627

  4. Chronic uranium exposure dose-dependently induces glutathione in rats without any nephrotoxicity.

    PubMed

    Poisson, C; Stefani, J; Manens, L; Delissen, O; Suhard, D; Tessier, C; Dublineau, I; Guéguen, Y

    2014-10-01

    Uranium is a heavy metal naturally found in the earth's crust that can contaminate the general public population when ingested. The acute effect and notably the uranium nephrotoxicity are well known but knowledge about the effect of chronic uranium exposure is less clear. In a dose-response study we sought to determine if a chronic exposure to uranium is toxic to the kidneys and the liver, and what the anti-oxidative system plays in these effects. Rats were contaminated for 3 or 9 months by uranium in drinking water at different concentrations (0, 1, 40, 120, 400, or 600 mg/L). Uranium tissue content in the liver, kidneys, and bones was linear and proportional to uranium intake after 3 and 9 months of contamination; it reached 6 μg per gram of kidney tissues for the highest uranium level in drinking water. Nevertheless, no histological lesions of the kidney were observed, nor any modification of kidney biomarkers such as creatinine or KIM-1. After 9 months of contamination at and above the 120-mg/L concentration of uranium, lipid peroxidation levels decreased in plasma, liver, and kidneys. Glutathione concentration increased in the liver for the 600-mg/L group, in the kidney it increased dose dependently, up to 10-fold, after 9 months of contamination. Conversely, chronic uranium exposure irregularly modified gene expression of antioxidant enzymes and activities in the liver and kidneys. In conclusion, chronic uranium exposure did not induce nephrotoxic effects under our experimental conditions, but instead reinforced the antioxidant system, especially by increasing glutathione levels in the kidneys.

  5. Dose dependence of mechanical properties in tantalum and tantalum alloys after low temperature irradiation

    SciTech Connect

    Byun, Thak Sang

    2008-01-01

    The dose dependence of mechanical properties was investigated for tantalum and tantalum alloys after low temperature irradiation. Miniature tensile specimens of three pure tantalum metals, ISIS Ta, Aesar Ta1, Aesar Ta2, and one tantalum alloy, Ta-1W, were irradiated by neutrons in the High Flux Isotope Reactor (HFIR) at ORNL to doses ranging from 0.00004 to 0.14 displacements per atom (dpa) in the temperature range 60 C 100 oC. Also, two tantalum-tungsten alloys, Ta-1W and Ta-10W, were irradiated by protons and spallation neutrons in the LANSCE facility at LANL to doses ranging from 0.7 to 7.5 dpa and from 0.7 to 25.2 dpa, respectively, in the temperature range 50 C 160 oC. Tensile tests were performed at room temperature and at 250oC at nominal strain rates of about 10-3 s-1. All neutron-irradiated materials underwent progressive irradiation hardening and loss of ductility with increasing dose. The ISIS Ta experienced embrittlement at 0.14 dpa, while the other metals retained significant necking ductility. Such a premature embrittlement in ISIS Ta is believed to be because of high initial oxygen concentrations picked up during a pre-irradiation anneal. The Ta-1W and Ta-10W specimens irradiated in spallation condition experienced prompt necking at yield since irradiation doses for those specimens were high ( 0.7 dpa). At the highest dose, 25.2 dpa, the Ta-10W alloy specimen broke with little necking strain. Among the test materials, the Ta-1W alloy displayed the best combination of strength and ductility. The plastic instability stress and true fracture stress were nearly independent of dose. Increasing test temperature decreased strength and delayed the onset of necking at yield.

  6. Population Pharmacokinetic Assessment and Pharmacodynamic Implications of Pediatric Cefepime Dosing for Susceptible-Dose-Dependent Organisms

    PubMed Central

    Shoji, Kensuke; Bradley, John S.; Reed, Michael D.; van den Anker, John N.; Domonoske, Christine

    2016-01-01

    The Clinical and Laboratory Standards Institute (CLSI) revised cefepime (CFP) breakpoints for Enterobacteriaceae in 2014, and MICs of 4 and 8 μg/ml were reclassified as susceptible-dose dependent (SDD). Pediatric dosing to provide therapeutic concentrations against SDD organisms has not been defined. CFP pharmacokinetics (PK) data from published pediatric studies were analyzed. Population PK parameters were determined using NONMEM, and Monte Carlo simulation was performed to determine an appropriate CFP dosage regimen for SDD organisms in children. A total of 664 CFP plasma concentrations from 91 neonates, infants, and children were included in this analysis. The median patient age was 1.0 month (interquartile range [IQR], 0.2 to 11.2 months). Serum creatinine (SCR) and postmenstrual age (PMA) were covariates in the final PK model. Simulations indicated that CFP dosing at 50 mg/kg every 8 h (q8h) (as 0.5-h intravenous [i.v.] infusions) will maintain free-CFP concentrations in serum of >4 and 8 μg/ml for >60% of the dose interval in 87.1% and 68.6% of pediatric patients (age, ≥30 days), respectively, and extending the i.v. infusion duration to 3 h results in 92.3% of patients with free-CFP levels above 8 μg/ml for >60% of the dose interval. CFP clearance (CL) is significantly correlated with PMA and SCR. A dose of 50 mg/kg of CFP every 8 to 12 h does not achieve adequate serum exposure for older children with serious infections caused by Gram-negative bacilli with a MIC of 8 μg/ml. Prolonged i.v. infusions may be useful for this population. PMID:26810655

  7. Dose-dependent and cell type-specific cell death and proliferation following in vitro exposure to radial extracorporeal shock waves.

    PubMed

    Hochstrasser, Tanja; Frank, Hans-Georg; Schmitz, Christoph

    2016-01-01

    Radial extracorporeal shock wave (rESW) therapy is widely used in musculoskeletal disorders and wound repair. However, the mechanisms of action are still largely unknown. The current study compared the effects of rESWs on two cell types. Human fetal foreskin fibroblasts (HFFF2) and human placental choriocarcinoma cell line JEG-3 were exposed to 0, 100, 200, 500 or 5000 rESWs generated with a Swiss DolorClast device (2.5 bar, 1 Hz). FACS analysis immediately after rESW exposure showed that initially, rESWs rather induced mechanical cell destruction than regulated or programmed cell death. Cell damage was nearly negated by reducing cavitation. Furthermore, cell viability decreased progressively with higher numbers of rESWs. Exposure to rESWs had no impact on growth potential of JEG-3 cells, but dose-dependently increased growth potential of HFFF2 cells. Cultivation of cells that were initially exposed to sham-rESWs in conditioned media increased the growth potential of HFFF2 cells, nevertheless, an even stronger effect was achieved by direct exposure to rESWs. Additionally, cell cycle distribution analysis demonstrated a shift in proportion from G0/G1 to G2/M phase in HFFF2 cells, but not in JEG-3 cells. These data demonstrate that rESWs leads to initial and subsequent dose-dependent and cell type-specific effects in vitro. PMID:27477873

  8. Dose-dependent and cell type-specific cell death and proliferation following in vitro exposure to radial extracorporeal shock waves

    PubMed Central

    Hochstrasser, Tanja; Frank, Hans-Georg; Schmitz, Christoph

    2016-01-01

    Radial extracorporeal shock wave (rESW) therapy is widely used in musculoskeletal disorders and wound repair. However, the mechanisms of action are still largely unknown. The current study compared the effects of rESWs on two cell types. Human fetal foreskin fibroblasts (HFFF2) and human placental choriocarcinoma cell line JEG-3 were exposed to 0, 100, 200, 500 or 5000 rESWs generated with a Swiss DolorClast device (2.5 bar, 1 Hz). FACS analysis immediately after rESW exposure showed that initially, rESWs rather induced mechanical cell destruction than regulated or programmed cell death. Cell damage was nearly negated by reducing cavitation. Furthermore, cell viability decreased progressively with higher numbers of rESWs. Exposure to rESWs had no impact on growth potential of JEG-3 cells, but dose-dependently increased growth potential of HFFF2 cells. Cultivation of cells that were initially exposed to sham-rESWs in conditioned media increased the growth potential of HFFF2 cells, nevertheless, an even stronger effect was achieved by direct exposure to rESWs. Additionally, cell cycle distribution analysis demonstrated a shift in proportion from G0/G1 to G2/M phase in HFFF2 cells, but not in JEG-3 cells. These data demonstrate that rESWs leads to initial and subsequent dose-dependent and cell type-specific effects in vitro. PMID:27477873

  9. Quantitative simulation of intracellular signaling cascades in a Virtual Liver: estimating dose dependent changes in hepatocellular proliferation and apoptosis

    EPA Science Inventory

    The US EPA Virtual Liver (v-Liver™) is developing an approach to predict dose-dependent hepatotoxicity as an in vivo tissue level response using in vitro data. The v-Liver accomplishes this using an in silico agent-based systems model that dynamically integrates environmental exp...

  10. Dose-dependent impact of pretreatment (imprinting) with histamine and serotonin on the phagocytic activity of Tetrahymena.

    PubMed

    Darvas, Z; Csaba, G

    1990-01-01

    Serotonin and histamine stimulate the phagocytic activity of Tetrahymena at primary interaction. The effect of histamine is dose-dependent. While serotonin elicits an imprinting-like phenomenon at a high concentration, histamine induces no imprinting, probably for 1 volutionary reasons.

  11. [Angiotensin II-receptor antagonists compared to other antihypertensives: still insufficient evidence for reducing the risk of cerebrovascular incidents].

    PubMed

    Meerum Terwogt, J M; Koopmans, R P; Roos, Y B W E M; van Montfrans, G A

    2008-01-12

    --There is growing evidence that angiotensin II-receptor antagonists may have protective effects for preventing cerebrovascular incidents. --It is unlikely that these effects are due only to a decrease in blood pressure. --One hypothesis is that high concentrations ofangiotensin II result in improved cerebral perfusion ofangiotensin type 2-receptor mediated mechanisms such as local vasodilatation and angiogenesis. --Several clinical and preclinical studies support this hypothesis. --The results of these studies are discussed in this overview. There is still insufficient evidence that a protective effect on the brain occurs.

  12. Role of insecticides in reducing thrips injury to plants and incidence of tomato spotted wilt virus in Virginia market-type peanut.

    PubMed

    Herbert, D Ames; Malone, S; Aref, S; Brandenburg, R L; Jordan, D L; Royals, B M; Johnson, P D

    2007-08-01

    Tomato spotted wilt virus (family Bunyaviridae, genus Tospovirus, TSWV), transmitted by many thrips species, is a devastating pathogen of peanut, Arachis hypogaea L. TSWV has become a serious problem in the Virginia/Carolina peanut-growing region of the United States. During 2002, TSWV was present in 47% of the North Carolina hectarage and caused a 5% yield reduction in Virginia. Factors influencing levels of TSWV in runner market-type peanut cultivars, which are primarily grown in Alabama, Flordia, Georgia, and Texas, have been integrated into an advisory to help those peanut growers reduce losses. An advisory based on the southeast runner market-type version is currently under development for virginia market-type peanut cultivars that are grown primarily in the Virginia/ Carolina region. A version based on preliminary field experiments was released in 2003. One factor used in both advisories relates to insecticide use to reduce the vector populations and disease incidence. This research elucidated the influence of insecticides on thrips populations, thrips plant injury, incidence of TSWV, and pod yield in virginia market-type peanut. Eight field trials from 2003 to 2005 were conducted at two locations. In-furrow application of aldicarb and phorate resulted in significant levels of thrips control, significant reductions in thrips injury to seedlings, reduced incidence of TSWV, and significant increases in pod yield. Foliar application of acephate after aldicarb or phorate applied in the seed furrow further reduced thrips plant injury and incidence of TSWV and improved yield. These findings will be used to improve the current virginia market-type TSWV advisory.

  13. Acupressure versus dilution of fentanyl to reduce incidence of fentanyl-induced cough in female cancer patients: a prospective randomized controlled study

    PubMed Central

    Doctor, Jeson Rajan; Kapila, Savi J; Gehdoo, Raghbirsingh P; Divatia, Jigeeshu V

    2016-01-01

    Background Fentanyl-induced cough (FIC) is a transient condition with a reported incidence of 18% to 65% depending on the dose and route of administration of fentanyl. Nonpharmacological methods to prevent FIC are more cost-effective than medications. Dilution of fentanyl has a proven role in the prevention of FIC. Acupressure can also prevent FIC because it has a proven role in the treatment of cough. Methods This study included 225 female patients with an American Society of Anesthesiologists physical status of I or II who were randomly divided into 3 groups of 75 patients each. Patients in the control group received undiluted fentanyl at 3 µg/kg, patients in the acupressure group received undiluted fentanyl at 3 µg/kg with acupressure, and patients in the dilution group received diluted fentanyl at 3 µg/kg. Coughing was noted within 2 min of fentanyl administration. The severity of FIC was graded as mild (1–2 coughs), moderate (3–4 coughs), or severe (≥5 coughs). The timing of coughs was also noted. Results The incidence of FIC was 12.7% in the control group, 6.8% in the dilution group, and 1.3% in the acupressure group. The difference in the incidence of cough was statistically significant (P = 0.008) between the control and acupressure groups. The difference in the severity of cough among the groups was not statistically significant. The median onset time of cough among all groups was 9 to 12 seconds. Conclusions The application of acupressure prior to administration of fentanyl significantly reduces the incidence of FIC. Dilution of fentanyl also reduces the incidence of FIC, but the difference is not statistically significant. PMID:27274367

  14. Dose-dependent tolerance to ozone. I. Tracheobronchial epithelial reorganization in rats after 20 months' exposure.

    PubMed Central

    Plopper, C. G.; Chu, F. P.; Haselton, C. J.; Peake, J.; Wu, J.; Pinkerton, K. E.

    1994-01-01

    Two salient features of the pulmonary response to reactive oxidant air pollutants such as ozone are the heterogeneity of response by site within the respiratory tract and the development of tolerance to injury with repeated exposure. The purpose of this study was to establish whether the development of tolerance to long-term exposure is associated with changes in the tracheobronchial epithelium. Male F344-N rats were exposed to 0, 0.12, 0.5, or 1.0 ppm ozone 6 hours/day for 5 days/week for 20 months and killed 1 week post-exposure. Samples for light microscopic morphometry were obtained by microdissection from each infusion-fixed trachea and left lung lobe and included: 1) a cranial bronchus with short path length (generation no. 4 to 5) and small diameter; 2) a central bronchus with short path length (generation no. 4 to 5) and large diameter; and 3) a caudal bronchus with long path length (generation no. 10 to 12) and small diameter. In addition, three sites within the central acinus were examined from cranial, central, and caudal regions. These sites included terminal bronchiole, 0.5 to 1 mm proximal to terminal bronchiole and bronchiolarized alveolar duct. Intraepithelial mucin storage (AB/PAS-positive material quantified by image analysis) within the trachea decreased with dose. Mucin storage was unchanged in the central bronchus, increased threefold with dose in the caudal bronchus, and was six times higher in the cranial bronchus at 1.0 ppm ozone. Epithelial composition was unchanged in trachea or any bronchi; however, we noted a significant dose-dependent increase in nonciliated cell mass and volume fraction in terminal bronchioles in all three regions. There was also a significant increase in nonciliated cell mass in the bronchiolarized alveolar ducts. Bronchiolar nonciliated cells were identified greater than fourfold further into alveolar ducts in 1.0 ppm exposed than in 0 ppm animals. Nonciliated cells occurred almost 200 microns deeper into alveolar

  15. In vitro monitoring of time and dose dependent cytotoxicity of aminated nanoparticles using Raman spectroscopy.

    PubMed

    Efeoglu, Esen; Casey, Alan; Byrne, Hugh J

    2016-09-21

    concentrations, the most significant changes were observed in the cytoplasm for both time dependent and dose dependent cases due to the route of endocytosis. The Raman spectral markers for lipidosis, ROS formation and oxidative stress related biochemical damage are determined and correlated with exposure dose and time, and the responses are correlated with conventional cytotoxicity assays.

  16. Time- and dose-dependent effects of roundup on human embryonic and placental cells.

    PubMed

    Benachour, N; Sipahutar, H; Moslemi, S; Gasnier, C; Travert, C; Séralini, G E

    2007-07-01

    Roundup is the major herbicide used worldwide, in particular on genetically modified plants that have been designed to tolerate it. We have tested the toxicity and endocrine disruption potential of Roundup (Bioforce on human embryonic 293 and placental-derived JEG3 cells, but also on normal human placenta and equine testis. The cell lines have proven to be suitable to estimate hormonal activity and toxicity of pollutants. The median lethal dose (LD(50)) of Roundup with embryonic cells is 0.3% within 1 h in serum-free medium, and it decreases to reach 0.06% (containing among other compounds 1.27 mM glyphosate) after 72 h in the presence of serum. In these conditions, the embryonic cells appear to be 2-4 times more sensitive than the placental ones. In all instances, Roundup (generally used in agriculture at 1-2%, i.e., with 21-42 mM glyphosate) is more efficient than its active ingredient, glyphosate, suggesting a synergistic effect provoked by the adjuvants present in Roundup. We demonstrated that serum-free cultures, even on a short-term basis (1 h), reveal the xenobiotic impacts that are visible 1-2 days later in serum. We also document at lower non-overtly toxic doses, from 0.01% (with 210 microM glyphosate) in 24 h, that Roundup is an aromatase disruptor. The direct inhibition is temperature-dependent and is confirmed in different tissues and species (cell lines from placenta or embryonic kidney, equine testicular, or human fresh placental extracts). Furthermore, glyphosate acts directly as a partial inactivator on microsomal aromatase, independently of its acidity, and in a dose-dependent manner. The cytotoxic, and potentially endocrine-disrupting effects of Roundup are thus amplified with time. Taken together, these data suggest that Roundup exposure may affect human reproduction and fetal development in case of contamination. Chemical mixtures in formulations appear to be underestimated regarding their toxic or hormonal impact.

  17. Perinatal bisphenol A exposure promotes dose-dependent alterations of the mouse methylome

    PubMed Central

    2014-01-01

    Background Environmental factors during perinatal development may influence developmental plasticity and disease susceptibility via alterations to the epigenome. Developmental exposure to the endocrine active compound, bisphenol A (BPA), has previously been associated with altered methylation at candidate gene loci. Here, we undertake the first genome-wide characterization of DNA methylation profiles in the liver of murine offspring exposed perinatally to multiple doses of BPA through the maternal diet. Results Using a tiered focusing approach, our strategy proceeds from unbiased broad DNA methylation analysis using methylation-based next generation sequencing technology to in-depth quantitative site-specific CpG methylation determination using the Sequenom EpiTYPER MassARRAY platform to profile liver DNA methylation patterns in offspring maternally exposed to BPA during gestation and lactation to doses ranging from 0 BPA/kg (Ctr), 50 μg BPA/kg (UG), or 50 mg BPA/kg (MG) diet (N = 4 per group). Genome-wide analyses indicate non-monotonic effects of DNA methylation patterns following perinatal exposure to BPA, corroborating previous studies using multiple doses of BPA with non-monotonic outcomes. We observed enrichment of regions of altered methylation (RAMs) within CpG island (CGI) shores, but little evidence of RAM enrichment in CGIs. An analysis of promoter regions identified several hundred novel BPA-associated methylation events, and methylation alterations in the Myh7b and Slc22a12 gene promoters were validated. Using the Comparative Toxicogenomics Database, a number of candidate genes that have previously been associated with BPA-related gene expression changes were identified, and gene set enrichment testing identified epigenetically dysregulated pathways involved in metabolism and stimulus response. Conclusions In this study, non-monotonic dose dependent alterations in DNA methylation among BPA-exposed mouse liver samples and their relevant pathways

  18. Prophylactic administration of a combined prebiotic and probiotic, or therapeutic administration of enrofloxacin, to reduce the incidence of bacterial chondronecrosis with osteomyelitis in broilers.

    PubMed

    Wideman, R F; Al-Rubaye, A; Kwon, Y M; Blankenship, J; Lester, H; Mitchell, K N; Pevzner, I Y; Lohrmann, T; Schleifer, J

    2015-01-01

    Bacteria entering the bloodstream via translocation from the gastrointestinal tract spread hematogenously and can trigger bacterial chondronecrosis with osteomyelitis (BCO) by infecting osteochondrotic microfractures in the epiphyseal-physeal cartilage of the proximal femora and tibiae. In experiment 1, broilers were fed control feed or the same feed containing BacPack 2X, which includes the prebiotic IMW50 (a mannan oligosaccharide beta-glucan yeast cell wall product) plus the probiotic Calsporin (Bacillus subtilis C-3102). Broilers reared on wire flooring consistently developed higher incidences of BCO than hatchmates reared on wood shavings litter (≥24 vs. ≤4%, respectively; P=0.001). Adding BacPack 2X to the feed on d 1 through 56 delayed the age of onset and reduced the cumulative incidence of BCO on wire flooring when compared with broilers fed the control feed (24.0 vs. 40.7%, respectively; P=0.003). In experiment 2, broilers reared on wire flooring received tap water on d 1 through 62 (control group) or therapeutic levels of the potent fluoroquinolone antimicrobial enrofloxacin in the water on d 35 through 54 (enrofloxacin group). During enrofloxacin administration, half as many birds developed BCO in the enrofloxacin group when compared with the control group (8.1 vs. 19.5%, respectively, on d 35 through 54; P=0.001), whereas both groups had similar BCO incidences subsequent to withdrawing enrofloxacin on d 55 through 62 (14.8 vs. 18.2% for the enrofloxacin vs. control groups; P=0.386). Cumulative lameness incidences for d 1 through 62 were higher for the control group than for the enrofloxacin group (39.0 vs. 25.8%, respectively; P=0.003). These results demonstrate that wire flooring imposes a rigorous challenge that leads to high incidences of BCO that can be difficult to suppress, even with therapeutic doses of enrofloxacin. Prophylactically adding BacPack 2X to the feed reduced the incidence of BCO lameness by a proportion similar to that achieved

  19. A cost-effectiveness analysis of identifying Fusobacterium necrophorum in throat swabs followed by antibiotic treatment to reduce the incidence of Lemierre's syndrome and peritonsillar abscesses.

    PubMed

    Bank, S; Christensen, K; Kristensen, L H; Prag, J

    2013-01-01

    The main purpose of this paper was to estimate the cost per quality-adjusted life year (QALY) saved by identifying Fusobacterium necrophorum in throat swabs followed by proper antibiotic treatment, to reduce the incidence of Lemierre's syndrome and peritonsillar abscesses (PTA) originating from a pharyngitis. The second purpose was to estimate the population size required to indicate that antibiotic treatment has an effect. Data from publications and our laboratory were collected. Monte Carlo simulation and one-way sensitivity analysis were used to analyse cost-effectiveness. The cost-effectiveness analysis shows that examining throat swabs from 15- to 24-year-olds for F. necrophorum followed by antibiotic treatment will probably be less costly than most other life-saving medical interventions, with a median cost of US$8,795 per QALY saved. To indicate a reduced incidence of Lemierre's syndrome and PTA in Denmark, the intervention probably has to be followed for up to 5 years. Identifying F. necrophorum in throat swabs from 15- to 24-year-olds followed by proper antibiotic treatment only requires a reduction of 20-25 % in the incidence of Lemierre's syndrome and PTA to be cost-effective. This study warrants further examination of the effect of antibiotic treatment on the outcome of F. necrophorum acute and recurrent pharyngitis, as well as the effect on Lemierre's syndrome and PTA.

  20. Reduced Ovarian Cancer Incidence in Women Exposed to Low Dose Ionizing Background Radiation or Radiation to the Ovaries after Treatment for Breast Cancer or Rectosigmoid Cancer

    PubMed Central

    Lehrer, Steven; Green, Sheryl; Rosenzweig, Kenneth E

    2016-01-01

    Background High dose ionizing radiation can induce ovarian cancer, but the effect of low dose radiation on the development of ovarian cancer has not been extensively studied. We evaluated the effect of low dose radiation and total background radiation, and the radiation delivered to the ovaries during the treatment of rectosigmoid cancer and breast cancer on ovarian cancer incidence. Materials and Methods Background radiation measurements are from Assessment of Variations in Radiation Exposure in the United States, 2011. Ovarian cancer incidence data are from the Centers for Disease Control and Prevention. Standardized incidence ratios (SIR) of ovarian cancer following breast cancer and rectosigmoid cancer are from Surveillance, Epidemiology, and End Results (SEER) data. Obesity data by US state are from the Centers for Disease Control and Prevention. Mean ages of US state populations are from the United States Census Bureau. Results We calculated standardized incidence ratios (SIR) from Surveillance, Epidemiology, and End Results (SEER) data, which reveal that in 194,042 cases of breast cancer treated with beam radiation, there were 796 cases of ovarian cancer by 120+ months of treatment (0.41%); in 283, 875 cases of breast cancer not treated with radiation, there were 1,531 cases of ovarian cancer by 120+ months (0.54%). The difference in ovarian cancer incidence in the two groups was significant (p < 0.001, two tailed Fisher exact test). The small dose of scattered ovarian radiation (about 3.09 cGy) from beam radiation to the breast appears to have reduced the risk of ovarian cancer by 24%. In 13,099 cases of rectal or rectosigmoid junction cancer treated with beam radiation in the SEER data, there were 20 cases of ovarian cancer by 120+ months of treatment (0.15%). In 33,305 cases of rectal or rectosigmoid junction cancer not treated with radiation, there were 91 cases of ovarian cancer by 120+ months (0.27%). The difference in ovarian cancer incidence in the

  1. Dose dependence of the production yield of endohedral 133Xe-fullerene by ion implantation

    NASA Astrophysics Data System (ADS)

    Watanabe, S.; Ishioka, N. S.; Shimomura, H.; Muramatsu, H.; Sekine, T.

    2003-05-01

    The production yield of endohedral 133Xe-fullerene by ion implantation has been studied by taking advantage of the radioactivity of 133Xe. Fullerene targets, which were produced by vacuum evaporation of C 60 or C 70 on a Ni backing, were bombarded with 30-38 keV 133Xe ions by using an isotope separator at doses ranging from 1 × 10 12 to 1 × 10 14 cm -2. The production yield of endohedral 133Xe-fullerene was determined by an high performance liquid chromatography analysis following the dissolution of the targets in o-dichlorobenzene. It was found that the production yield decreased with increasing dose and incident energy, and the production yield of 133Xe@C 70 was higher than that of 133Xe@C 60 for the same dose and incident energy. Those production yields are discussed in connection with amorphization of fullerene molecules in collisions with 133Xe ions.

  2. Dose-Dependent Response of Personal Glucose Meters to Nicotinamide Coenzymes: Applications to Point-of-Care Diagnostics of Many Non-Glucose Targets in a Single Step.

    PubMed

    Zhang, Jingjing; Xiang, Yu; Wang, Miao; Basu, Ananda; Lu, Yi

    2016-01-11

    We report a discovery that personal glucose meters (PGMs) can give a dose-dependent response to nicotinamide coenzymes, such as the reduced form of nicotinamide adenine dinucleotide (NADH). We have developed methods that take advantage of this discovery to perform one-step homogeneous assays of many non-glucose targets that are difficult to recognize by DNAzymes, aptamers, or antibodies, and without the need for conjugation and multiple steps of sample dilution, separation, or fluid manipulation. The methods are based on the target-induced consumption or production of NADH through cascade enzymatic reactions. Simultaneous monitoring of the glucose and L-lactate levels in human plasma from patients with diabetes is demonstrated and the results are comparable to those from current standard test methods. Since a large number of commercially available enzymatic assay kits utilize NADH in their detection, this discovery will allow the transformation of almost all of these clinical lab tests into POC tests that use a PGM.

  3. Methotrexate Reduces the Incidence of Severe Acute Graft-versus-Host Disease without Increasing the Risk of Relapse after Reduced-Intensity Allogeneic Stem Cell Transplantation from Unrelated Donors.

    PubMed

    Vigouroux, Stéphane; Tabrizi, Reza; Melot, Cyril; Coiffard, Joelle; Lafarge, Xavier; Marit, Gérald; Bouabdallah, Krimo; Pigneux, Arnaud; Leguay, Thibaut; Dilhuydy, Marie-Sarah; Schmitt, Anna; Boiron, Jean-Michel; Milpied, Noël

    2011-01-01

    Optimized prophylaxis against graft-versus-host disease (GVHD) after unrelated reduced-intensity allogeneic transplantation when preceded by a conditioning regimen utilizing antithymocyte globulin (ATG) is poorly defined. To investigate the effects of methotrexate (MTX) in this treatment setting, we conducted a retrospective analysis. Sixty-three patients were selected based on the administration of a total dose of 5 mg/kg of ATG in the conditioning regimen and then separated into either group M+ (n = 39), which received MTX or group M- (n = 24), which did not. All patients received cyclosporine. In the M- and M+ groups, cumulative incidences (CI) of grade III-IV acute GVHD (aGVHD) were 43% and 10%, respectively (P = .002). Multivariate analysis indicated that grade III-IV aGVHD was favored by both the absence of MTX and the provision of a female donor for a male recipient. At 2 years, the M+ and M- groups exhibited, respectively: overall survival of 69% and 40% (P = .06), disease-free survival of 57% and 43% (P = .2), nonrelapse mortality of 20% and 44% (P = .1), and incidence of relapse of 27% and 35% (P = .6). These data suggest that MTX reduces the incidence of severe aGVHD without increasing the risk of relapse but with an accompanying trend toward improved survival after unrelated reduced-intensity transplantation with ATG in the conditioning regimen.

  4. Folic Acid supplementary reduce the incidence of adenocarcinoma in a mouse model of colorectal cancer: microarray gene expression profile

    PubMed Central

    2011-01-01

    Background Whether Folic acid is a potential drug that may prevent the progression of colorectal carcinoma and when to use are important healthy issues we focus on. Our study is to examine the effect of folic acid on the development of the CRC and the optimal time folic acid should be provided in a mouse-ICR model induced by 1, 2-Dimethylhydrazine. Also, we investigated the gene expression profile of this model related to folic acid. Method Female ICR mouse (n = 130) were divided into 7 groups either with the treatment of 1, 2-Dimethylhydrazine (20 mg/kg bodyweight) weekly or folic acid (8 mg/kg bodyweight) twice a week for 12 or 24 weeks. Using a 4 × 44 K Agilent whole genome oligo microarray assay, different gene expression among groups (NS, DMH, FA2, FA3) were identified and selected genes were validated by real-time polymerase chain reaction. Results Animals with a supplementary of folic acid showed a significant decrease in the incidence, the maximum diameter and multiplicity of adenocarcinomas (P < 0.05). Furthermore, there were fewer adenomas or adenocarcinomas developed in the group of folic acid supplementation in pre-adenoma stage compared to group of post-adenoma stage. Meanwhile, about 1070 genes that were changed by 1, 2-Dimethylhydrazine can be reversed by folic acid and 172 differentially genes were identified between the groups of pre- and post- adenoma stage using microarray gene expression analysis. Conclusion Our study demonstrated that folic acid supplementary was significantly associated with the decrease risk of CRC. And the subgroup of providing folic acid without precancerous lesions was more effective than that with precancerous lesions. PMID:22206623

  5. Reducing a spatial database to its effective dimensionality for logistic-regression analysis of incidence of livestock disease.

    PubMed

    Duchateau, L; Kruska, R L; Perry, B D

    1997-10-01

    Large databases with multiple variables, selected because they are available and might provide an insight into establishing causal relationships, are often difficult to analyse and interpret because of multicollinearity. The objective of this study was to reduce the dimensionality of a multivariable spatial database of Zimbabwe, containing many environmental variables that were collected to predict the distribution of outbreaks of theileriosis (the tick-borne infection of cattle caused by Theileria parva and transmitted by the brown ear tick). Principal-component analysis and varimax rotation of the principal components were first used to select a reduced number of variables. The logistic-regression model was evaluated by appropriate goodness-of-fit tests.

  6. Use of External Beam Radiotherapy Is Associated With Reduced Incidence of Second Primary Head and Neck Cancer: A SEER Database Analysis

    SciTech Connect

    Rusthoven, Kyle; Chen Changhu Raben, David; Kavanagh, Brian

    2008-05-01

    Purpose: Patients with head and neck cancer have a significant risk of developing a second primary cancer of the head and neck. We hypothesized that treatment with external beam radiotherapy (RT) might reduce this risk, because RT can eradicate occult foci of second head and neck cancer (HNCA). Methods and Materials: The data of patients with Surveillance, Epidemiology, and End Results Historic Stage A localized squamous cell carcinoma of the oral cavity, larynx, and pharynx were queried using the Surveillance, Epidemiology, and End Results database. For patients treated with or without RT, the incidence of second HNCA was determined and compared using the log-rank method. Cox proportional hazards analysis was performed for each site, evaluating the influence of covariates on the risk of second HNCA. Results: Between 1973 and 1997, 27,985 patients were entered with localized HNCA. Of these patients, 44% had received RT and 56% had not. The 15-year incidence of second HNCA was 7.7% with RT vs. 10.5% without RT (hazard ratio 0.71, p <0.0001). The effect of RT was more profound in patients diagnosed between 1988 and 1997 (hazard ratio 0.53, p <0.0001) and those with pharynx primaries (hazard ratio 0.47, p <0.0001). On multivariate analysis, RT was associated with a reduced risk of second HNCA for pharynx (p <0.0001) and larynx (p = 0.04) tumors. For oral cavity primaries, RT was associated with an increased risk of second HNCA in patients treated before 1988 (p <0.001), but had no influence on patients treated between 1988 and 1997 (p = 0.91). Conclusion: For localized HNCA, RT is associated with a reduced incidence of second HNCA. These observations are consistent with the eradication of microscopic foci of second HNCA with external beam RT.

  7. Fibrinolytic Activity and Dose-Dependent Effect of Incubating Human Blood Clots in Caffeic Acid Phenethyl Ester: In Vitro Assays

    PubMed Central

    Elnager, Abuzar; Hassan, Rosline; Idris, Zamzuri; Mustafa, Zulkifli; Wan-Arfah, Nadiah; Sulaiman, S. A.; Gan, Siew Hua; Abdullah, Wan Zaidah

    2015-01-01

    Background. Caffeic acid phenethyl ester (CAPE) has been reported to possess time-dependent fibrinolytic activity by in vitro assay. This study is aimed at investigating fibrinolytic dose-dependent activity of CAPE using in vitro assays. Methods. Standardized human whole blood (WB) clots were incubated in either blank controls or different concentrations of CAPE (3.75, 7.50, 15.00, 22.50, and 30.00 mM). After 3 hours, D-dimer (DD) levels and WB clot weights were measured for each concentration. Thromboelastography (TEG) parameters were recorded following CAPE incubation, and fibrin morphology was examined under a confocal microscope. Results. Overall, mean DD (μg/mL) levels were significantly different across samples incubated with different CAPE concentrations, and the median pre- and postincubation WB clot weights (grams) were significantly decreased for each CAPE concentration. Fibrin removal was observed microscopically and indicated dose-dependent effects. Based on the TEG test, the Ly30 fibrinolytic parameter was significantly different between samples incubated with two different CAPE concentrations (15.0 and 22.50 mM). The 50% effective dose (ED50) of CAPE (based on DD) was 1.99 mg/mL. Conclusions. This study suggests that CAPE possesses fibrinolytic activity following in vitro incubation and that it has dose-dependent activities. Therefore, further investigation into CAPE as a potential alternative thrombolytic agent should be conducted. PMID:25664321

  8. Statins Dose-Dependently Exert Significant Chemopreventive Effects Against Various Cancers in Chronic Obstructive Pulmonary Disease Patients: A Population-Based Cohort Study

    PubMed Central

    Chen, Chun-Chao; Hsu, Yi-Ping; Liu, Ju-Chi; Kao, Pai-Feng; Sung, Li-Chin; Lin, Chao-Feng; Hao, Wen-Rui; Liu, Shing-Hwa; Wu, Szu-Yuan

    2016-01-01

    PURPOSE: Chronic obstructive pulmonary disease (COPD) is associated with an increased cancer risk. We evaluated the chemopreventive effect of statins against all cancers in COPD patients and identified the statin with the strongest chemopreventive effect. PATIENTS AND METHODS: All patients diagnosed with COPD at health care facilities in Taiwan (n = 116,017) from January 1, 2001, to December 31, 2012, were recruited. Each patient was followed to assess the following protective and risk factors for all cancers: age; sex; comorbidities (diabetes, hypertension, dyslipidemia) and the Charlson comorbidity index [CCI]); urbanization level; monthly income; and nonstatin drug use. The index date of statins use was the date of COPD confirmation. Propensity scores (PSs) were derived using a logistic regression model to estimate the effect of statins by considering the covariates predicting intervention (statins) receipt. To examine the dose-response relationship, we categorized statin use into four groups in each cohort (<28 [statin nonusers], 28-90, 91-365, and >365 cumulative defined daily dose). RESULTS: After PS adjustment for age, sex, CCI, diabetes, hypertension, dyslipidemia, urbanization level, and monthly income, we analyzed the all-cancer risk. The adjusted hazard ratios (aHRs) for the all-cancer risk were lower among statin users than among statin nonusers (aHR = 0.46, 95% confidence interval: 0.43 to 0.50). The aHRs for the all-cancer risk were lower among patients using rosuvastatin, simvastatin, atorvastatin, pravastatin, and fluvastatin than among statin nonusers (aHRs = 0.42, 0.55, 0.59, 0.66, and 0.78, respectively). Sensitivity analysis indicated that statins dose-dependently reduced the all-cancer risk. CONCLUSION: Statins dose-dependently exert a significant chemopreventive effect against various cancers in COPD patients. In particular, rosuvastatin has the strongest chemopreventive effect.

  9. Dose-Dependent AMPK-Dependent and Independent Mechanisms of Berberine and Metformin Inhibition of mTORC1, ERK, DNA Synthesis and Proliferation in Pancreatic Cancer Cells

    PubMed Central

    Ming, Ming; Sinnett-Smith, James; Wang, Jia; Soares, Heloisa P.; Young, Steven H.; Eibl, Guido; Rozengurt, Enrique

    2014-01-01

    Natural products represent a rich reservoir of potential small chemical molecules exhibiting anti-proliferative and chemopreventive properties. Here, we show that treatment of pancreatic ductal adenocarcinoma (PDAC) cells (PANC-1, MiaPaCa-2) with the isoquinoline alkaloid berberine (0.3–6 µM) inhibited DNA synthesis and proliferation of these cells and delay the progression of their cell cycle in G1. Berberine treatment also reduced (by 70%) the growth of MiaPaCa-2 cell growth when implanted into the flanks of nu/nu mice. Mechanistic studies revealed that berberine decreased mitochondrial membrane potential and intracellular ATP levels and induced potent AMPK activation, as shown by phosphorylation of AMPK α subunit at Thr-172 and acetyl-CoA carboxylase (ACC) at Ser79. Furthermore, berberine dose-dependently inhibited mTORC1 (phosphorylation of S6K at Thr389 and S6 at Ser240/244) and ERK activation in PDAC cells stimulated by insulin and neurotensin or fetal bovine serum. Knockdown of α1 and α2 catalytic subunit expression of AMPK reversed the inhibitory effect produced by treatment with low concentrations of berberine on mTORC1, ERK and DNA synthesis in PDAC cells. However, at higher concentrations, berberine inhibited mitogenic signaling (mTORC1 and ERK) and DNA synthesis through an AMPK-independent mechanism. Similar results were obtained with metformin used at doses that induced either modest or pronounced reductions in intracellular ATP levels, which were virtually identical to the decreases in ATP levels obtained in response to berberine. We propose that berberine and metformin inhibit mitogenic signaling in PDAC cells through dose-dependent AMPK-dependent and independent pathways. PMID:25493642

  10. Statins Dose-Dependently Exert Significant Chemopreventive Effects Against Various Cancers in Chronic Obstructive Pulmonary Disease Patients: A Population-Based Cohort Study

    PubMed Central

    Chen, Chun-Chao; Hsu, Yi-Ping; Liu, Ju-Chi; Kao, Pai-Feng; Sung, Li-Chin; Lin, Chao-Feng; Hao, Wen-Rui; Liu, Shing-Hwa; Wu, Szu-Yuan

    2016-01-01

    PURPOSE: Chronic obstructive pulmonary disease (COPD) is associated with an increased cancer risk. We evaluated the chemopreventive effect of statins against all cancers in COPD patients and identified the statin with the strongest chemopreventive effect. PATIENTS AND METHODS: All patients diagnosed with COPD at health care facilities in Taiwan (n = 116,017) from January 1, 2001, to December 31, 2012, were recruited. Each patient was followed to assess the following protective and risk factors for all cancers: age; sex; comorbidities (diabetes, hypertension, dyslipidemia) and the Charlson comorbidity index [CCI]); urbanization level; monthly income; and nonstatin drug use. The index date of statins use was the date of COPD confirmation. Propensity scores (PSs) were derived using a logistic regression model to estimate the effect of statins by considering the covariates predicting intervention (statins) receipt. To examine the dose-response relationship, we categorized statin use into four groups in each cohort (<28 [statin nonusers], 28-90, 91-365, and >365 cumulative defined daily dose). RESULTS: After PS adjustment for age, sex, CCI, diabetes, hypertension, dyslipidemia, urbanization level, and monthly income, we analyzed the all-cancer risk. The adjusted hazard ratios (aHRs) for the all-cancer risk were lower among statin users than among statin nonusers (aHR = 0.46, 95% confidence interval: 0.43 to 0.50). The aHRs for the all-cancer risk were lower among patients using rosuvastatin, simvastatin, atorvastatin, pravastatin, and fluvastatin than among statin nonusers (aHRs = 0.42, 0.55, 0.59, 0.66, and 0.78, respectively). Sensitivity analysis indicated that statins dose-dependently reduced the all-cancer risk. CONCLUSION: Statins dose-dependently exert a significant chemopreventive effect against various cancers in COPD patients. In particular, rosuvastatin has the strongest chemopreventive effect. PMID:27698930

  11. Mediterranean Diet Reduces the Adverse Effect of the TCF7L2-rs7903146 Polymorphism on Cardiovascular Risk Factors and Stroke Incidence

    PubMed Central

    Corella, Dolores; Carrasco, Paula; Sorlí, Jose V.; Estruch, Ramón; Rico-Sanz, Jesús; Martínez-González, Miguel Ángel; Salas-Salvadó, Jordi; Covas, M. Isabel; Coltell, Oscar; Arós, Fernando; Lapetra, José; Serra-Majem, Lluís; Ruiz-Gutiérrez, Valentina; Warnberg, Julia; Fiol, Miquel; Pintó, Xavier; Ortega-Azorín, Carolina; Muñoz, Miguel Ángel; Martínez, J. Alfredo; Gómez-Gracia, Enrique; González, José I.; Ros, Emilio; Ordovás, José M.

    2013-01-01

    OBJECTIVE Transcription factor 7-like 2 (TCF7L2) polymorphisms are strongly associated with type 2 diabetes, but controversially with plasma lipids and cardiovascular disease. Interactions of the Mediterranean diet (MedDiet) on these associations are unknown. We investigated whether the TCF7L2-rs7903146 (C>T) polymorphism associations with type 2 diabetes, glucose, lipids, and cardiovascular disease incidence were modulated by MedDiet. RESEARCH DESIGN AND METHODS A randomized trial (two MedDiet intervention groups and a control group) with 7,018 participants in the PREvención con DIetaMEDiterránea study was undertaken and major cardiovascular events assessed. Data were analyzed at baseline and after a median follow-up of 4.8 years. Multivariable-adjusted Cox regression was used to estimate hazard ratios (HRs) for cardiovascular events. RESULTS The TCF7L2-rs7903146 polymorphism was associated with type 2 diabetes (odds ratio 1.87 [95% CI 1.62–2.17] for TT compared with CC). MedDiet interacted significantly with rs7903146 on fasting glucose at baseline (P interaction = 0.004). When adherence to the MedDiet was low, TT had higher fasting glucose concentrations (132.3 ± 3.5 mg/dL) than CC+CT (127.3 ± 3.2 mg/dL) individuals (P = 0.001). Nevertheless, when adherence was high, this increase was not observed (P = 0.605). This modulation was also detected for total cholesterol, LDL cholesterol, and triglycerides (P interaction < 0.05 for all). Likewise, in the randomized trial, TT subjects had a higher stroke incidence in the control group (adjusted HR 2.91 [95% CI 1.36–6.19]; P = 0.006 compared with CC), whereas dietary intervention with MedDiet reduced stroke incidence in TT homozygotes (adjusted HR 0.96 [95% CI 0.49–1.87]; P = 0.892 for TT compared with CC). CONCLUSIONS Our novel results suggest that MedDiet may not only reduce increased fasting glucose and lipids in TT individuals, but also stroke incidence. PMID:23942586

  12. Time- and dose-dependent effects of ethanol on mouse embryonic stem cells.

    PubMed

    Worley, Sarah L; Vaughn, Brittney J; Terry, Alexander I; Gardiner, Catherine S; DeKrey, Gregory K

    2015-11-01

    Ethanol is a common solvent used with mouse embryonic stem (mES) cells in protocols to test chemicals for evidence of developmental toxicity. In this study, dose-response relationships for ethanol toxicity in mES cells were examined. For cells maintained in an undifferentiated state, ethanol significantly reduced viable cell numbers with estimated half maximal inhibitory concentrations of 1.5% and 0.8% ethanol after 24 and 48h, respectively, observations which correlated with significantly increased expression of apoptotic markers. For cells cultured to induce cardiomyocyte formation, up to 0.5% ethanol during the first two days failed to alter the outcome of differentiation, whereas 0.3% ethanol for 11 days significantly reduced the fraction of cultures containing contracting areas, an observation that correlated with significantly reduced cell numbers. These results suggest that ethanol is not an inert solvent at concentrations that might be used for developmental toxicity testing.

  13. Pretreatment with Assafoetida exerts dose-dependent dual effects on rat hearts

    PubMed Central

    Esmailidehaj, Mansour; Kakoo, Mohadeseh; Rezvani, Mohammad Ebrahim; Mosaddeghmehrjardi, Mohammad Hossein

    2014-01-01

    Context: Although many studies displayed the favorable effects of Assafoetida, some of them reported that high doses of Assafoetida could lead to harmful effects. Aims: In this study, the effect of pretreatment with Assafoetida investigated on ischemic–reperfusion injury in isolated rat heart model. Materials and Methods: Thirty two male Wistar rats were divided into 4 groups of eight. Group 1 as the control (Con) group and three other groups as the treatment groups that given Assafoetida by gavage at levels of 25, 50 and 100 mg/kg, once a day for four weeks (T25, T50 and T100 groups). Then their hearts were subjected to 30 min global ischemia and 90 min reperfusion under langendorff apparatus. Results: The data shown that hemodynamic parameters including left ventricular developed pressure (LVDP) and maximum and minimum of pressure changes (±dp/dt) were increased in T25 and decreased in T50 and T100 groups during reperfusion in comparison with Con group. There was not any significant difference in the incidence of irreversible ventricular fibrillation between T25 and Con group, while it was increased in T50 and T100 groups significantly. There was not any significant difference in infarct size between all groups. Conclusion: These data indicate that pretreatment of rats with Assafoetida have cardioprotective effects in low doses and cardiotoxic effects in higher doses. Therefore, it needs more investigation in the future. PMID:24914280

  14. Dose dependency of time of onset of radiation-induced growth hormone deficiency

    SciTech Connect

    Clayton, P.E.; Shalet, S.M. )

    1991-02-01

    Growth hormone (GH) secretion during insulin-induced hypoglycemia was assessed on 133 occasions in 82 survivors of childhood malignant disease. All had received cranial irradiation with a dose range to the hypothalamic-pituitary axis of 27 to 47.5 Gy (estimated by a schedule of 16 fractions over 3 weeks) and had been tested on one or more occasions between 0.2 and 18.9 years after treatment. Results of one third of the GH tests were defined as normal (GH peak response, greater than 15 mU/L) within the first 5 years, in comparison with 16% after 5 years. Stepwise multiple linear regression analysis showed that dose (p = 0.007) and time from irradiation (p = 0.03), but not age at therapy, had a significant influence on peak GH responses. The late incidence of GH deficiency was similar over the whole dose range (4 of 26 GH test results normal for less than 30 Gy and 4 of 25 normal for greater than or equal to 30 Gy after 5 years), but the speed of onset over the first years was dependent on dose. We conclude that the requirement for GH replacement therapy and the timing of its introduction will be influenced by the dose of irradiation received by the hypothalamic-pituitary axis.

  15. Oxytocin treatment immediately after calving does not reduce the incidence of retained fetal membranes or improve reproductive performance in crossbred Zebu cows.

    PubMed

    Palomares, R A; Gutiérrez, J C; Portillo, G; Boscan, J C; Montero, M; López, Y; Maxwell, H S; Carson, R L; Soto, E

    2010-11-01

    The objective was to determine the effect of oxytocin treatments after calving on the incidence of RFM and reproductive performance in dual purpose cows under tropical conditions. Five hundred thirty six pluriparous, crossbred Zebu cows were randomly assigned to two groups: Oxy (n = 280): cows were given 30 IU of oxytocin im immediately after normal unassisted calving, and again 6 h later; C (n = 256): control. Expulsion of fetal membranes was evaluated 24 h after delivery. After a 30-d voluntary waiting period, AI was done 12 h after cows were detected in estrus. Oxytocin had no effect on the incidence of RFM (4.6 vs. 3.1% for Oxy and C, respectively, P > 0.05). Cows in Oxy and C had similar first service and overall pregnancy rates (54.0 vs. 47.8% and 75.4 vs. 73.4%; respectively, P > 0.05). There were no differences between Oxy and C for calving to first estrus (83.6 ± 3.7 vs. 77.2 ± 3.8 d) and calving to conception intervals (113.6 ± 5.0 vs. 110.5 ± 5.2 d), as well as rates of anestrus (13.6 vs. 13.7%), repeat breeding (21.8 vs. 20.7%), and culling (15.7 vs. 16.4%). In conclusion, oxytocin treatment after normal unassisted calving did not significantly reduce the incidence of RFM or improve reproductive performance in crossbred Zebu cows under tropical conditions.

  16. Dose-Dependent Pulmonary Toxicity After Postoperative Intensity-Modulated Radiotherapy for Malignant Pleural Mesothelioma

    SciTech Connect

    Rice, David C. Smythe, W. Roy; Liao Zhongxing; Guerrero, Thomas; Chang, Joe Y.; McAleer, Mary F.; Jeter, Melenda D.; Correa, Arlene Ph.D.; Vaporciyan, Ara A.; Liu, H. Helen; Komaki, Ritsuko; Forster, Kenneth M.; Stevens, Craig W.

    2007-10-01

    Purpose: To determine the incidence of fatal pulmonary events after extrapleural pneumonectomy and hemithoracic intensity-modulated radiotherapy (IMRT) for malignant pleural mesothelioma. Methods and Materials: We retrospectively reviewed the records of 63 consecutive patients with malignant pleural mesothelioma who underwent extrapleural pneumonectomy and IMRT at University of Texas M. D. Anderson Cancer Center. The endpoints studied were pulmonary-related death (PRD) and non-cancer-related death within 6 months of IMRT. Results: Of the 63 patients, 23 (37%) had died within 6 months of IMRT (10 of recurrent cancer, 6 of pulmonary causes [pneumonia in 4 and pneumonitis in 2], and 7 of other noncancer causes [pulmonary embolus in 2, sepsis after bronchopleural fistula in 1, and cause unknown but without pulmonary symptoms or recurrent disease in 4]). On univariate analysis, the factors that predicted for PRD were a lower preoperative ejection fraction (p = 0.021), absolute volume of lung spared at 10 Gy (p = 0.025), percentage of lung volume receiving {>=}20 Gy (V{sub 20}; p 0.002), and mean lung dose (p = 0.013). On multivariate analysis, only V{sub 20} was predictive of PRD (p = 0.017; odds ratio, 1.50; 95% confidence interval, 1.08-2.08) or non-cancer-related death (p = 0.033; odds ratio, 1.21; 95% confidence interval, 1.02-1.45). Conclusion: The results of our study have shown that fatal pulmonary toxicities were associated with radiation to the contralateral lung. V{sub 20} was the only independent determinant for risk of PRD or non-cancer-related death. The mean V{sub 20} of the non-PRD patients was considerably lower than that accepted during standard thoracic radiotherapy, implying that the V{sub 20} should be kept as low as possible after extrapleural pneumonectomy.

  17. What evidence exists for initiatives to reduce risk and incidence of sexual violence in armed conflict and other humanitarian crises? A systematic review.

    PubMed

    Spangaro, Jo; Adogu, Chinelo; Ranmuthugala, Geetha; Powell Davies, Gawaine; Steinacker, Léa; Zwi, Anthony

    2013-01-01

    Sexual violence is highly prevalent in armed conflict and other humanitarian crises and attracting increasing policy and practice attention. This systematic review aimed to canvas the extent and impact of initiatives to reduce incidence, risk and harm from sexual violence in conflict, post-conflict and other humanitarian crises, in low and middle income countries. Twenty three bibliographic databases and 26 websites were searched, covering publications from 1990 to September 2011 using database-specific keywords for sexual violence and conflict or humanitarian crisis. The 40 included studies reported on seven strategy types: i) survivor care; ii) livelihood initiatives; iii) community mobilisation; iv) personnel initiatives; v) systems and security responses; vi) legal interventions and vii) multiple component interventions. Conducted in 26 countries, the majority of interventions were offered in African countries. Despite the extensive literature on sexual violence by combatants, most interventions addressed opportunistic forms of sexual violence committed in post-conflict settings. Only one study specifically addressed the disaster setting. Actual implementation of initiatives appeared to be limited as was the quality of outcome studies. No studies prospectively measured incidence of sexual violence, although three studies provided some evidence of reductions in association with firewood distribution to reduce women's exposure, as did one program to prevent sexual exploitation and abuse by peacekeeping forces. Apparent increases to risk resulted from lack of protection, stigma and retaliation associated with interventions. Multiple-component interventions and sensitive community engagement appeared to contribute to positive outcomes. Significant obstacles prevent women seeking help following sexual violence, pointing to the need to protect anonymity and preventive strategies. This review contributes a conceptual framework for understanding the forms, settings

  18. Black chokeberry juice (Aronia melanocarpa) reduces incidences of urinary tract infection among nursing home residents in the long term--a pilot study.

    PubMed

    Handeland, Maria; Grude, Nils; Torp, Torfinn; Slimestad, Rune

    2014-06-01

    Urinary tract infection (UTI) is a major problem in nursing homes, and the mainstay of treatment is antibiotics. The increasing prevalence of uropathogens resistant to antimicrobial agents has stimulated interest in specific nutrients, for example, cranberries, to prevent recurring UTI. Black chokeberry (Aronia melanocarpa [Michx] Elliott) is a rich source of phenolics, and thus, dietary intake of black chokeberry juice may reduce the incidences of UTI requiring medical treatment. In this pilot study, we examined the frequency of medically treated UTI among residents in 6 nursing homes who were offered black chokeberry juice or a placebo during a 6-month crossover intervention. The residents were offered a placebo drink for a 3-month period followed by chokeberry juice for the next 3 months (group A) or vice versa (group B). The juice was characterized by a high content of total phenolics (715 mg gallic acid equivalent, 100 mL(-1)), including B-type procyanidins, anthocyanins, and chlorogenic acids. Daily intake of chokeberry juice was 156 mL per resident in group A (n = 110) and 89 mL per resident in group B (n = 126). Urinary tract infection comprised 55% of all medically treated infections during the study period. The results revealed no immediate reduction in the frequency of UTI or the total use of antibiotics; however, during the subsequent 3-month period of juice administration, a reduction in antibiotics toward UTI was observed in both groups. The incidence of UTI was reduced by 55% in group A and 38% in group B. No changes in other infections or in use of prophylactics were observed.

  19. Black chokeberry juice (Aronia melanocarpa) reduces incidences of urinary tract infection among nursing home residents in the long term--a pilot study.

    PubMed

    Handeland, Maria; Grude, Nils; Torp, Torfinn; Slimestad, Rune

    2014-06-01

    Urinary tract infection (UTI) is a major problem in nursing homes, and the mainstay of treatment is antibiotics. The increasing prevalence of uropathogens resistant to antimicrobial agents has stimulated interest in specific nutrients, for example, cranberries, to prevent recurring UTI. Black chokeberry (Aronia melanocarpa [Michx] Elliott) is a rich source of phenolics, and thus, dietary intake of black chokeberry juice may reduce the incidences of UTI requiring medical treatment. In this pilot study, we examined the frequency of medically treated UTI among residents in 6 nursing homes who were offered black chokeberry juice or a placebo during a 6-month crossover intervention. The residents were offered a placebo drink for a 3-month period followed by chokeberry juice for the next 3 months (group A) or vice versa (group B). The juice was characterized by a high content of total phenolics (715 mg gallic acid equivalent, 100 mL(-1)), including B-type procyanidins, anthocyanins, and chlorogenic acids. Daily intake of chokeberry juice was 156 mL per resident in group A (n = 110) and 89 mL per resident in group B (n = 126). Urinary tract infection comprised 55% of all medically treated infections during the study period. The results revealed no immediate reduction in the frequency of UTI or the total use of antibiotics; however, during the subsequent 3-month period of juice administration, a reduction in antibiotics toward UTI was observed in both groups. The incidence of UTI was reduced by 55% in group A and 38% in group B. No changes in other infections or in use of prophylactics were observed. PMID:25026919

  20. What Evidence Exists for Initiatives to Reduce Risk and Incidence of Sexual Violence in Armed Conflict and Other Humanitarian Crises? A Systematic Review

    PubMed Central

    Spangaro, Jo; Adogu, Chinelo; Ranmuthugala, Geetha; Powell Davies, Gawaine; Steinacker, Léa; Zwi, Anthony

    2013-01-01

    Sexual violence is highly prevalent in armed conflict and other humanitarian crises and attracting increasing policy and practice attention. This systematic review aimed to canvas the extent and impact of initiatives to reduce incidence, risk and harm from sexual violence in conflict, post-conflict and other humanitarian crises, in low and middle income countries. Twenty three bibliographic databases and 26 websites were searched, covering publications from 1990 to September 2011 using database-specific keywords for sexual violence and conflict or humanitarian crisis. The 40 included studies reported on seven strategy types: i) survivor care; ii) livelihood initiatives; iii) community mobilisation; iv) personnel initiatives; v) systems and security responses; vi) legal interventions and vii) multiple component interventions. Conducted in 26 countries, the majority of interventions were offered in African countries. Despite the extensive literature on sexual violence by combatants, most interventions addressed opportunistic forms of sexual violence committed in post-conflict settings. Only one study specifically addressed the disaster setting. Actual implementation of initiatives appeared to be limited as was the quality of outcome studies. No studies prospectively measured incidence of sexual violence, although three studies provided some evidence of reductions in association with firewood distribution to reduce women's exposure, as did one program to prevent sexual exploitation and abuse by peacekeeping forces. Apparent increases to risk resulted from lack of protection, stigma and retaliation associated with interventions. Multiple-component interventions and sensitive community engagement appeared to contribute to positive outcomes. Significant obstacles prevent women seeking help following sexual violence, pointing to the need to protect anonymity and preventive strategies. This review contributes a conceptual framework for understanding the forms, settings

  1. Acute ethanol ingestion produces dose-dependent effects on motor behavior in the honey bee (Apis mellifera).

    PubMed

    Maze, Ian S; Wright, Geraldine A; Mustard, Julie A

    2006-01-01

    Ethanol consumption produces characteristic behavioral states in animals that include sedation, disorientation, and disruption of motor function. Using individual honey bees, we assessed the effects of ethanol ingestion on motor function via continuous observations of their behavior. Consumption of 1 M sucrose solutions containing a range of ethanol doses led to hemolymph ethanol levels of approximately 40-100 mM. Using ethanol doses in this range, we observed time and dose-dependent effects of ethanol on the percent of time our subjects spent walking, stopped, or upside down, and on the duration and frequency of bouts of behavior. The effects on grooming and flying behavior were more complex. Behavioral recovery from ethanol treatment was both time and ethanol dose dependent, occurring between 12 and 24 h post-ingestion for low doses and at 24-48 h for higher doses. Furthermore, the amount of ethanol measured in honey bee hemolymph appeared to correlate with recovery. We predict that the honey bee will prove to be an excellent model system for studying the influence of ethanol on the neural mechanisms underlying behavior.

  2. Sex- and dose-dependency in the pharmacokinetics and pharmacodynamics of (+)-methamphetamine and its metabolite (+)-amphetamine in rats

    SciTech Connect

    Milesi-Halle, Alessandra; Hendrickson, Howard P.; Laurenzana, Elizabeth M.; Gentry, W. Brooks; Owens, S. Michael . E-mail: mowens@uams.edu

    2005-12-15

    These studies investigated how (+)-methamphetamine (METH) dose and rat sex affect the pharmacological response to METH in Sprague-Dawley rats. The first set of experiments determined the pharmacokinetics of METH and its pharmacologically active metabolite (+)-amphetamine (AMP) in male and female Sprague-Dawley rats after 1.0 and 3.0 mg/kg METH doses. The results showed significant sex-dependent changes in METH pharmacokinetics, and females formed significantly lower amounts of AMP. While the area under the serum concentration-time curve in males increased proportionately with the METH dose, the females showed a disproportional increase. The sex differences in systemic clearance, renal clearance, volume of distribution, and percentage of unchanged METH eliminated in the urine suggested dose-dependent pharmacokinetics in female rats. The second set of studies sought to determine the behavioral implications of these pharmacokinetic differences by quantifying locomotor activity in male and female rats after saline, 1.0, and 3.0 mg/kg METH. The results showed sex- and dose-dependent differences in METH-induced locomotion, including profound differences in the temporal profile of effects at higher dose. These findings show that the pharmacokinetic and metabolic profile of METH (slower METH clearance and lower AMP metabolite formation) plays a significant role in the differential pharmacological response to METH in male and female rats.

  3. The nonmonotonic dose dependence of optically stimulated luminescence in Al2O3:C: Analytical and numerical simulation results

    NASA Astrophysics Data System (ADS)

    Chen, R.; Pagonis, V.; Lawless, J. L.

    2006-02-01

    Nonmonotonic dose dependence of optically stimulated luminescence (OSL) has been reported in a number of materials including Al2O3:C which is one of the main dosimetric materials. In a recent work, the nonmonotonic effect has been shown to result, under certain circumstances, from the competition either during excitation or during readout between trapping states or recombination centers. In the present work, we report on a study of the effect in a more concrete framework of two trapping states and two kinds of recombination centers involved in the luminescence processes in Al2O3:C. Using sets of trapping parameters, based on available experimental data, previously utilized to explain the nonmonotonic dose dependence of thermoluminescence including nonzero initial occupancies of recombination centers (F+ centers), the OSL along with the occupancies of the relevant traps and centers are simulated numerically. The connection between these different resulting quantities is discussed, giving a better insight as to the ranges of the increase and decrease of the integral OSL as a function of dose, as well as the constant equilibrium value occurring at high doses.

  4. Dose-dependent fate of GFP-expressing Escherichia coli in the alimentary canal of adult house flies.

    PubMed

    Kumar, N H V; Nayduch, D

    2016-06-01

    The adult house fly Musca domestica (L.) (Diptera: Muscidae) can disseminate bacteria from microbe-rich substrates to areas in which humans and domesticated animals reside. Because bacterial abundance fluctuates widely across substrates, flies encounter and ingest varying amounts of bacteria. This study investigated the dose-dependent survival of bacteria in house flies. Flies were fed four different 'doses' of green fluorescent protein (GFP)-expressing Escherichia coli (GFP E. coli) (very low, low, medium, high) and survival was determined at 1, 4, 10 and 22 h post-ingestion by culture and epifluorescent microscopy. Over 22 h, the decline in GFP E. coli was significant in all treatments (P < 0.04) except the very low dose treatment (P = 0.235). Change in survival (ΔS) did not differ between flies fed low and very low doses of bacteria across all time-points, although ΔS in both treatments differed from that in flies fed high and medium doses of bacteria at several time-points. At 4, 10 and 22 h, GFP E. coli ΔS significantly differed between medium and high dose-fed flies. A threshold dose, above which bacteria are detected and destroyed by house flies, may exist and is likely to be immune-mediated. Understanding dose-dependent bacterial survival in flies can help in predicting bacteria transmission potential.

  5. Dose-dependent fate of GFP-expressing Escherichia coli in the alimentary canal of adult house flies.

    PubMed

    Kumar, N H V; Nayduch, D

    2016-06-01

    The adult house fly Musca domestica (L.) (Diptera: Muscidae) can disseminate bacteria from microbe-rich substrates to areas in which humans and domesticated animals reside. Because bacterial abundance fluctuates widely across substrates, flies encounter and ingest varying amounts of bacteria. This study investigated the dose-dependent survival of bacteria in house flies. Flies were fed four different 'doses' of green fluorescent protein (GFP)-expressing Escherichia coli (GFP E. coli) (very low, low, medium, high) and survival was determined at 1, 4, 10 and 22 h post-ingestion by culture and epifluorescent microscopy. Over 22 h, the decline in GFP E. coli was significant in all treatments (P < 0.04) except the very low dose treatment (P = 0.235). Change in survival (ΔS) did not differ between flies fed low and very low doses of bacteria across all time-points, although ΔS in both treatments differed from that in flies fed high and medium doses of bacteria at several time-points. At 4, 10 and 22 h, GFP E. coli ΔS significantly differed between medium and high dose-fed flies. A threshold dose, above which bacteria are detected and destroyed by house flies, may exist and is likely to be immune-mediated. Understanding dose-dependent bacterial survival in flies can help in predicting bacteria transmission potential. PMID:26843509

  6. Co-administration of morphine and gabapentin leads to dose dependent synergistic effects in a rat model of postoperative pain.

    PubMed

    Papathanasiou, Theodoros; Juul, Rasmus Vestergaard; Heegaard, Anne-Marie; Kreilgaard, Mads; Lund, Trine Meldgaard

    2016-01-20

    Despite much evidence that combination of morphine and gabapentin can be beneficial for managing postoperative pain, the nature of the pharmacological interaction of the two drugs remains unclear. The aim of this study was to assess the interaction of morphine and gabapentin in range of different dose combinations and investigate whether co-administration leads to synergistic effects in a preclinical model of postoperative pain. The pharmacodynamic effects of morphine (1, 3 and 7mg/kg), gabapentin (10, 30 and 100mg/kg) or their combination (9 combinations in total) were evaluated in the rat plantar incision model using an electronic von Frey device. The percentage of maximum possible effect (%MPE) and the area under the response curve (AUC) were used for evaluation of the antihyperalgesic effects of the drugs. Identification of synergistic interactions was based on Loewe additivity response surface analyses. The combination of morphine and gabapentin resulted in synergistic antihyperalgesic effects in a preclinical model of postoperative pain. The synergistic interactions were found to be dose dependent and the increase in observed response compared to the theoretical additive response ranged between 26 and 58% for the synergistic doses. The finding of dose-dependent synergistic effects highlights that choosing the right dose-dose combination is of importance in postoperative pain therapy. Our results indicate benefit of high doses of gabapentin as adjuvant to morphine. If these findings translate to humans, they might have important implications for the treatment of pain in postoperative patients.

  7. Complementary and dose-dependent action of AtCCS52A isoforms in endoreduplication and plant size control.

    PubMed

    Baloban, Mikhail; Vanstraelen, Marleen; Tarayre, Sylvie; Reuzeau, Christophe; Cultrone, Antonietta; Mergaert, Peter; Kondorosi, Eva

    2013-06-01

    · The dimension of organs depends on the number and the size of their component cells. Formation of polyploid cells by endoreduplication cycles is predominantly associated with increases in the cell size and implicated in organ growth. In plants, the CCS52A proteins play a major role in the switch from mitotic to endoreduplication cycles controlling thus the number of mitotic cells and the endoreduplication events in the differentiating cells. · Arabidopsis has two CCS52A isoforms; AtCCS52A1 and AtCCS52A2. Here we focused on their roles in endoreduplication and cell size control during plant development. We demonstrate their complementary and dose-dependent actions that are dependent on their expression patterns. Moreover, the impact of CCS52A overexpression on organ size in transgenic plants was dependent on the expression level; while enhanced expression of the CCS52A genes positively correlated with the ploidy levels, organ sizes were negatively affected by strong overexpression whereas milder overexpression resulted in a significant increase in the organ sizes. · Taken together, these finding support both complementary and dose-dependent actions for the Arabidopsis CCS52A isoforms in plant development and demonstrate that elevated ectopic CCS52A expression positively correlates with organ size, opening a route to higher biomass production.

  8. Dose-dependent effects of intravenous lorazepam on cardiovascular activity, plasma catecholamines and psychological function during rest and mental stress.

    PubMed

    Tulen, J H; Moleman, P; Boomsma, F; van Steenis, H G; van den Heuij, V J

    1991-01-01

    Dose-dependent effects of intravenously administered lorazepam on psychophysiological activity during rest and mental stress were studied in order to examine differential responses to doses which may induce anxiolysis or sedation. In a double-blind randomized cross-over study, nine male volunteers participated in a placebo and a lorazepam session, during which the subjects repeatedly performed a 10-min version of the Stroop Color Word Test (CWT), with 10 min of rest between the CWTs. Lorazepam was administered before each rest period in increasing doses of 0.0, 0.6, 0.13, 0.25 and 0.5 mg (total cumulative dose: 0.94 mg). Heart rate showed a dose-dependent decrease during rest with an ED50 of 0.13 mg lorazepam, while lorazepam had no effect on the cardiovascular and plasma catecholamine response magnitudes to the CWT. Subjective fatigue and reaction time increased significantly after 0.94 mg lorazepam, while at the same dose vigor decreased; state anxiety after the CWT was not influenced by lorazepam. These data show differential effects of lorazepam on cardiovascular, biochemical and psychological function. While heart rate was suppressed at low doses during rest and reaction time and subjective fatigue increased at doses which induced sedation, state anxiety and physiological response patterns to the CWT were not influenced by lorazepam.

  9. Dose-dependent lipid peroxidation induction on ex vivo intestine tracts exposed to chyme samples from fumonisins contaminated corn samples.

    PubMed

    Garbetta, A; Debellis, L; De Girolamo, A; Schena, R; Visconti, A; Minervini, F

    2015-08-01

    Fumonisins (FBs), Fusarium mycotoxins common food contaminant, are a potent inducer of oxidative stress and lipid peroxidation in intestinal cells. In order to verify this toxic effect in intestine tract, the aim was to assess lipid peroxidation (as malondialdehyde MDA increased levels) on intestine rat samples exposed to chyme samples from in vitro digestion of FBs contaminated corn samples. Naturally (9.61±3.2 μg/gr), artificially (726±94 μg/gr) and spiked corn samples at EU permitted FBs levels were digested and added to luminal side of Ussing chamber for 120 min. Fumonisins-free corn sample was used as control. The MDA increase was observed just in 83% of intestine samples exposed at EU FBs levels and the digestion process seems to reduce this incidence (50% of samples). Malondialdehyde levels were FBs dose- and subject-related and ranged from 0.07±0.01 to 3.59±0.6 nmol/mg. Highest incidence and MDA % increment (I) were found when intestine tracts were exposed to chymes from artificially corn sample. The induction of lipid peroxidation induced by FBs could be due to interactions between FBs and intestinal membranes, with consequent modifications in membrane permeability and oxygen diffusion-concentration, as suggested by other authors. PMID:25956791

  10. Dose-dependent lipid peroxidation induction on ex vivo intestine tracts exposed to chyme samples from fumonisins contaminated corn samples.

    PubMed

    Garbetta, A; Debellis, L; De Girolamo, A; Schena, R; Visconti, A; Minervini, F

    2015-08-01

    Fumonisins (FBs), Fusarium mycotoxins common food contaminant, are a potent inducer of oxidative stress and lipid peroxidation in intestinal cells. In order to verify this toxic effect in intestine tract, the aim was to assess lipid peroxidation (as malondialdehyde MDA increased levels) on intestine rat samples exposed to chyme samples from in vitro digestion of FBs contaminated corn samples. Naturally (9.61±3.2 μg/gr), artificially (726±94 μg/gr) and spiked corn samples at EU permitted FBs levels were digested and added to luminal side of Ussing chamber for 120 min. Fumonisins-free corn sample was used as control. The MDA increase was observed just in 83% of intestine samples exposed at EU FBs levels and the digestion process seems to reduce this incidence (50% of samples). Malondialdehyde levels were FBs dose- and subject-related and ranged from 0.07±0.01 to 3.59±0.6 nmol/mg. Highest incidence and MDA % increment (I) were found when intestine tracts were exposed to chymes from artificially corn sample. The induction of lipid peroxidation induced by FBs could be due to interactions between FBs and intestinal membranes, with consequent modifications in membrane permeability and oxygen diffusion-concentration, as suggested by other authors.

  11. Dose-dependent LDL-cholesterol lowering effect by plant stanol ester consumption: clinical evidence.

    PubMed

    Laitinen, Kirsi; Gylling, Helena

    2012-10-22

    Elevated serum lipids are linked to cardiovascular diseases calling for effective therapeutic means to reduce particularly LDL-cholesterol (LDL-C) levels. Plant stanols reduce levels of LDL-C by partly blocking cholesterol absorption. Accordingly the consumption of foods with added plant stanols, typically esterified with vegetable oil fatty acids in commercial food products, are recommended for lowering serum cholesterol levels. A daily intake of 1.5 to 2.4 g of plant stanols has been scientifically evaluated to lower LDL-C by 7 to 10% in different populations, ages and with different diseases. Based on earlier studies, a general understanding is that no further reduction may be achieved in intakes in excess of approximately 2.5 g/day. Recent studies however suggest that plant stanols show a continuous dose-response effect in serum LDL-C lowering. This review discusses the evidence for a dose-effect relationship between plant stanol ester consumption and reduction of LDL-C concentrations with daily intakes of plant stanols of 4 g/day or more. We identified five such studies and the overall data demonstrate a linear dose-effect relationship with the most pertinent LDL-Cholesterol lowering outcome, 18%, achieved by a daily intake of 9 to 10 g of plant stanols. Along with reduction in LDL-C, the studies demonstrated a decrease in cholesterol absorption markers, the serum plant sterol to cholesterol ratios, by increasing the dose of plant stanol intake. None of the studies with daily intakes up to 10 g of plant stanols reported adverse clinical or biochemical effects from plant stanols. In a like manner, the magnitude of decrease in serum antioxidant vitamins was not related to the dose of plant stanols consumed and the differences between plant stanol ester consumers and controls were minor and insignificant or nonexisting. Consumption of plant stanols in high doses is feasible as a range of food products are commercially available for consumption including spreads

  12. DEHP (DI-N-ETHYLHEXYL PHTHALATE), WHEN ADMINISTERED DURING SEXUAL DIFFERENTIATION, INDUCES DOSE DEPENDENT DECREASES IN FETAL TESTIS GENE EXPRESSION AND STEROID HORMONE SYNTHESIS

    EPA Science Inventory

    DEHP (di-n-ethylhexyl phthalate), when administered during sexual differentiation, induces dose dependent decreases in fetal testis gene expression and steroid hormone synthesis.
    Vickie S. Wilson, Christy Lambright, Johnathan Furr, Kathy Bobseine, Carmen Wood, Gary Held, and ...

  13. Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.

    PubMed

    Rose, Jed E; Behm, Frédérique M; Drgon, Tomas; Johnson, Catherine; Uhl, George R

    2010-01-01

    Improving and targeting nicotine replacement therapy (NRT) are cost-effective strategies for reducing adverse health consequences for smokers. Treatment studies document the efficacy of precessation NRT and support important roles for level of nicotine dependence and precessation smoking reduction in successful quitting. However, prior work has not identified the optimal precessation dose or means for personalizing NRT. Genome-wide association has identified groups of genomic markers associated with successful quitting, allowing us to develop a v1.0 "quit-success" genotype score. We now report influences of v1.0 quit-success genotype score, level of dependence and precessation smoking reduction in a smoking cessation trial that examined effects of 21 versus 42 mg/24 h precessation NRT. Four hundred seventy-nine smokers were randomized to 21 or 42 mg NRT, initiated 2 wks prior to target quit dates. We monitored self-reported abstinence and end-expired air carbon monoxide (CO). Genotyping used Affymetrix arrays (Santa Clara, CA, USA). The primary outcome was 10-wk continuous smoking abstinence. NRT dose, level of nicotine dependence and genotype scores displayed significant interactive effects on successful quitting. Successful abstinence also was predicted by CO reductions during precessation NRT. These results document ways in which smoking cessation strategies can be personalized based on levels of nicotine dependence, genotype scores and CO monitoring. These assessments, taken together, can help match most smokers with optimal NRT doses and help rapidly identify some who may be better treated using other methods.

  14. The dichotomy of memantine treatment for ischemic stroke: dose-dependent protective and detrimental effects.

    PubMed

    Trotman, Melissa; Vermehren, Philipp; Gibson, Claire L; Fern, Robert

    2015-02-01

    Excitotoxicity is a major contributor to cell death during the acute phase of ischemic stroke but aggressive pharmacological targeting of excitotoxicity has failed clinically. Here we investigated whether pretreatment with low doses of memantine, within the range currently used and well tolerated for the treatment of Alzheimer's disease, produce a protective effect in stroke. A coculture preparation exposed to modeled ischemia showed cell death associated with rapid glutamate rises and cytotoxic Ca(2+) influx. Cell death was significantly enhanced in the presence of high memantine concentrations. However, low memantine concentrations significantly protected neurons and glia via excitotoxic cascade interruption. Mice were systemically administered a range of memantine doses (0.02, 0.2, 2, 10, and 20 mg/kg/day) starting 24 hours before 60 minutes reversible focal cerebral ischemia and continuing for a 48-hour recovery period. Low dose (0.2 mg/kg/day) memantine treatment significantly reduced lesion volume (by 30% to 50%) and improved behavioral outcomes in stroke lesions that had been separated into either small/striatal or large/striatocortical infarcts. However, higher doses of memantine (20 mg/kg/day) significantly increased injury. These results show that clinically established low doses of memantine should be considered for patients 'at risk' of stroke, while higher doses are contraindicated.

  15. Preoperative ephedrine counters hypotension with propofol anesthesia during valve surgery: a dose dependent study.

    PubMed

    El-Tahan, Mohamed R

    2011-01-01

    The prophylactic use of small doses of ephedrine may counter the hypotension response to propofol anesthesia with minimal hemodynamic changes. One hundred-fifty patients scheduled for valve surgery were randomly assigned into five groups (n = 30 for each) to receive saline, 0.07, 0.1, or 0.15 mg/kg of ephedrine, or phenylephrine 1.5 μg/kg before induction of propofol-fentanyl anesthesia. After induction, patient receiving ephedrine had higher mean arterial pressure, systemic vascular resistance (SVRI), cardiac (CI), stroke volume (SVI), and left ventricular stroke work (LVSWI) indices. Patients received 0.15 mg/kg of ephedrine showed additional increased heart rate and frequent ischemic episodes (P < 0.001). However, those who received phenylephrine showed greater rise in SVRI, reduced CI, SVI, and LVSWI and more frequent ischemic episodes. We conclude that the prophylactic use of small doses of ephedrine (0.07-0.1 mg/kg) is safe and effective in the counteracting propofol-induced hypotension during anesthesia for valve surgery.

  16. Project Accept (HPTN 043): A Community-Based Intervention to Reduce HIV Incidence in Populations at Risk for HIV in Sub-Saharan Africa and Thailand

    PubMed Central

    Khumalo-Sakutukwa, Gertrude; Morin, Stephen F.; Fritz, Katherine; Charlebois, Edwin D.; van Rooyen, Heidi; Chingono, Alfred; Modiba, Precious; Mrumbi, Khalifa; Visrutaratna, Surasing; Singh, Basant; Sweat, Michael; Celentano, David D.; Coates, Thomas J

    2009-01-01

    Background Changing community norms to increase awareness of HIV status and reduce HIV-related stigma has the potential to reduce the incidence of HIV-1 infection in the developing world. Methods We developed and implemented a multi-level intervention providing community-based HIV mobile voluntary counseling and testing (CBVCT), community mobilization (CM), and post-test support services (PTSS). Forty-eight communities in Tanzania, Zimbabwe, South Africa and Thailand were randomized to receive the intervention or standard clinic-based VCT (SVCT), the comparison condition. We monitored utilization of CBVCT and SVCT by community of residence at 3 sites, which was used to assess differential uptake. We also developed Quality Assurance procedures to evaluate staff fidelity to the intervention. Findings In the first year of the study a four-fold increase in testing was observed in the intervention versus comparison communities. We also found an overall 95% adherence to intervention components. Study outcomes, including prevalence of recent HIV infection and community-level HIV stigma, will be assessed after three years of intervention. Conclusion The provision of mobile services, combined with appropriate support activities, may have significant effects on utilization of VCT. These findings also provide early support for community mobilization as a strategy for increasing testing rates. PMID:18931624

  17. Dose-dependent effects of levetiracetam after hypoxia and hypothermia in the neonatal mouse brain.

    PubMed

    Strasser, Katja; Lueckemann, Laura; Kluever, Verena; Thavaneetharajah, Sinthuya; Hoeber, Daniela; Bendix, Ivo; Fandrey, Joachim; Bertsche, Astrid; Felderhoff-Mueser, Ursula

    2016-09-01

    Perinatal asphyxia to the developing brain remains a major cause of morbidity. Hypothermia is currently the only established neuroprotective treatment available for term born infants with hypoxic-ischemic encephalopathy, saving one in seven to eight infants from developing severe neurological deficits. Therefore, additional treatments with clinically applicable drugs are indispensable. This study investigates a potential additive neuroprotective effect of levetiracetam combined with hypothermia after hypoxia-induced brain injury in neonatal mice. 9-day-old C57BL/6-mice (P9) were subjected either to acute hypoxia or room-air. After 90min of systemic hypoxia (6% O2), pups were randomized into six groups: 1) vehicle, 2) low-dose levetiracetam (LEV), 3) high-dose LEV, 4) hypothermia (HT), 5) HT combined with low-dose LEV and 6) HT combined with high-dose LEV. Pro-apoptotic factors, neuronal structures, and myelination were analysed by histology and on protein level at appropriate time points. On P28 to P37 long-term outcome was assessed by neurobehavioral testing. Hypothermia confers acute and long-term neuroprotection by reducing apoptosis and preservation of myelinating oligodendrocytes and neurons in a model of acute hypoxia in the neonatal mouse brain. Low-dose LEV caused no adverse effects after neonatal hypoxic brain damage treated with hypothermia whereas administration of high-dose LEV alone or in combination with hypothermia increased neuronal apoptosis after hypoxic brain injury. LEV in low- dosage had no additive neuroprotective effect following acute hypoxic brain injury. PMID:27216570

  18. In vitro nicotine-induced oxidative stress in mice peritoneal macrophages: a dose-dependent approach.

    PubMed

    Mahapatra, Santanu Kar; Das, Subhasis; Bhattacharjee, Surajit; Gautam, N; Majumdar, Subrata; Roy, Somenath

    2009-02-01

    The immune cells use reactive oxygen species (ROS) for carrying out their normal functions while an excess amount of ROS can attack cellular components that lead to cell damage. In the present study, peritoneal macrophages (6 x 10(6) cells, >95% viable) isolated from male Swiss mice were treated with nicotine (1 mM, 5 mM, 10 mM, 25 mM, and 50 mM) in vitro for 12 h and the superoxide anion generation, lipid peroxidation, protein oxidation and antioxidant enzymes status were monitored. Maximum superoxide radical generation was found at the dose of 10 mM nicotine. The lipid peroxidation and protein oxidation were increased significantly (p < 0.05) along with the increasing dose of nicotine. The reduced glutathione level, catalase, superoxide dismutase, glutathione peroxidase, and glutathione reductase activities were decreased significantly (p < 0.05), and oxidized glutathione level was increased significantly (p < 0.05) with the increasing dose of the nicotine. From these experiments, it was also observed that all the changes in peritoneal macrophages with 10 mM, 25 mM, and 50 mM nicotine had no significant difference. To observe the effect of nicotine in vivo, this study examined the liver and spleen antioxidant status after nicotine administration (1 mg/kg BW) intraperitoneally in mice and found the diminished SOD activity and GSH level. It may be concluded that nicotine is able to enhance the production of ROS that produced oxidative stress in murine peritoneal macrophages. It also suggested that, 10 mM in vitro nicotine treatment for 12 h is the effective dose. PMID:19778253

  19. Dose-dependent effects of mTOR inhibition on weight and mitochondrial disease in mice

    PubMed Central

    Johnson, Simon C.; Yanos, Melana E.; Bitto, Alessandro; Castanza, Anthony; Gagnidze, Arni; Gonzalez, Brenda; Gupta, Kanav; Hui, Jessica; Jarvie, Conner; Johnson, Brittany M.; Letexier, Nicolas; McCanta, Lanny; Sangesland, Maya; Tamis, Oliver; Uhde, Lauren; Van Den Ende, Alex; Rabinovitch, Peter S.; Suh, Yousin; Kaeberlein, Matt

    2015-01-01

    Rapamycin extends lifespan and attenuates age-related pathologies in mice when administered through diet at 14 parts per million (PPM). Recently, we reported that daily intraperitoneal injection of rapamycin at 8 mg/kg attenuates mitochondrial disease symptoms and progression in the Ndufs4 knockout mouse model of Leigh Syndrome. Although rapamycin is a widely used pharmaceutical agent dosage has not been rigorously examined and no dose-response profile has been established. Given these observations we sought to determine if increased doses of oral rapamycin would result in more robust impact on mTOR driven parameters. To test this hypothesis, we compared the effects of dietary rapamycin at doses ranging from 14 to 378 PPM on developmental weight in control and Ndufs4 knockout mice and on health and survival in the Ndufs4 knockout model. High dose rapamycin was well tolerated, dramatically reduced weight gain during development, and overcame gender differences. The highest oral dose, approximately 27-times the dose shown to extend murine lifespan, increased survival in Ndufs4 knockout mice similarly to daily rapamycin injection without observable adverse effects. These findings have broad implications for the effective use of rapamycin in murine studies and for the translational potential of rapamycin in the treatment of mitochondrial disease. This data, further supported by a comparison of available literature, suggests that 14 PPM dietary rapamycin is a sub-optimal dose for targeting mTOR systemically in mice. Our findings suggest that the role of mTOR in mammalian biology may be broadly underestimated when determined through treatment with rapamycin at commonly used doses. PMID:26257774

  20. Dose-Dependent Effect of Granulocyte Transfusions in Hematological Patients with Febrile Neutropenia.

    PubMed

    Teofili, Luciana; Valentini, Caterina Giovanna; Di Blasi, Roberta; Orlando, Nicoletta; Fianchi, Luana; Zini, Gina; Sica, Simona; De Stefano, Valerio; Pagano, Livio

    2016-01-01

    It is still under debate whether granulocyte transfusions (GTs) substantially increase survival in patients with febrile neutropenia. We retrospectively examined data relative to 96 patients with hematological malignancies receiving 491 GTs during 114 infectious episodes (IE). Patients were grouped according to the median doses of granulocytes transfused during the infectious episode (low-dose group: <1.5-x108 cells/Kg; standard-dose group: 1.5-3.0x108 cells/Kg and high-dose group: >3.0x108 cells/Kg). The impact of clinical, microbiological and GT-related variables on the infection-related mortality (IRM) was investigated. The IRM was not influenced by the number of GTs or by the total amount of granulocytes received, whereas a dose-related effect of the median dose received for IE was detected at univariate analysis (IRM of 18.4% in the standard-dose group, 44.4% in the low-dose group and 48.4% in the high-dose group, p = 0.040) and confirmed at multivariate analysis (OR 3.7, IC 95% 1.5-8.9; 0.004 for patients not receiving standard doses of GTs). Moreover, patients receiving GTs at doses lower or greater than standard had increased risk for subsequent ICU admission and reduced overall survival. The dose-related effect of GTs was confirmed in bacterial but not in fungal infections. Preliminary findings obtained from a subgroup of patients candidate to GTs revealed that levels of inflammatory response mediators increase in a dose-related manner after GTs, providing a possible explanation for the detrimental effect exerted by high-dose transfusions. GTs can constitute a valuable tool to improve the outcome of infections in neutropenic patients, provided that adequate recipient-tailored doses are supplied. Further investigations of the immunomodulatory effects of GTs are recommended. PMID:27487075

  1. Dose-dependent effects of alcohol administration on behavioral profiles in the MCSF test.

    PubMed

    Karlsson, Oskar; Roman, Erika

    2016-02-01

    The acute effects of alcohol administration are age-, dose-, time- and task-dependent. Although generally considered to be a sedative drug, alcohol has both stimulatory and depressant effects on behavior, depending on dose and time. Alcohol-induced motor activating effects are consistently shown in mice but rarely demonstrated in adult, outbred rats using conventional behavioral tests. The aim of the present experiment was to study acute alcohol-induced effects on behavioral profiles in a more complex environment using the novel multivariate concentric square field™ (MCSF) test, designed for assessing different behaviors in the same trial including locomotor activity. Adult male Wistar rats (Sca:WI) were administered one intraperitoneal (i.p.) injection of alcohol (0.0 g/kg, 0.5 g/kg, 1.0 g/kg, or 1.5 g/kg) 5 min prior to the 30-min MCSF test. The two highest doses induced marked motor-suppressing effects. A significant interaction between group and time was found in general activity when comparing rats exposed to alcohol at 0.0 g/kg and 0.5 g/kg. In contrast to the 0.0 g/kg dose that increased the activity over time, animals administered the low dose (0.5 g/kg) demonstrated an initial high activity followed by a decline over time. No indications for acute alcohol-induced anxiolytic-like effects were found. The multivariate setting in the MCSF test appears to be sensitive for detecting motor-activating effects of low doses of alcohol as well as reduced locomotion at doses lower than in other behavioral tasks. The detection of subtle changes in behavior across time and dose is important for understanding alcohol-induced effects. This approach may be useful in evaluating alcohol doses that correspond to different degrees of intoxication in humans. PMID:26695588

  2. Dose-Dependent Effect of Granulocyte Transfusions in Hematological Patients with Febrile Neutropenia

    PubMed Central

    Di Blasi, Roberta; Orlando, Nicoletta; Fianchi, Luana; Zini, Gina; Sica, Simona; De Stefano, Valerio; Pagano, Livio

    2016-01-01

    It is still under debate whether granulocyte transfusions (GTs) substantially increase survival in patients with febrile neutropenia. We retrospectively examined data relative to 96 patients with hematological malignancies receiving 491 GTs during 114 infectious episodes (IE). Patients were grouped according to the median doses of granulocytes transfused during the infectious episode (low-dose group: <1.5-x108 cells/Kg; standard-dose group: 1.5–3.0x108 cells/Kg and high-dose group: >3.0x108 cells/Kg). The impact of clinical, microbiological and GT-related variables on the infection-related mortality (IRM) was investigated. The IRM was not influenced by the number of GTs or by the total amount of granulocytes received, whereas a dose-related effect of the median dose received for IE was detected at univariate analysis (IRM of 18.4% in the standard-dose group, 44.4% in the low-dose group and 48.4% in the high-dose group, p = 0.040) and confirmed at multivariate analysis (OR 3.7, IC 95% 1.5–8.9; 0.004 for patients not receiving standard doses of GTs). Moreover, patients receiving GTs at doses lower or greater than standard had increased risk for subsequent ICU admission and reduced overall survival. The dose-related effect of GTs was confirmed in bacterial but not in fungal infections. Preliminary findings obtained from a subgroup of patients candidate to GTs revealed that levels of inflammatory response mediators increase in a dose-related manner after GTs, providing a possible explanation for the detrimental effect exerted by high-dose transfusions. GTs can constitute a valuable tool to improve the outcome of infections in neutropenic patients, provided that adequate recipient-tailored doses are supplied. Further investigations of the immunomodulatory effects of GTs are recommended. PMID:27487075

  3. The dose-dependence biological effect of laser fluence on rabbit fibroblasts derived from urethral scar.

    PubMed

    Yang, Yong; Yu, Bo; Sun, Dongchong; Wu, Yuanyi; Xiao, Yi

    2015-04-01

    Two-micrometer laser vaporization resection has been used in clinic for years, but some patients received the treatment are still faced with excessive and abnormal wound repair which leads to the recurrent of urethral stricture eventually. Fibroblasts play a key role in the processes of "narrow-expansion/operation-restenosis" recurring problems. Here, we investigated the effect of laser fluence biomodulation on urethral scar fibroblasts as well as the underlying mechanism. Urethral scar fibroblasts were isolated and cultured, and laser irradiation (2 μm) was applied at different laser fluence or doses (0, 0.125, 0.5, 2, 8, 32 J/cm(2)) with a single exposure in 1 day. The effect of 2-μm laser irradiation on cell proliferation, viability, and expression of scar formation related genes were investigated. Two-micrometer laser irradiation with intermediate dose (8 J/cm(2)) promoted scar fibroblasts proliferation and reactive oxygen species (ROS) production, while higher doses of 32 J/cm(2) are suppressive as it decreased the survival rate, viability, and proliferation of fibroblasts. In addition, qRT-PCR and Western blotting results both proven that collagen type I, collagen IV, MMP9, and CTGF display significant increase, yet the TGF-β1 expression was severely reduced at intermediate dose (8 J/cm(2)) group when compared with the others groups. Our findings suggest the scar formation-related genes are sensitive to intermediate laser irradiation dose, the most in scar fibroblasts. We revealed the bioeffect and molecular mechanism of 2-μm laser irradiation on rabbit urethral scar fibroblasts. Our study provides new insights into the mechanisms which involved in the excessive and abnormal wound repair of 2-μm laser vaporization resection. These results could potentially contribute to further study on biological effects and application of 2-μm laser irradiation in urethral stricture therapy.

  4. Vitamin C neuroprotection against dose-dependent glutamate-induced neurodegeneration in the postnatal brain.

    PubMed

    Shah, Shahid Ali; Yoon, Gwang Ho; Kim, Hyun-Ok; Kim, Myeong Ok

    2015-05-01

    Glutamate-induced excitotoxicity due to over-activation of glutamate receptors and associated energy depletion (phosphorylation and activation of AMPK) results in neuronal cell death in various neurological disorders. Restoration of energy balance during an excitotoxic insult is critical for neuronal survival. Ascorbic acid (vitamin C), an essential nutrient with well-known antioxidant potential, protects the brain from oxidative damage in various models of neurodegeneration. In this study, we reported the therapeutic efficacy of vitamin C in response to glutamate-induced excitation, resulting in energy depletion and apoptosis in the hippocampus of the developing rat brain. A single subcutaneous injection of glutamate at two different concentrations (5 and 10 mg/kg) in postnatal day 7 rat pups increased brain glutamate levels and increased the protein expression of neuronal apoptotic markers. Both doses of glutamate upregulated the ratio of pro-apoptotic Bax to anti-apoptotic Bcl-2, cytochrome-c release, caspase-3 activation and the expression of PARP-1. However, co-treatment of vitamin C (250 mg/kg) with glutamate decreased brain glutamate levels and reversed the changes induced by glutamate in the developing hippocampus. Interestingly, only a high dose of glutamate caused the phosphorylation and activation of AMPK and induced neuronal cell death, whereas a low dose of glutamate failed to mediate these effects. Vitamin C supplementation reduced the glutamate-induced phosphorylation of AMPK and attenuated neuronal cell death, as assessed morphologically by Fluoro Jade B in the hippocampal CA1 region of the developing brain. Taken together, our results indicated that glutamate in both concentrations is toxic to the immature rat brain, whereas vitamin C is pharmacologically effective against glutamate-induced neurodegeneration. PMID:25701025

  5. Vitamin C neuroprotection against dose-dependent glutamate-induced neurodegeneration in the postnatal brain.

    PubMed

    Shah, Shahid Ali; Yoon, Gwang Ho; Kim, Hyun-Ok; Kim, Myeong Ok

    2015-05-01

    Glutamate-induced excitotoxicity due to over-activation of glutamate receptors and associated energy depletion (phosphorylation and activation of AMPK) results in neuronal cell death in various neurological disorders. Restoration of energy balance during an excitotoxic insult is critical for neuronal survival. Ascorbic acid (vitamin C), an essential nutrient with well-known antioxidant potential, protects the brain from oxidative damage in various models of neurodegeneration. In this study, we reported the therapeutic efficacy of vitamin C in response to glutamate-induced excitation, resulting in energy depletion and apoptosis in the hippocampus of the developing rat brain. A single subcutaneous injection of glutamate at two different concentrations (5 and 10 mg/kg) in postnatal day 7 rat pups increased brain glutamate levels and increased the protein expression of neuronal apoptotic markers. Both doses of glutamate upregulated the ratio of pro-apoptotic Bax to anti-apoptotic Bcl-2, cytochrome-c release, caspase-3 activation and the expression of PARP-1. However, co-treatment of vitamin C (250 mg/kg) with glutamate decreased brain glutamate levels and reversed the changes induced by glutamate in the developing hippocampus. Interestingly, only a high dose of glutamate caused the phosphorylation and activation of AMPK and induced neuronal cell death, whereas a low dose of glutamate failed to mediate these effects. Vitamin C supplementation reduced the glutamate-induced phosphorylation of AMPK and attenuated neuronal cell death, as assessed morphologically by Fluoro Jade B in the hippocampal CA1 region of the developing brain. Taken together, our results indicated that glutamate in both concentrations is toxic to the immature rat brain, whereas vitamin C is pharmacologically effective against glutamate-induced neurodegeneration.

  6. Laying the foundation for Connect to Protect: a multi-site community mobilization intervention to reduce HIV/AIDS incidence and prevalence among urban youth.

    PubMed

    Ziff, Mauri A; Harper, Gary W; Chutuape, Kate S; Deeds, Bethany Griffin; Futterman, Donna; Francisco, Vincent T; Muenz, Larry R; Ellen, Jonathan M

    2006-05-01

    Despite the considerable resources that have been dedicated to HIV prevention interventions and services over the past decade, HIV incidence among young people in the United States remains alarmingly high. One reason is that the majority of prevention efforts continue to focus solely on modifying individual behavior, even though public health research strongly suggests that changes to a community's structural elements, such as their programs, practices, and laws or policies, may result in more effective and sustainable outcomes. Connect to Protect is a multi-city community mobilization intervention that focuses on altering or creating community structural elements in ways that will ultimately reduce youth HIV incidence and prevalence. The project, which spans 6 years, is sponsored by the Adolescent Medicine Trials Network for HIV/AIDS Interventions at multiple urban clinical research sites. This paper provides an overview of the study's three phases and describes key factors in setting a firm foundation for the initiation and execution of this type of undertaking. Connect to Protect's community mobilization approach to achieving structural change represents a relatively new and broad direction in HIV prevention research. To optimize opportunities for its success, time and resources must be initially placed into laying the groundwork. This includes activities such as building a strong overarching study infrastructure to ensure protocol tasks can be met across sites; tapping into local site and community expertise and knowledge; forming collaborative relationships between sites and community organizations and members; and fostering community input on and support for changes at a structural level. Failing to take steps such as these may lead to insurmountable implementation problems for an intervention of this kind. PMID:16739051

  7. Laying the Foundation for Connect to Protect®: A Multi-Site Community Mobilization Intervention to Reduce HIV/AIDS Incidence and Prevalence among Urban Youth

    PubMed Central

    Ziff, Mauri A.; Harper, Gary W.; Chutuape, Kate S.; Deeds, Bethany Griffin; Futterman, Donna; Francisco, Vincent T.; Muenz, Larry R.

    2006-01-01

    Despite the considerable resources that have been dedicated to HIV prevention interventions and services over the past decade, HIV incidence among young people in the United States remains alarmingly high. One reason is that the majority of prevention efforts continue to focus solely on modifying individual behavior, even though public health research strongly suggests that changes to a community's structural elements, such as their programs, practices, and laws or policies, may result in more effective and sustainable outcomes. Connect to Protect is a multi-city community mobilization intervention that focuses on altering or creating community structural elements in ways that will ultimately reduce youth HIV incidence and prevalence. The project, which spans 6 years, is sponsored by the Adolescent Medicine Trials Network for HIV/AIDS Interventions at multiple urban clinical research sites. This paper provides an overview of the study's three phases and describes key factors in setting a firm foundation for the initiation and execution of this type of undertaking. Connect to Protect's community mobilization approach to achieving structural change represents a relatively new and broad direction in HIV prevention research. To optimize opportunities for its success, time and resources must be initially placed into laying the groundwork. This includes activities such as building a strong overarching study infrastructure to ensure protocol tasks can be met across sites; tapping into local site and community expertise and knowledge; forming collaborative relationships between sites and community organizations and members; and fostering community input on and support for changes at a structural level. Failing to take steps such as these may lead to insurmountable implementation problems for an intervention of this kind. PMID:16739051

  8. Vitamin D receptor expression in human bone tissue and dose-dependent activation in resorbing osteoclasts

    PubMed Central

    Zarei, Allahdad; Morovat, Alireza; Javaid, Kassim; Brown, Cameron P

    2016-01-01

    The effects of vitamin D on osteoblast mineralization are well documented. Reports of the effects of vitamin D on osteoclasts, however, are conflicting, showing both inhibition and stimulation. Finding that resorbing osteoclasts in human bone express vitamin D receptor (VDR), we examined their response to different concentrations of 25-hydroxy vitamin D3 [25(OH)D3] (100 or 500 nmol·L−1) and 1,25-dihydroxy vitamin D3 [1,25(OH)2D3] (0.1 or 0.5 nmol·L−1) metabolites in cell cultures. Specifically, CD14+ monocytes were cultured in charcoal-stripped serum in the presence of receptor activator of nuclear factor kappa-B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). Tartrate-resistant acid phosphatase (TRAP) histochemical staining assays and dentine resorption analysis were used to identify the size and number of osteoclast cells, number of nuclei per cell and resorption activity. The expression of VDR was detected in human bone tissue (ex vivo) by immunohistochemistry and in vitro cell cultures by western blotting. Quantitative reverse transcription-PCR (qRT-PCR) was used to determine the level of expression of vitamin D-related genes in response to vitamin D metabolites. VDR-related genes during osteoclastogenesis, shown by qRT-PCR, was stimulated in response to 500 nmol·L−1 of 25(OH)D3 and 0.1–0.5 nmol·L−1 of 1,25(OH)2D3, upregulating cytochrome P450 family 27 subfamily B member 1 (CYP27B1) and cytochrome P450 family 24 subfamily A member 1 (CYP24A1). Osteoclast fusion transcripts transmembrane 7 subfamily member 4 (tm7sf4) and nuclear factor of activated T-cell cytoplasmic 1 (nfatc1) where downregulated in response to vitamin D metabolites. Osteoclast number and resorption activity were also increased. Both 25(OH)D3 and 1,25(OH)2D3 reduced osteoclast size and number when co-treated with RANKL and M-CSF. The evidence for VDR expression in resorbing osteoclasts in vivo and low-dose effects of 1,25(OH)2D3 on osteoclasts in vitro

  9. Oral Administration of Recombinant Lactococcus lactis Expressing HSP65 and Tandemly Repeated P277 Reduces the Incidence of Type I Diabetes in Non-Obese Diabetic Mice

    PubMed Central

    Ma, Yanjun; Liu, Jingjing; Hou, Jing; Dong, Yuankai; Lu, Yong; Jin, Liang; Cao, Rongyue; Li, Taiming; Wu, Jie

    2014-01-01

    Diabetes mellitus type 1 (DM1) is an autoimmune disease that gradually destroys insulin-producing beta-cells. We have previously reported that mucosal administration of fusion protein of HSP65 with tandem repeats of P277 (HSP65-6P277) can reduce the onset of DM1 in non-obese diabetic (NOD) mice. To deliver large amounts of the fusion protein and to enhance long-term immune tolerance effects, in the present study, we investigated the efficacy of using orally administrated L. lactis expressing HSP65-6P277 to reduce the incidence of DM1 in NOD mice. L. lactis strain NZ9000 was engineered to express HSP65-6P277 either constitutively or by nisin induction. After immunization via gavage with the recombinant L. lactis strains to groups of 4-week old female NOD mice for 36 weeks, we observed that oral administration of recombinant L. Lactis resulted in the prevention of hyperglycemia, improved glucose tolerance and reduced insulitis. Immunologic analysis showed that treatment with recombinant L. lactis induced HSP65- and P277- specific T cell immuno-tolerance, as well as antigen-specific proliferation of splenocytes. The results revealed that the DM1-preventing function was in part caused by a reduction in the pro-inflammatory cytokine IFN-γ and an increase in the anti-inflammatory cytokine IL-10. Orally administered recombinant L. lactis delivering HSP65-6P277 may be an effective therapeutic approach in preventing DM1. PMID:25157497

  10. Dose-dependent changes in the synaptic strength on dopamine neurons and locomotor activity after cocaine exposure

    PubMed Central

    Wanat, M.J.; Bonci, A.

    2016-01-01

    Changes in synaptic strength on ventral tegmental area (VTA) dopamine neurons are thought to play a critical role in the development of addiction-related behaviors. However, it is unknown how a single injection of cocaine at different doses affects locomotor activity, behavioral sensitization, and glutamatergic synaptic strength on VTA dopamine neurons in mice. We observed that behavioral sensitization to a challenge cocaine injection scaled with the dose of cocaine received one day prior. Interestingly, the locomotor activity after the initial exposure to different doses of cocaine corresponded to the changes in glutamatergic strength on VTA dopamine neurons. These results in mice suggest that a single exposure to cocaine dose-dependently affects excitatory synapses on VTA dopamine neurons, and that this acute synaptic alteration is directly associated with the locomotor responses to cocaine and not to behavioral sensitization. PMID:18655120

  11. Tissue factor pathway inhibitor dose-dependently inhibits coagulation activation without influencing the fibrinolytic and cytokine response during human endotoxemia.

    PubMed

    de Jonge, E; Dekkers, P E; Creasey, A A; Hack, C E; Paulson, S K; Karim, A; Kesecioglu, J; Levi, M; van Deventer, S J; van Der Poll, T

    2000-02-15

    Inhibition of the tissue factor pathway has been shown to attenuate the activation of coagulation and to prevent death in a gram-negative bacteremia primate model of sepsis. It has been suggested that tissue factor influences inflammatory cascades other than the coagulation system. The authors sought to determine the effects of 2 different doses of recombinant tissue factor pathway inhibitor (TFPI) on endotoxin-induced coagulant, fibrinolytic, and cytokine responses in healthy humans. Two groups, each consisting of 8 healthy men, were studied in a double-blind, randomized, placebo-controlled crossover study. Subjects were studied on 2 different occasions. They received a bolus intravenous injection of 4 ng/kg endotoxin, which was followed by a 6-hour continuous infusion of TFPI or placebo. Eight subjects received 0.05 mg/kg per hour TFPI after a bolus of 0.0125 mg/kg (low-dose group), and 8 subjects received 0.2 mg/kg per hour after a bolus of 0.05 mg/kg (high-dose group). Endotoxin injection induced the activation of coagulation, the activation and subsequent inhibition of fibrinolysis, and the release of proinflammatory and antiinflammatory cytokines. TFPI infusion induced a dose-dependent attenuation of thrombin generation, as measured by plasma F1 + 2 and thrombin-antithrombin complexes, with a complete blockade of coagulation activation after high-dose TFPI. Endotoxin-induced changes in the fibrinolytic system and cytokine levels were not altered by either low-dose or high-dose TFPI. The authors concluded that TFPI effectively and dose-dependently attenuates the endotoxin-induced coagulation activation in humans without influencing the fibrinolytic and cytokine response. (Blood. 2000;95:1124-1129)

  12. Feeding Blueberry Diets to Young Rats Dose-Dependently Inhibits Bone Resorption through Suppression of RANKL in Stromal Cells

    PubMed Central

    Zhang, Jian; Lazarenko, Oxana P.; Kang, Jie; Blackburn, Michael L.; Ronis, Martin J. J.; Badger, Thomas M.; Chen, Jin-Ran

    2013-01-01

    Previous studies have demonstrated that weanling rats fed AIN-93G semi-purified diets supplemented with 10% whole blueberry (BB) powder for two weeks beginning on postnatal day 21 (PND21) significantly increased bone formation at PND35. However, the minimal level of dietary BB needed to produce these effects is, as yet, unknown. The current study examined the effects of three different levels of BB diet supplementation (1, 3, and 5%) for 35 days beginning on PND25 on bone quality, and osteoclastic bone resorption in female rats. Peripheral quantitative CT scan (pQCT) of tibia, demonstrated that bone mineral density (BMD) and content (BMC) were dose-dependently increased in BB-fed rats compared to controls (P<0.05). Significantly increased bone mass after feeding 5% BB extracts was also observed in a TEN (total enteral nutrition) rat model in which daily caloric and food intake was precisely controlled. Expression of RANKL (receptor activator of nuclear factor-κB ligand) a protein essential for osteoclast formation was dose-dependently decreased in the femur of BB animals. In addition, expression of PPARγ (peroxisome proliferator-activated receptor γ) which regulates bone marrow adipogenesis was suppressed in BB diet rats compared to non-BB diet controls. Finally, a set of in vitro cell cultures revealed that the inhibitory effect of BB diet rat serum on RANKL expression was more profound in mesenchymal stromal cells compared to its effect on mature osteoblasts, pre-adipocytes and osteocytes. These results suggest that inhibition of bone resorption may contribute to increased bone mass during early development after BB consumption. PMID:23936431

  13. Penicillin-induced epilepsy model in rats: dose-dependant effect on hippocampal volume and neuron number.

    PubMed

    Akdogan, Ilgaz; Adiguzel, Esat; Yilmaz, Ismail; Ozdemir, M Bulent; Sahiner, Melike; Tufan, A Cevik

    2008-10-22

    This study was designed to evaluate the penicillin-induced epilepsy model in terms of dose-response relationship of penicillin used to induce epilepsy seizure on hippocampal neuron number and hippocampal volume in Sprague-Dawley rats. Seizures were induced with 300, 500, 1500 and 2000IU of penicillin-G injected intracortically in rats divided in four experimental groups, respectively. Control group was injected intracortically with saline. Animals were decapitated on day 7 of treatment and brains were removed. The total neuron number of pyramidal cell layer from rat hippocampus was estimated using the optical fractionator method. The volume of same hippocampal areas was estimated using the Cavalieri method. Dose-dependent decrease in hippocampal neuron number was observed in three experimental groups (300, 500 and 1500IU of penicillin-G), and the effects were statistically significant when compared to the control group (P<0.009). Dose-dependent decrease in hippocampal volume, on the other hand, was observed in all three of these groups; however, the difference compared to the control group was only statistically significant in 1500IU of penicillin-G injected group (P<0.009). At the dose of 2000IU penicillin-G, all animals died due to status seizures. These results suggest that the appropriate dose of penicillin has to be selected for a given experimental epilepsy study in order to demonstrate the relevant epileptic seizure and its effects. Intracortical 1500IU penicillin-induced epilepsy model may be a good choice to practice studies that investigate neuroprotective mechanisms of the anti-epileptic drugs.

  14. Symmetrical Dose-Dependent DNA-Methylation Profiles in Children with Deletion or Duplication of 7q11.23

    PubMed Central

    Strong, Emma; Butcher, Darci T.; Singhania, Rajat; Mervis, Carolyn B.; Morris, Colleen A.; De Carvalho, Daniel; Weksberg, Rosanna; Osborne, Lucy R.

    2015-01-01

    Epigenetic dysfunction has been implicated in a growing list of disorders that include cancer, neurodevelopmental disorders, and neurodegeneration. Williams syndrome (WS) and 7q11.23 duplication syndrome (Dup7) are rare neurodevelopmental disorders with broad phenotypic spectra caused by deletion and duplication, respectively, of a 1.5-Mb region that includes several genes with a role in epigenetic regulation. We have identified striking differences in DNA methylation across the genome between blood cells from children with WS or Dup7 and blood cells from typically developing (TD) children. Notably, regions that were differentially methylated in both WS and Dup7 displayed a significant and symmetrical gene-dose-dependent effect, such that WS typically showed increased and Dup7 showed decreased DNA methylation. Differentially methylated genes were significantly enriched with genes in pathways involved in neurodevelopment, autism spectrum disorder (ASD) candidate genes, and imprinted genes. Using alignment with ENCODE data, we also found the differentially methylated regions to be enriched with CCCTC-binding factor (CTCF) binding sites. These findings suggest that gene(s) within 7q11.23 alter DNA methylation at specific sites across the genome and result in dose-dependent DNA-methylation profiles in WS and Dup7. Given the extent of DNA-methylation changes and the potential impact on CTCF binding and chromatin regulation, epigenetic mechanisms most likely contribute to the complex neurological phenotypes of WS and Dup7. Our findings highlight the importance of DNA methylation in the pathogenesis of WS and Dup7 and provide molecular mechanisms that are potentially shared by WS, Dup7, and ASD. PMID:26166478

  15. Ferulic Acid modulates altered lipid profiles and prooxidant/antioxidant status in circulation during nicotine-induced toxicity: a dose-dependent study.

    PubMed

    Sudheer, Adluri Ram; Chandran, Kalpana; Marimuthu, Srinivasan; Menon, Venugopal Padmanabhan

    2005-01-01

    Nicotine, an active ingredient of tobacco smoke, is known to induce hyperlipidemia and disturb the prooxidant-antioxidant status. In our study, ferulic acid, a naturally occurring nutritional compound, was tested for its antioxidant and antihyperlipidemic property in a dose-dependent manner against nicotine-induced toxicity in female Wistar rats. We tested three different doses of ferulic acid-10 mg, 20 mg, and 40 mg/kg body weight-for their protective effects. The activities of biochemical marker enzymes lactate dehydrogenase and alkaline phosphatase, levels of peroxidative indices (thiobarbituric acid reactive substances and hydroperoxides), nitric oxide, and circulatory lipids (cholesterol, triglycerides, free fatty acids, and phospholipids) were increased significantly in the nicotine-treated group when compared to normal, which were brought down in ferulic acid-treated groups. The antioxidant status (superoxide dismutase, catalase, glutathione peroxidase, vitamin E, and reduced glutathione) was found to be decreased in the nicotine-treated group, and was significantly increased in ferulic acid-administered groups. Further, ferulic acid also positively modulated the nicotine-induced changes in the micronutrients (zinc and copper) level. The dose 20 mg/kg body weight was found to be more effective than the other two doses. Our data suggest that FA exerts its preventive effects by modulating the degree of lipid peroxidation, antioxidant status, lipid profiles, and trace element levels during nicotine-induced toxicity. PMID:20021059

  16. Sex- and dose-dependent effects of post-trial calcium channel blockade by magnesium chloride on memory for inhibitory avoidance conditioning.

    PubMed

    Wilmott, Lynda A; Thompson, Lucien T

    2013-11-15

    Calcium influx through voltage-dependent Ca(2+) channels is critical for many neuronal processes required for learning and memory. Persistent increases in cytosolic intracellular Ca(2+) concentrations in aging neurons are associated with learning impairments, while small transient subcellular changes in intracellular calcium concentrations play critical roles in neural plasticity in young neurons. In the present study, young male and female Fisher 344 × Brown Norway (FBN) hybrid rats were administered different doses of magnesium chloride (0.0, 100.0, or 200.0mg/kg, i.p.) following a single inhibitory avoidance training trial. Extracellular magnesium ions can non-specifically block voltage-gated calcium channels, and/or reduce the calcium conductance gated via glutamate and serine's activation of neuronal NMDA receptors. In our study, magnesium chloride dose-dependently enhanced memory compared to controls (significantly increased latency to enter a dark compartment previously paired with an aversive stimulus) when tested 48 h later as compared to controls. A leftward shift in the dose response curve for memory enhancement by magnesium chloride was observed for male compared to female rats. These findings provide further insights into calcium-dependent modulation of aversive memory, and should be considered when assessing the design of effective treatment options for both male and female patients with dementia or other memory problems.

  17. In-vitro and in-vivo evidence of dose-dependent decrease of uropathogenic Escherichia coli virulence after consumption of commercial Vaccinium macrocarpon (cranberry) capsules.

    PubMed

    Lavigne, J-P; Bourg, G; Combescure, C; Botto, H; Sotto, A

    2008-04-01

    This study evaluated the antibacterial efficacy of the consumption of cranberry capsules vs. placebo in the urine of healthy volunteers. A first double-blind, randomised, crossover trial involved eight volunteers who had followed three regimens, with or without cranberry, with a wash-out period of at least 6 days between each regimen. Twelve hours after consumption of cranberry or placebo hard capsules, the first urine of the morning was collected. Different Escherichia coli strains were cultured in the urine samples. Urinary antibacterial adhesion activity was measured in vitro using the human T24 epithelial cell-line, and in vivo using the Caenorhabditis elegans killing model. With the in-vitro model, 108 mg of cranberry induced a significant reduction in bacterial adherence to T24 cells as compared with placebo (p <0.001). A significant dose-dependent decrease in bacterial adherence in vitro was noted after the consumption of 108 and 36 mg of cranberry (p <0.001). The in-vivo model confirmed that E. coli strains had a reduced ability to kill C. elegans after growth in the urine of patients who consumed cranberry capsules. Overall, these in-vivo and in-vitro studies suggested that consumption of cranberry juice represents an interesting new strategy to prevent recurrent urinary tract infection.

  18. An Upgrade on the Rabbit Model of Anthracycline-Induced Cardiomyopathy: Shorter Protocol, Reduced Mortality, and Higher Incidence of Overt Dilated Cardiomyopathy

    PubMed Central

    Talavera, Jesús; Fernández-Del-Palacio, María Josefa; García-Nicolás, Obdulio; Seva, Juan; Brooks, Gavin; Moraleda, Jose M.

    2015-01-01

    Current protocols of anthracycline-induced cardiomyopathy in rabbits present with high premature mortality and nephrotoxicity, thus rendering them unsuitable for studies requiring long-term functional evaluation of myocardial function (e.g., stem cell therapy). We compared two previously described protocols to an in-house developed protocol in three groups: Group DOX2 received doxorubicin 2 mg/kg/week (8 weeks); Group DAU3 received daunorubicin 3 mg/kg/week (10 weeks); and Group DAU4 received daunorubicin 4 mg/kg/week (6 weeks). A cohort of rabbits received saline (control). Results of blood tests, cardiac troponin I, echocardiography, and histopathology were analysed. Whilst DOX2 and DAU3 rabbits showed high premature mortality (50% and 33%, resp.), DAU4 rabbits showed 7.6% premature mortality. None of DOX2 rabbits developed overt dilated cardiomyopathy; 66% of DAU3 rabbits developed overt dilated cardiomyopathy and quickly progressed to severe congestive heart failure. Interestingly, 92% of DAU4 rabbits showed overt dilated cardiomyopathy and 67% developed congestive heart failure exhibiting stable disease. DOX2 and DAU3 rabbits showed alterations of renal function, with DAU3 also exhibiting hepatic function compromise. Thus, a shortened protocol of anthracycline-induced cardiomyopathy as in DAU4 group results in high incidence of overt dilated cardiomyopathy, which insidiously progressed to congestive heart failure, associated to reduced systemic compromise and very low premature mortality. PMID:26788502

  19. An Upgrade on the Rabbit Model of Anthracycline-Induced Cardiomyopathy: Shorter Protocol, Reduced Mortality, and Higher Incidence of Overt Dilated Cardiomyopathy.

    PubMed

    Talavera, Jesús; Giraldo, Alejandro; Fernández-Del-Palacio, María Josefa; García-Nicolás, Obdulio; Seva, Juan; Brooks, Gavin; Moraleda, Jose M

    2015-01-01

    Current protocols of anthracycline-induced cardiomyopathy in rabbits present with high premature mortality and nephrotoxicity, thus rendering them unsuitable for studies requiring long-term functional evaluation of myocardial function (e.g., stem cell therapy). We compared two previously described protocols to an in-house developed protocol in three groups: Group DOX2 received doxorubicin 2 mg/kg/week (8 weeks); Group DAU3 received daunorubicin 3 mg/kg/week (10 weeks); and Group DAU4 received daunorubicin 4 mg/kg/week (6 weeks). A cohort of rabbits received saline (control). Results of blood tests, cardiac troponin I, echocardiography, and histopathology were analysed. Whilst DOX2 and DAU3 rabbits showed high premature mortality (50% and 33%, resp.), DAU4 rabbits showed 7.6% premature mortality. None of DOX2 rabbits developed overt dilated cardiomyopathy; 66% of DAU3 rabbits developed overt dilated cardiomyopathy and quickly progressed to severe congestive heart failure. Interestingly, 92% of DAU4 rabbits showed overt dilated cardiomyopathy and 67% developed congestive heart failure exhibiting stable disease. DOX2 and DAU3 rabbits showed alterations of renal function, with DAU3 also exhibiting hepatic function compromise. Thus, a shortened protocol of anthracycline-induced cardiomyopathy as in DAU4 group results in high incidence of overt dilated cardiomyopathy, which insidiously progressed to congestive heart failure, associated to reduced systemic compromise and very low premature mortality.

  20. Nilotinib is associated with a reduced incidence of BCR-ABL mutations vs imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase.

    PubMed

    Hochhaus, Andreas; Saglio, Giuseppe; Larson, Richard A; Kim, Dong-Wook; Etienne, Gabriel; Rosti, Gianantonio; De Souza, Carmino; Kurokawa, Mineo; Kalaycio, Matt E; Hoenekopp, Albert; Fan, Xiaolin; Shou, Yaping; Kantarjian, Hagop M; Hughes, Timothy P

    2013-05-01

    In patients with chronic myeloid leukemia, BCR-ABL mutations contribute to resistance to tyrosine kinase inhibitor therapy. We examined the occurrence of treatment-emergent mutations and their impact on response in patients from the ENESTnd phase 3 trial. At the 3-year data cutoff, mutations were detected in approximately twice as many patients (21) on imatinib 400 mg once daily as on nilotinib (11 patients each on nilotinib 300 mg twice daily and nilotinib 400 mg twice daily). The majority of mutations occurred in patients with intermediate or high Sokal scores. Most mutations (14 [66.7%]) emerging during imatinib treatment were imatinib-resistant and nilotinib-sensitive. Incidence of the T315I mutation was low (found in 3, 2, and 3 patients on nilotinib 300 mg twice daily, nilotinib 400 mg twice daily, and imatinib, respectively) and mostly occurred in patients with high Sokal scores. Of the patients with emergent mutations, 1 of 11, 2 of 11, and 7 of 21 patients on nilotinib 300 mg twice daily, nilotinib 400 mg twice daily, and imatinib, respectively, progressed to accelerated phase/blast crisis (AP/BC) on treatment. Overall, nilotinib led to fewer treatment-emergent BCR-ABL mutations than imatinib and reduced rates of progression to AP/BC in patients with these mutations. (Clinicaltrials.gov NCT00471497).

  1. The SAFE project: 'plant food allergies: field to table strategies for reducing their incidence in Europe' an EC-funded study.

    PubMed

    Hoffmann-Sommergruber, K

    2005-04-01

    The true prevalence of food allergy as an IgE mediated reaction is still under discussion. Using apple as a model allergen source a multidisciplinary consortium worked together at developing various strategies for reducing the incidence of fruit allergies in an EC-funded project. Patient allergen profiles were established using in vitro and in vivo tests with respect to geographic area and mild or severe symptoms. Apple allergens (Mal d 1-Mal d 4) were characterised, variants identified, cloned and sequenced. These individual allergens were used to increase the sensitivity and specificity of diagnosis. Furthermore, they provided better prognosis of disease severity. RT-PCR and ELISA were developed for determining the allergen specific mRNA and expressed allergenic protein in a large number of apple cultivars. Similarly, changes in allergen characteristics from harvest through storage to processing and the impact of agronomic practices were investigated. Allergen genes were mapped on a molecular linkage map of apple. The biological function of Mal d 1 was studied using the RNA interference strategy. Finally, consumer attitudes in Northern, Central and Southern Europe were gauged on the acceptability of low allergen cultivars or a GMO and its impact on product quality.

  2. Combination therapy reduces the incidence of no-reflow after primary per-cutaneous coronary intervention in patients with ST-segment elevation acute myocardial infarction

    PubMed Central

    Zhou, Shan-Shan; Tian, Feng; Chen, Yun-Dai; Wang, Jing; Sun, Zhi-Jun; Guo, Jun; Jin, Qin-Hua

    2015-01-01

    -dose statin pre-treatment, intracoronary administration of adenosine during PCI procedure and platelet membrane glycoprotein IIb/IIIa receptor antagonist reduce the incidence of no-reflow after primary PCI in patients with acute myocardial infarction who are at high risk of no-reflow. PMID:25870616

  3. Sex- and dose-dependent effects of calcium ion irradiation on behavioral performance of B6D2F1 mice during contextual fear conditioning training.

    PubMed

    Raber, Jacob; Weber, Sydney J; Kronenberg, Amy; Turker, Mitchell S

    2016-06-01

    The space radiation environment includes energetic charged particles that may impact behavioral and cognitive performance. The relationship between the dose and the ionization density of the various types of charged particles (expressed as linear energy transfer or LET), and cognitive performance is complex. In our earlier work, whole body exposure to (28)Si ions (263 MeV/n, LET=78keV/μm; 1.6 Gy) affected contextual fear memory in C57BL/6J × DBA2/J F1 (B6D2F1) mice three months following irradiation but this was not the case following exposure to (48)Ti ions (1 GeV/n, LET=107keV/μm; 0.2 or 0.4 Gy). As an increased understanding of the impact of charged particle exposures is critical for assessment of risk to the CNS of astronauts during and following missions, in this study we used (40)Ca ion beams (942 MeV/n, LET=90keV/μm) to determine the behavioral and cognitive effects for the LET region between that of Si ions and Ti ions. (40)Ca ion exposure reduced baseline activity in a novel environment in a dose-dependent manner, which suggests reduced motivation to explore and/or a diminished level of curiosity in a novel environment. In addition, exposure to (40)Ca ions had sex-dependent effects on response to shock. (40)Ca ion irradiation reduced the response to shock in female, but not male, mice. In contrast, (40)Ca ion irradiation did not affect fear learning, memory, or extinction of fear memory for either gender at the doses employed in this study. Thus (40)Ca ion irradiation affected behavioral, but not cognitive, performance. The effects of (40)Ca ion irradiation on behavioral performance are relevant, as a combination of novelty and aversive environmental stimuli is pertinent to conditions experienced by astronauts during and following space missions. PMID:27345201

  4. Sex- and dose-dependent effects of calcium ion irradiation on behavioral performance of B6D2F1 mice during contextual fear conditioning training

    NASA Astrophysics Data System (ADS)

    Raber, Jacob; Weber, Sydney J.; Kronenberg, Amy; Turker, Mitchell S.

    2016-06-01

    The space radiation environment includes energetic charged particles that may impact behavioral and cognitive performance. The relationship between the dose and the ionization density of the various types of charged particles (expressed as linear energy transfer or LET), and cognitive performance is complex. In our earlier work, whole body exposure to 28Si ions (263 MeV/n, LET = 78keV / μ m ; 1.6 Gy) affected contextual fear memory in C57BL/6J × DBA2/J F1 (B6D2F1) mice three months following irradiation but this was not the case following exposure to 48Ti ions (1 GeV/n, LET = 107keV / μ m ; 0.2 or 0.4 Gy). As an increased understanding of the impact of charged particle exposures is critical for assessment of risk to the CNS of astronauts during and following missions, in this study we used 40Ca ion beams (942 MeV/n, LET = 90keV / μm) to determine the behavioral and cognitive effects for the LET region between that of Si ions and Ti ions. 40Ca ion exposure reduced baseline activity in a novel environment in a dose-dependent manner, which suggests reduced motivation to explore and/or a diminished level of curiosity in a novel environment. In addition, exposure to 40Ca ions had sex-dependent effects on response to shock. 40Ca ion irradiation reduced the response to shock in female, but not male, mice. In contrast, 40Ca ion irradiation did not affect fear learning, memory, or extinction of fear memory for either gender at the doses employed in this study. Thus 40Ca ion irradiation affected behavioral, but not cognitive, performance. The effects of 40Ca ion irradiation on behavioral performance are relevant, as a combination of novelty and aversive environmental stimuli is pertinent to conditions experienced by astronauts during and following space missions.

  5. Sex- and dose-dependent effects of calcium ion irradiation on behavioral performance of B6D2F1 mice during contextual fear conditioning training.

    PubMed

    Raber, Jacob; Weber, Sydney J; Kronenberg, Amy; Turker, Mitchell S

    2016-06-01

    The space radiation environment includes energetic charged particles that may impact behavioral and cognitive performance. The relationship between the dose and the ionization density of the various types of charged particles (expressed as linear energy transfer or LET), and cognitive performance is complex. In our earlier work, whole body exposure to (28)Si ions (263 MeV/n, LET=78keV/μm; 1.6 Gy) affected contextual fear memory in C57BL/6J × DBA2/J F1 (B6D2F1) mice three months following irradiation but this was not the case following exposure to (48)Ti ions (1 GeV/n, LET=107keV/μm; 0.2 or 0.4 Gy). As an increased understanding of the impact of charged particle exposures is critical for assessment of risk to the CNS of astronauts during and following missions, in this study we used (40)Ca ion beams (942 MeV/n, LET=90keV/μm) to determine the behavioral and cognitive effects for the LET region between that of Si ions and Ti ions. (40)Ca ion exposure reduced baseline activity in a novel environment in a dose-dependent manner, which suggests reduced motivation to explore and/or a diminished level of curiosity in a novel environment. In addition, exposure to (40)Ca ions had sex-dependent effects on response to shock. (40)Ca ion irradiation reduced the response to shock in female, but not male, mice. In contrast, (40)Ca ion irradiation did not affect fear learning, memory, or extinction of fear memory for either gender at the doses employed in this study. Thus (40)Ca ion irradiation affected behavioral, but not cognitive, performance. The effects of (40)Ca ion irradiation on behavioral performance are relevant, as a combination of novelty and aversive environmental stimuli is pertinent to conditions experienced by astronauts during and following space missions.

  6. The Challenges to Improve Farm Animal Welfare in the United Kingdom by Reducing Disease Incidence with Greater Veterinary Involvement on Farm

    PubMed Central

    Scott, Philip R.

    2013-01-01

    Simple Summary Sick cattle and sheep are often treated by farmers without prior veterinary examination and, as a consequence, incorrect diagnoses and inappropriate therapies are common, but these failings largely go undetected and unreported. Many farmers maintain that market forces render veterinary care of individual sick sheep and cattle too expensive. Delays in requesting veterinary attention are not uncommon causing unnecessary animal suffering and a poorer outcome. Incidence rates of endemic diseases in the United Kingdom are too high, causing animal welfare concerns, but these could be reduced by the implementation of proven veterinary flock/herd health programmes. Abstract The Cattle Health and Welfare Group of Great Britain report (CHAWG; 2012) lists the most important cattle diseases and disorders but fails to fully acknowledge the importance of animal mental health and; in so doing; misses the opportunity to further promote animal welfare. There are effective prevention regimens; including vaccination; husbandry and management strategies for all ten listed animal health concerns in the CHAWG report; however control measures are infrequently implemented because of perceived costs and unwillingness of many farmers to commit adequate time and resources to basic farm management tasks such as biosecurity; and biocontainment. Reducing disease prevalence rates by active veterinary herd and flock health planning; and veterinary care of many individual animal problems presently “treated” by farmers; would greatly improve animal welfare. Published studies have highlighted that treatments for lame sheep are not implemented early enough with many farmers delaying treatment for weeks; and sometimes even months; which adversely affects prognosis. Disease and welfare concerns as a consequence of sheep ectoparasites could be greatly reduced if farmers applied proven control strategies detailed in either veterinary flock health plans or advice available from expert

  7. Aeromonas hydrophila OmpW PLGA Nanoparticle Oral Vaccine Shows a Dose-Dependent Protective Immunity in Rohu (Labeo rohita)

    PubMed Central

    Dubey, Saurabh; Avadhani, Kiran; Mutalik, Srinivas; Sivadasan, Sangeetha Madambithara; Maiti, Biswajit; Paul, Joydeb; Girisha, Shivani Kallappa; Venugopal, Moleyur Nagarajappa; Mutoloki, Stephen; Evensen, Øystein; Karunasagar, Indrani; Munang’andu, Hetron Mweemba

    2016-01-01

    Aeromonas hydrophila is a Gram-negative bacterium that causes high mortality in different fish species and at different growth stages. Although vaccination has significantly contributed to the decline of disease outbreaks in aquaculture, the use of oral vaccines has lagged behind the injectable vaccines due to lack of proven efficacy, that being from primary immunization or by use of boost protocols. In this study, the outer membrane protein W (OmpW) of A. hydrophila was cloned, purified, and encapsulated in poly d,l-lactide-co-glycolic acid (PLGA) nanoparticles (NPs) for oral vaccination of rohu (Labeo rohita Hamilton). The physical properties of PLGA NPs encapsulating the recombinant OmpW (rOmpW) was characterized as having a diameter of 370–375 nm, encapsulation efficiency of 53% and −19.3 mV zeta potential. In vitro release of rOmpW was estimated at 34% within 48 h of incubation in phosphate-buffered saline. To evaluate the efficacy of the NP-rOmpW oral vaccine, two antigen doses were orally administered in rohu with a high antigen (HiAg) dose that had twice the amount of antigens compared to the low antigen (LoAg) dose. Antibody levels obtained after vaccination showed an antigen dose dependency in which fish from the HiAg group had higher antibody levels than those from the LoAg group. The antibody levels corresponded with post challenge survival proportions (PCSPs) and relative percent survival (RPS) in which the HiAg group had a higher PCSP and RPS than the LoAg group. Likewise, the ability to inhibit A. hydrophila growth on trypticase soy agar (TSA) by sera obtained from the HiAg group was higher than that from the LoAg group. Overall, data presented here shows that OmpW orally administered using PLGA NPs is protective against A. hydrophila infection with the level of protective immunity induced by oral vaccination being antigen dose-dependent. Future studies should seek to optimize the antigen dose and duration of oral immunization in rohu in order to

  8. Aeromonas hydrophila OmpW PLGA Nanoparticle Oral Vaccine Shows a Dose-Dependent Protective Immunity in Rohu (Labeo rohita).

    PubMed

    Dubey, Saurabh; Avadhani, Kiran; Mutalik, Srinivas; Sivadasan, Sangeetha Madambithara; Maiti, Biswajit; Paul, Joydeb; Girisha, Shivani Kallappa; Venugopal, Moleyur Nagarajappa; Mutoloki, Stephen; Evensen, Øystein; Karunasagar, Indrani; Munang'andu, Hetron Mweemba

    2016-01-01

    Aeromonas hydrophila is a Gram-negative bacterium that causes high mortality in different fish species and at different growth stages. Although vaccination has significantly contributed to the decline of disease outbreaks in aquaculture, the use of oral vaccines has lagged behind the injectable vaccines due to lack of proven efficacy, that being from primary immunization or by use of boost protocols. In this study, the outer membrane protein W (OmpW) of A. hydrophila was cloned, purified, and encapsulated in poly d,l-lactide-co-glycolic acid (PLGA) nanoparticles (NPs) for oral vaccination of rohu (Labeo rohita Hamilton). The physical properties of PLGA NPs encapsulating the recombinant OmpW (rOmpW) was characterized as having a diameter of 370-375 nm, encapsulation efficiency of 53% and -19.3 mV zeta potential. In vitro release of rOmpW was estimated at 34% within 48 h of incubation in phosphate-buffered saline. To evaluate the efficacy of the NP-rOmpW oral vaccine, two antigen doses were orally administered in rohu with a high antigen (HiAg) dose that had twice the amount of antigens compared to the low antigen (LoAg) dose. Antibody levels obtained after vaccination showed an antigen dose dependency in which fish from the HiAg group had higher antibody levels than those from the LoAg group. The antibody levels corresponded with post challenge survival proportions (PCSPs) and relative percent survival (RPS) in which the HiAg group had a higher PCSP and RPS than the LoAg group. Likewise, the ability to inhibit A. hydrophila growth on trypticase soy agar (TSA) by sera obtained from the HiAg group was higher than that from the LoAg group. Overall, data presented here shows that OmpW orally administered using PLGA NPs is protective against A. hydrophila infection with the level of protective immunity induced by oral vaccination being antigen dose-dependent. Future studies should seek to optimize the antigen dose and duration of oral immunization in rohu in order to

  9. Prophylactic plastic surgery closure of neurosurgical scalp incisions reduces the incidence of wound complications in previously-operated patients treated with bevacizumab (Avastin®) and radiation.

    PubMed

    Golas, Alyssa Reiffel; Boyko, Tatiana; Schwartz, Theodore H; Stieg, Philip E; Boockvar, John A; Spector, Jason A

    2014-09-01

    Neurosurgical craniotomy, craniectomy, or other trans-galeal interventions are performed for a variety of indications, including the resection of benign or malignant tumors, hematoma evacuation, and for the management of intractable seizure disorders. Despite an overall low complication rate of intervention, wound healing complications such as dehiscence, surgical site infection, and cerebrospinal fluid leak are not uncommon. A retrospective review was performed of all patients who underwent scalp incision closure at a single institution by a single plastic surgeon between 2006 and 2013. Sixty patients (83 procedures) were included in the study. Fifty-seven patients (95.0 %) underwent previous craniotomy, craniectomy, or other trans-galeal procedure. Of the total 60 patients, 35 patients received preoperative radiation. Sixteen patients received bevacizumab prior to their index case, while 12 received bevacizumab postoperatively. Ten patients (16.7 %) required additional plastic surgical intervention for wound complications after their index plastic surgery procedure. Plastic surgery was consulted prophylactically in 34 patients (38 procedures). When plastic surgery was consulted prophylactically, 4 patients (11.8 %) required further wound revision. None of the 14 patients who underwent prophylactic plastic surgery closure for previous scalp incision, preoperative bevacizumab, and XRT administration required re-intervention. Plastic surgery closure of complex scalp incisions reduces the incidence of wound complications among patients who underwent previous neurosurgical intervention, XRT administration, and preoperative bevacizumab administration. This is particularly true when plastic surgery closure is performed "prophylactically." Further collaboration between the neurosurgical and plastic surgery teams is therefore warranted, particularly in the setting of these high-risk cases.

  10. Cost-Effectiveness of an Intervention to Reduce HIV/STI Incidence and Promote Condom Use among Female Sex Workers in the Mexico–US Border Region

    PubMed Central

    Burgos, José L.; Gaebler, Julia A.; Strathdee, Steffanie A.; Lozada, Remedios; Staines, Hugo; Patterson, Thomas L.

    2010-01-01

    Background Previous research demonstrated efficacy of a brief behavioral intervention to reduce incidence of HIV and sexually transmitted infections (STIs) among female sex workers (FSWs) in Tijuana and Ciudad Juarez, Mexico, cities on Mexico's border with the US. We assessed this intervention's cost-effectiveness. Methodology and Principal Findings A life-time Markov model was developed to estimate HIV cases prevented, changes in quality-adjusted life expectancy (QALE), and costs per additional quality-adjusted life year gained (QALY), comparing (in US$2,009) no intervention to a once-only and annual intervention. Future costs and health benefits were discounted annually at 3%. Sensitivity analyses evaluated model robustness. We found that for a hypothetical 1,000 FSWs receiving the once-only intervention, there were 33 HIV cases prevented and 5.7 months of QALE gained compared to no intervention. The additional cost per QALY gained was US$183. For FSWs receiving the intervention annually, there were 29 additional HIV cases prevented and 4.5 additional months of QALE compared to the once-only intervention. The additional cost per QALY was US$1,075. When highly active antiretroviral therapy (HAART) was included in the model, the annual intervention strategy resulted in net savings and dominated both once-only and no intervention strategies, and remained robust across extensive sensitivity analyses. Even when considering clinical benefits from HAART, ignoring added costs, the cost per QALY gained remained below three times the Mexican GDP per capita, and below established cost-effectiveness thresholds. Conclusions/Significance This brief intervention was shown to be cost-effective among FSWs in two Mexico-US border cities and may have application for FSWs in other resource-limited settings. Trial Registration ClinicalTrials.gov NCT00338845 PMID:20617193

  11. Tart cherry juice induces differential dose-dependent effects on apoptosis, but not cellular proliferation, in MCF-7 human breast cancer cells.

    PubMed

    Martin, Keith R; Wooden, Alissa

    2012-11-01

    Consumption of polyphenol-rich fruits, for example, tart cherries, is associated with a lower risk of cardiovascular disease and cancer. This is due, in large part, to the diverse myriad bioactive agents, that is, polyphenol anthocyanins, present in fruits. Anthocyanin-rich tart cherries purportedly modulate numerous cellular processes associated with oncogenesis such as apoptosis, cellular proliferation (CP), and cell cycle progression, although the effective concentrations eliciting these effects are unclear. We hypothesized that several dose-dependent effects over a large concentration range of 100% tart cherry juice (TCJ) would exist and affect these processes differentially with the potential for cellular protection and cellular death either by apoptosis or by necrosis. In this in vitro study, we tested the dose response of TCJ on CP and cell death in MCF-7 human breast cancer cells. TCJ was added at 0.03-30% (v/v) to cells and incubated overnight with the medium alone or with increasing TCJ. Bromodeoxyuridine incorporation was significantly reduced by 20% at ≥10% (v/v) TCJ and associated with necrosis, but was not different between the control and treatment groups at <10% TCJ. MTT reduction was also significantly reduced by 27% and 80% at 10% and 30% TCJ, respectively, and associated with necrosis. Apoptosis, but not necrosis, was increased ∼63% at 3% TCJ (∼307 nM monomeric anthocyanins), yet significantly decreased (P<.05) by 20% at 1% TCJ (920 nM) both of which were physiologically relevant concentrations of anthocyanins. The data support a biphasic effect on apoptosis and no effect on proliferation. PMID:23057779

  12. Acute paraquat exposure determines dose-dependent oxidative injury of multiple organs and metabolic dysfunction in rats: impact on exercise tolerance.

    PubMed

    Novaes, Rômulo D; Gonçalves, Reggiani V; Cupertino, Marli C; Santos, Eliziária C; Bigonha, Solange M; Fernandes, Geraldo J M; Maldonado, Izabel R S C; Natali, Antônio J

    2016-04-01

    This study investigated the pathological morphofunctional adaptations related to the imbalance of exercise tolerance triggered by paraquat (PQ) exposure in rats. The rats were randomized into four groups with eight animals each: (a) SAL (control): 0.5 ml of 0.9% NaCl solution; (b) PQ10: PQ 10 mg/kg; (c) PQ20: PQ 20 mg/kg; and (d) PQ30: PQ 30 mg/kg. Each group received a single injection of PQ. After 72 hours, the animals were subjected to an incremental aerobic running test until fatigue in order to determine exercise tolerance, blood glucose and lactate levels. After the next 24 h, lung, liver and skeletal muscle were collected for biometric, biochemical and morphological analyses. The animals exposed to PQ exhibited a significant anticipation of anaerobic metabolism during the incremental aerobic running test, a reduction in exercise tolerance and blood glucose levels as well as increased blood lactate levels during exercise compared to control animals. PQ exposure increased serum transaminase levels and reduced the glycogen contents in liver tissue and skeletal muscles. In the lung, the liver and the skeletal muscle, PQ exposure also increased the contents of malondialdehyde, protein carbonyl, 8-hydroxy-2'-deoxyguanosine, superoxide dismutase and catalase, as well as a structural remodelling compared to the control group. All these changes were dose-dependent. Reduced exercise tolerance after PQ exposure was potentially influenced by pathological remodelling of multiple organs, in which glycogen depletion in the liver and skeletal muscle and the imbalance of glucose metabolism coexist with the induction of lipid, protein and DNA oxidation, a destructive process not counteracted by the upregulation of endogenous antioxidant enzymes. PMID:27277193

  13. Methylprednisolone induces activation of the contact system in a dose-dependent manner. An in vitro study.

    PubMed

    Roeise, O; Nuijens, J H; Hack, C E; Bouma, B N; Stadaas, J O; Aasen, A O

    1990-03-15

    The effect of methylprednisolone sodium succinate (MP) on the contact system of plasma was studied in human citrated pool plasma. Contact activation was demonstrated by the presence of plasma kallikrein (KK) activity and activated Hageman factor (FXIIa) and/or KK in complex with C1 inhibitor (C1inh), detected by chromogenic peptide substrates or radioimmunoassays, using monoclonal antibodies directed to neodeterminants exposed on complexed C1inh, respectively. When plasma and different doses of MP were incubated for a period of 24 hours, the highest dose of MP (10 mg/ml) gave rapid and marked increases in KK activities and concentrations of C1inh complexes. MP at 5 mg/ml plasma also induced activation of the contact system, although this activation was less pronounced. Even the lower dose of MP (1 mg/ml), which is equivalent to doses used in humans, increased plasma concentrations of KK-C1inh complexes. In conclusion, this in vitro study shows that MP in a dose-dependent way activates the contact system of plasma.

  14. A UV–Induced Genetic Network Links the RSC Complex to Nucleotide Excision Repair and Shows Dose-Dependent Rewiring

    PubMed Central

    Srivas, Rohith; Costelloe, Thomas; Carvunis, Anne-Ruxandra; Sarkar, Sovan; Malta, Erik; Sun, Su Ming; Pool, Marijke; Licon, Katherine; van Welsem, Tibor; van Leeuwen, Fred; McHugh, Peter J.; van Attikum, Haico; Ideker, Trey

    2014-01-01

    SUMMARY Efficient repair of UV-induced DNA damage requires the precise coordination of nucleotide excision repair (NER) with numerous other biological processes. To map this crosstalk, we generated a differential genetic interaction map centered on quantitative growth measurements of >45,000 double mutants before and after different doses of UV radiation. Integration of genetic data with physical interaction networks identified a global map of 89 UV-induced functional interactions amongst 62 protein complexes, including a number of links between the RSC complex and several NER factors. We show that RSC is recruited to both silenced and transcribed loci following UV damage where it facilitates efficient repair by promoting nucleosome remodeling. Finally, a comparison of the response to high versus low levels of UV shows that the degree of genetic rewiring correlates with dose of UV and reveals a network of dose-specific interactions. This study makes available a large resource of UV-induced interactions, and it illustrates a methodology for identifying dose-dependent interactions based on quantitative shifts in genetic networks. PMID:24360959

  15. Excessive dietary phosphorus intake impairs endothelial function in young healthy men: a time- and dose-dependent study.

    PubMed

    Nishi, Tamae; Shuto, Emi; Ogawa, Mariko; Ohya, Miho; Nakanishi, Misaki; Masuda, Masashi; Katsumoto, Misaki; Yamanaka-Okumura, Hisami; Sakai, Tohru; Takeda, Eiji; Sakaue, Hiroshi; Taketani, Yutaka

    2015-01-01

    Excessive dietary phosphorus (P) has been speculated to be a risk factor for cardiovascular disease (CVD). Here, we performed a double-blinded crossover study to investigate the time- and dose-dependent effects of dietary P intake on endothelial function in healthy subjects. Sixteen healthy male volunteers were given meals containing 400, 800, and 1,200 mg P (P400, P800, and P1200 meals, respectively) with at least 7 days between doses. There were no differences in nutritional composition among the experimental diets except for P content. Blood biochemistry data and flow-mediated dilation (%FMD) of the brachial artery were measured while fasted, at 0 h, 1 h, 2 h, and 4 h after meal ingestion, and the next morning while fasted. The P800 and P1200 meals significantly increased serum P levels at 1-4 h after ingestion. A significant decrease in %FMD was observed between 1-4 h,while the P400 meal did not affect %FMD. We observed no differences among meals in serum P levels or %FMD the next morning. A significant negative correlation was observed between %FMD and serum P. These results indicate that excessive dietary P intake can acutely impair endothelial function in healthy people.

  16. Dose-dependent targeted knockout methodology combined with deep structure elucidation strategies for Chinese licorice chemical profiling.

    PubMed

    Jiang, Zhenzuo; Wang, Yuefei; Zhu, Yan; Zhang, Lei; Chai, Xin; Jiang, Miaomiao; Shan, Lihua

    2015-11-10

    One of the limitations with regards to the chemical profiling of Chinese herbs is that low-level compounds are masked by high-level structures. Here, we established a novel methodology based on a dose-dependent targeted knockout (DDTK) technique combined with deep structure elucidation strategies to allow the chemical profiling of Chinese licorice. We employed ultra-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UPLC-Q/TOF MS) incorporated with the DDTK technique to identify the compounds in different concentration samples and found that the compounds at the high- or medium-level were detected readily in the sample at a low concentration; subsequently, minor or trace-level constituents were identified in the sample at a high concentration by rejecting high-level constituents detected in the sample at a low concentration based on a heart-cutting technique during analysis. In this study, among the 232 compounds detected, 27 compounds were unequivocally identified and 165 compounds, including 29 new compounds and two new natural products, were tentatively characterized. The novel methodology established in this work paves the way the further identification of compounds from complicated mixtures, especially traditional Chinese medicines.

  17. A UV-induced genetic network links the RSC complex to nucleotide excision repair and shows dose-dependent rewiring.

    PubMed

    Srivas, Rohith; Costelloe, Thomas; Carvunis, Anne-Ruxandra; Sarkar, Sovan; Malta, Erik; Sun, Su Ming; Pool, Marijke; Licon, Katherine; van Welsem, Tibor; van Leeuwen, Fred; McHugh, Peter J; van Attikum, Haico; Ideker, Trey

    2013-12-26

    Efficient repair of UV-induced DNA damage requires the precise coordination of nucleotide excision repair (NER) with numerous other biological processes. To map this crosstalk, we generated a differential genetic interaction map centered on quantitative growth measurements of >45,000 double mutants before and after different doses of UV radiation. Integration of genetic data with physical interaction networks identified a global map of 89 UV-induced functional interactions among 62 protein complexes, including a number of links between the RSC complex and several NER factors. We show that RSC is recruited to both silenced and transcribed loci following UV damage where it facilitates efficient repair by promoting nucleosome remodeling. Finally, a comparison of the response to high versus low levels of UV shows that the degree of genetic rewiring correlates with dose of UV and reveals a network of dose-specific interactions. This study makes available a large resource of UV-induced interactions, and it illustrates a methodology for identifying dose-dependent interactions based on quantitative shifts in genetic networks.

  18. The Aurora-A inhibitor MLN8237 affects multiple mitotic processes and induces dose-dependent mitotic abnormalities and aneuploidy

    PubMed Central

    Asteriti, Italia Anna; Cesare, Erica Di; Mattia, Fabiola De; Hilsenstein, Volker; Neumann, Beate; Cundari, Enrico; Lavia, Patrizia; Guarguaglini, Giulia

    2014-01-01

    Inhibition of Aurora kinase activity by small molecules is being actively investigated as a potential anti-cancer strategy. A successful therapeutic use of Aurora inhibitors relies on a comprehensive understanding of the effects of inactivating Aurora kinases on cell division, a challenging aim given the pleiotropic roles of those kinases during mitosis. Here we have used the Aurora-A inhibitor MLN8237, currently under phase-I/III clinical trials, in dose-response assays in U2OS human cancer cells synchronously proceeding towards mitosis. By following the behaviour and fate of single Aurora-inhibited cells in mitosis by live microscopy, we show that MLN8237 treatment affects multiple processes that are differentially sensitive to the loss of Aurora-A function. A role of Aurora-A in controlling the orientation of cell division emerges. MLN8237 treatment, even in high doses, fails to induce efficient elimination of dividing cells, or of their progeny, while inducing significant aneuploidy in daughter cells. The results of single-cell analyses show a complex cellular response to MLN8237 and evidence that its effects are strongly dose-dependent: these issues deserve consideration in the light of the design of strategies to kill cancer cells via inhibition of Aurora kinases. PMID:25153724

  19. Dose-Dependent Effects of Glucocorticoids on Pulmonary Vascular Development in a Murine Model of Hyperoxic Lung Injury

    PubMed Central

    Perez, Marta; Wisniewska, Kamila; Lee, Keng Jin; Cardona, Herminio J.; Taylor, Joann M.; Farrow, Kathryn N.

    2015-01-01

    BACKGROUND Exposure of neonatal mice to hyperoxia results in pulmonary vascular remodeling and aberrant phosphodiesterase-5 (PDE5) signaling. Although glucocorticoids are frequently utilized in the NICU, little is known about their effects on the developing pulmonary vasculature and on PDE5. We sought to determine the effects of hydrocortisone (HC) on pulmonary vascular development and on PDE5 in a neonatal mouse model of hyperoxic lung injury. METHODS C57BL/6 mice were placed in 21% O2 or 75% O2 within 24h of birth and received HC (1, 5, or 10 mg/kg subcutaneously every other day) or vehicle. At 14d, right ventricular hypertrophy (RVH), medial wall thickness (MWT), lung morphometry, and pulmonary artery (PA) PDE5 activity were assessed. PDE5 activity was measured in isolated pulmonary artery smooth muscle cells (PASMC) exposed to 21% or 95% O2 ± 100nM HC for 24h. RESULTS Hyperoxia resulted in alveolar simplification, RVH, increased MWT, and increased PA PDE5 activity. HC decreased hyperoxia-induced RVH and attenuated MWT. HC had dose-dependent effects on alveolar simplification. HC decreased hyperoxia-induced PDE5 activity in vivo and in vitro. CONCLUSIONS HC decreases hyperoxia-induced pulmonary vascular remodeling and attenuates PDE5 activity. These findings suggest that HC may protect against hyperoxic injury in the developing pulmonary vasculature. PMID:26756781

  20. The relationship between dose-dependent antitussive and bronchodilatory effects of Opilia celtidifolia polysaccharide and nitric oxide in guinea pigs.

    PubMed

    Sutovská, M; Franová, S; Sadlonová, V; Grønhaug, T E; Diallo, D; Paulsen, B S; Capek, P

    2010-11-01

    A crude polysaccharide composed of uronic acids (32%), arabinose (26%), glucose (15%), galactose (11%), rhamnose (7%), mannose (5%), xylose (4%) and small amount of fucose residues has been isolated from the leaves of Opilia celtidifolia by boiled water extraction. Chemical analyses of Opilia polysaccharide revealed the prevalence of a pectin material with high arabinose and galacturonic acid contents. Opilia polysaccharide showed significant biological effects on chemically induced cough reflex and reactivity of airways smooth muscle in vitro and in vivo conditions in guinea pigs test system. Tests confirmed the dose-dependent cough-suppressive effect of Opilia polysaccharide comparable with activity of centrally acting codeine. Further, the bronchodilatory tests resulted in significant decrease in the values of specific airway resistance, which is very sensitive predictor of airway smooth muscle reactivity in vivo conditions regardless of bronchoconstricting mechanism. The results of in vitro experiments confirmed not only the bronchodilatory effect Opilia polysaccharide but revealed that its bronchodilatory mechanism is partially accompanied with enhanced NO production.

  1. Short communication: Experimental toxocarosis in Chinese Kun Ming mice: Dose-dependent larval distribution and modulation of immune responses.

    PubMed

    Ma, Guangxu; Tan, Yancai; Hu, Ling; Luo, Yongfang; Zhu, Honghong; Zhou, Rongqiong

    2015-12-01

    Toxocarosis is an important parasitic zoonosis which is mainly caused by the infective larvae of Toxocara canis. To identify whether there are correlations among the infectious dose, the larval migrans and immune modulation in inbred Chinese Kun Ming (KM) mice, experimental infections were carried out with a range of dosages of 100, 500, 1000, 2000, and 3000 embryonated eggs (EE). Pathogenic reactions were observed in terms of physical and central nervous symptoms. Distributions of T. canis larvae in liver, lung, kidney, heart and brain organs were respectively detected by scanning tissue sections. Moreover, quantitative real-time PCR was employed to identify the variations of Th2 immune response. The results showed that high inocula resulted in advanced larval emergences and arrested migrations in liver, lung, kidney and brain. However, no larvae were found in any of the histological sections of heart tissues. Higher levels of interleukin (IL)-4, IL-5, and IL-10 were detected along with the increasing inoculation doses, but the heaviest inoculum (3000 EE in this study) resulted in the sharp reduction of these ILs. Although no neurological symptoms or mortalities were noticed, these results indicated dose-dependent distribution patterns and immune regulations of T. canis larvae infection in KM mice. PMID:26679790

  2. Simvastatin Results in a Dose-Dependent Toxic Effect on Spiral Ganglion Neurons in an In Vitro Organotypic Culture Assay

    PubMed Central

    Leitmeyer, Katharina; Glutz, Andrea; Setz, Cristian; Wieland, Leonie; Egloff, Sulamith; Bodmer, Daniel

    2016-01-01

    Statins are inhibitors of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase, an enzyme necessary for the production of mevalonate. They are widely used as cholesterol-lowering drugs. However, conflicting data about the effect of statins on neuronal cells has been published. To explore the effect of simvastatin on spiral ganglion neurons (SGNs), SG explants of 5-day-old rats were treated with increasing concentrations of simvastatin. In addition, SG explants were treated with mevalonate and with the combination of simvastatin and mevalonate. SGN number, length of the neurites, area of nonneuronal supporting cells, and neuronal survival were analyzed. Simvastatin treatment results in a significant dose-dependent decrease of SG neurite number, length of neurites, area of supporting cells, and SG neuronal survival compared to control. Interestingly, treatment with mevalonate in addition to simvastatin increased SG neuronal survival compared to simvastatin treatment only. However, treatment with mevalonate in addition to simvastatin did not influence SG neurite number, length of neurites, and area of supporting cells compared to simvastatin treatment only. Our results suggest a neurotoxic effect of simvastatin on SGNs in vitro. Neurotoxicity seems to be at least partially mediated by the mevalonate pathway. Therefore, caution is warranted to use simvastatin as a potential otoprotective drug. PMID:27051663

  3. Cell nanomechanics and focal adhesions are regulated by retinol and conjugated linoleic acid in a dose-dependent manner.

    PubMed

    Silberberg, Yaron R; Yakubov, Gleb E; Horton, Michael A; Pelling, Andrew E

    2009-07-15

    Retinol and conjugated linoleic acid (CLA) have previously been shown to have an important role in gene expression and various cellular processes, including differentiation, proliferation and cell death. In this study we have investigated the effect of retinol and CLA, both individually and in combination, on the intracellular cytoskeleton, focal adhesions (FAs) and the nanomechanical properties of 3T3 fibroblasts. We observed a dose-dependent decrease in the formation of FAs following treatment with either compound, which was directly correlated to an increase in cell height (>30%) and a decrease in the measured Young's modulus (approximately 28%). Furthermore, treatments with both compounds demonstrated an increased effect and led to a reduction of >70% in the average number of FAs per cell and a decrease of >50% in average cell stiffness. These data reveal that retinol and CLA disrupt FA formation, leading to an increase in cell height and a significant decrease in stiffness. These results may broaden our understanding of the interplay between cell nanomechanics and cellular contact with the external microenvironment, and help to shed light on the important role of retinoids and CLA in health and disease. PMID:19546491

  4. Blue-violet light irradiation dose dependently decreases carotenoids in human skin, which indicates the generation of free radicals.

    PubMed

    Vandersee, Staffan; Beyer, Marc; Lademann, Juergen; Darvin, Maxim E

    2015-01-01

    In contrast to ultraviolet and infrared irradiation, which are known to facilitate cutaneous photoaging, immunosuppression, or tumour emergence due to formation of free radicals and reactive oxygen species, potentially similar effects of visible light on the human skin are still poorly characterized. Using a blue-violet light irradiation source and aiming to characterize its potential influence on the antioxidant status of the human skin, the cutaneous carotenoid concentration was measured noninvasively in nine healthy volunteers using resonance Raman spectroscopy following irradiation. The dose-dependent significant degradation of carotenoids was measured to be 13.5% and 21.2% directly after irradiation at 50 J/cm² and 100 J/cm² (P < 0.05). The irradiation intensity was 100 mW/cm². This is above natural conditions; the achieved doses, though, are acquirable under natural conditions. The corresponding restoration lasted 2 and 24 hours, respectively. The degradation of cutaneous carotenoids indirectly shows the amount of generated free radicals and especially reactive oxygen species in human skin. In all volunteers the cutaneous carotenoid concentration dropped down in a manner similar to that caused by the infrared or ultraviolet irradiations, leading to the conclusion that also blue-violet light at high doses could represent a comparably adverse factor for human skin.

  5. Possible mechanisms of dose-dependent cough suppressive effect of Althaea officinalis rhamnogalacturonan in guinea pigs test system.

    PubMed

    Sutovská, M; Nosálová, G; Sutovský, J; Franová, S; Prisenznáková, L; Capek, P

    2009-07-01

    The rhamnogalacturonan, isolated from the roots of medicinal plant Althaea officinalis L., showed various biological effects on the citric acid-induced cough reflex and reactivity of airways smooth muscle in vitro and in vivo conditions. It possessed dose-dependent cough suppression effect comparable with opioid agonist codeine. However, reactivity of the airways smooth muscle, measured in vitro as well as in vivo conditions was not significantly affected by rhamnogalacturonan and thus bronchodilatory activity did not participate in the cough suppression effect of polysaccharide tested. Moreover, the cough suppression effect of the polymer was not significantly modified by pretreatment of K(+)(ATP) ion channels with selective antagonist and therefore activation of this type of ion channels is not involved in the mechanism of rhamnogalacturonan cough suppressive ability. On the contrary, pretreatment of animals with selective 5-HT(2) receptors antagonist significantly decreased rhamnogalacturonan antitussive efficacy. From this point of view it seems that the cough suppression effect of the polymer is associated with the serotonergic 5-HT(2) receptor's function.

  6. Dose-dependent Effect of Boric Acid on Myogenic Differentiation of Human Adipose-derived Stem Cells (hADSCs).

    PubMed

    Apdik, Hüseyin; Doğan, Ayşegül; Demirci, Selami; Aydın, Safa; Şahin, Fikrettin

    2015-06-01

    Boron, a vital micronutrient for plant metabolism, is not fully elucidated for embryonic and adult body development, and tissue regeneration. Although optimized amount of boron supplement has been shown to be essential for normal gestational development in zebrafish and frog and beneficial for bone regeneration in higher animals, effects of boron on myogenesis and myo-regeneration remains to be solved. In the current study, we investigated dose-dependent activity of boric acid on myogenic differentiation of human adipose-derived stem cells (hADSCs) using immunocytochemical, gene, and protein expression analysis. The results revealed that while low- (81.9 μM) and high-dose (819.6 μM) boron treatment increased myogenic gene expression levels such as myosin heavy chain (MYH), MyoD, myogenin, and desmin at day 4 of differentiation, high-dose treatment decreased myogenic-related gene and protein levels at day 21 of differentiation, confirmed by immunocytochemical analysis. The findings of the study present not only an understanding of boron's effect on myogenic differentiation but also an opportunity for the development of scaffolds to be used in skeletal tissue engineering and supplements for embryonic muscle growth. However, fine dose tuning and treatment period arranging are highly warranted as boron treatment over required concentrations and time might result in detrimental outcomes to myogenesis and myo-regeneration.

  7. Surrogate light chain expression beyond the pre-B cell stage promotes tolerance in a dose-dependent fashion.

    PubMed

    Kil, Laurens P; Corneth, Odilia B J; de Bruijn, Marjolein J W; Asmawidjaja, Patrick S; Krause, Arndt; Lubberts, Erik; van Loo, Pieter Fokko; Hendriks, Rudi W

    2015-02-01

    While surrogate light chain (SLC) expression is normally terminated in differentiating pre-B cells, co-expression of SLC and conventional light chains has been reported in a small population of autoreactive peripheral human B cells that accumulate in arthritic joints. Despite this association with autoimmunity the contribution of SLC expressing mature B cells to disease development is still unknown. We studied the pathogenicity of SLC(+) B cells in a panel of mice that transgenically express the SLC components VpreB and λ5 throughout B cell development. Here we report that although VpreB or λ5 expression mildly activated mature B cells, only moderate VpreB expression levels - in the absence of λ5 - enhanced IgG plasma cell formation. However, no autoantibody production was detectable in VpreB or λ5 transgenic mice and VpreB expression could not accelerate autoimmunity. Instead, moderate VpreB expression partially protected mice from induced autoimmune arthritis. In support of a tolerogenic role of SLC-transgenic B cells, we observed that in a dose-dependent manner SLC expression beyond the pre-B cell stage enhanced clonal deletion among immature and transitional B cells and rendered mature B cells anergic. These findings suggest that SLC expression does not propagate autoimmunity, but instead may impose tolerance.

  8. Dose-dependent effects of caffeine in human Sertoli cells metabolism and oxidative profile: relevance for male fertility.

    PubMed

    Dias, Tânia R; Alves, Marco G; Bernardino, Raquel L; Martins, Ana D; Moreira, Ana C; Silva, Joaquina; Barros, Alberto; Sousa, Mário; Silva, Branca M; Oliveira, Pedro F

    2015-02-01

    Caffeine is a widely consumed substance present in several beverages. There is an increasing consumption of energetic drinks, rich in caffeine, among young individuals in reproductive age. Caffeine has been described as a modulator of cellular metabolism. Hence, we hypothesized that it alters human Sertoli cells (hSCs) metabolism and oxidative profile, which are essential for spermatogenesis. For that purpose, hSCs were cultured with increasing doses of caffeine (5, 50, 500 μM). Caffeine at the lowest concentrations (5 and 50 μM) stimulated lactate production, but only hSCs exposed to 50 μM showed increased expression of glucose transporters (GLUTs). At the highest concentration (500 μM), caffeine stimulated LDH activity to sustain lactate production. Notably, the antioxidant capacity of hSCs decreased in a dose-dependent manner and SCs exposed to 500 μM caffeine presented a pro-oxidant potential, with a concurrent increase of protein oxidative damage. Hence, moderate consumption of caffeine appears to be safe to male reproductive health since it stimulates lactate production by SCs, which can promote germ cells survival. Nevertheless, caution should be taken by heavy consumers of energetic beverages and food supplemented with caffeine to avoid deleterious effects in hSCs functioning and thus, abnormal spermatogenesis.

  9. Blue-Violet Light Irradiation Dose Dependently Decreases Carotenoids in Human Skin, Which Indicates the Generation of Free Radicals

    PubMed Central

    Vandersee, Staffan; Beyer, Marc; Lademann, Juergen; Darvin, Maxim E.

    2015-01-01

    In contrast to ultraviolet and infrared irradiation, which are known to facilitate cutaneous photoaging, immunosuppression, or tumour emergence due to formation of free radicals and reactive oxygen species, potentially similar effects of visible light on the human skin are still poorly characterized. Using a blue-violet light irradiation source and aiming to characterize its potential influence on the antioxidant status of the human skin, the cutaneous carotenoid concentration was measured noninvasively in nine healthy volunteers using resonance Raman spectroscopy following irradiation. The dose-dependent significant degradation of carotenoids was measured to be 13.5% and 21.2% directly after irradiation at 50 J/cm² and 100 J/cm² (P < 0.05). The irradiation intensity was 100 mW/cm². This is above natural conditions; the achieved doses, though, are acquirable under natural conditions. The corresponding restoration lasted 2 and 24 hours, respectively. The degradation of cutaneous carotenoids indirectly shows the amount of generated free radicals and especially reactive oxygen species in human skin. In all volunteers the cutaneous carotenoid concentration dropped down in a manner similar to that caused by the infrared or ultraviolet irradiations, leading to the conclusion that also blue-violet light at high doses could represent a comparably adverse factor for human skin. PMID:25741404

  10. High-throughput Protease Activity Cytometry Reveals Dose-dependent Heterogeneity in PMA-mediated ADAM17 Activation†

    PubMed Central

    Wu, Lidan; Claas, Allison M.; Sarkar, Aniruddh; Lauffenburger, Douglas A.; Han, Jongyoon

    2015-01-01

    As key components of autocrine signaling, pericellular proteases, A Disintegrin and Metalloproteinases (ADAMs) in particular, are known to impact the microenvironment of individual cells and have significant implications in various pathological situations including cancer, inflammatory and vascular diseases.1-3 There is great incentive to develop a high-throughput platform for single-cell measurement of pericellular protease activity, as it is essential for studying the heterogeneity of protease response and the corresponding cell behavioral consequences. In this work, we developed a microfluidic platform to simultaneously monitor protease activity of many single cells in a time-dependent manner. This platform isolates individual microwells rapidly on demand and thus allows single-cell activity measurement of both cell-surface and secreted proteases by confining individual cells with diffusive FRET-based substrates. With this platform, we observed dose-dependent heterogeneous protease activation of HepG2 cells treated with phorbol 12-myristate 13-acetate (PMA). To study the temporal behavior of PMA-induced protease response, we monitored the pericellular protease activity of the same single cells during three different time periods and revealed the diversity in the dynamic patterns of single-cell protease activity profile upon PMA stimulation. The unique temporal information of single-cell protease response can help unveil the complicated functional role of pericellular proteases. PMID:25832727

  11. Host manipulation by the orange leafhopper Cicadulina bipunctata: gall induction on distant leaves by dose-dependent stimulation

    NASA Astrophysics Data System (ADS)

    Matsukura, Keiichiro; Matsumura, Masaya; Tokuda, Makoto

    2009-09-01

    The evolution of the gall-inducing ability in insects and the adaptive significance of the galling habit have been addressed by many studies. Cicadulina bipunctata, the maize orange leafhopper, is an ideal study organism for evaluating these topics because it can be mass-reared and it feeds on model plants such as rice ( Oryza sativa) and maize ( Zea mays). To reveal differences between gall inductions by C. bipunctata and other gall inducers, we conducted four experiments concerning (a) the relationship between the feeding site and gall-induction sites of C. bipunctata on maize, (b) the effects of leafhopper sex and density, (c) the effects of length of infestation on gall induction, and (d) the effects of continuous infestation. C. bipunctata did not induce galls on the leaves where it fed but induced galls on other leaves situated at more distal positions. The degree of gall induction was significantly correlated with infestation density and length. These results indicate that C. bipunctata induces galls in a dose-dependent manner on leaves distant from feeding sites, probably by injecting chemical(s) to the plant during feeding. We suggest that insect galls are induced by a chemical stimulus injected by gall inducers during feeding into the hosts.

  12. Dose dependent translocations of fluorescent probes of PIP2 hydrolysis in cells exposed to nanosecond pulsed electric fields

    NASA Astrophysics Data System (ADS)

    Tolstykh, Gleb P.; Tarango, Melissa; Roth, Caleb C.; Ibey, Bennett L.

    2014-03-01

    Previously, it was demonstrated that small nanometer-sized pores (nanopores) are preferentially formed after exposure to nanosecond pulsed electric fields (nsPEF). We have reported that nanoporation of the plasma membrane directly affects the phospholipids of the cell membrane, ultimately culminating in phosphatidylinositol4,5- bisphosphate (PIP2) intracellular signaling. PIP2, located within the internal layer of the plasma membrane, plays a critical role as a regulator of ion transport proteins, a source of second messenger compounds, and an anchor for cytoskeletal elements. In this proceeding, we present data that demonstrates that nsPEFs initiate electric field dose-dependent PIP2 hydrolysis and/or depletion from the plasma membrane through the observation of the accumulation of inositol1,4,5-trisphosphate (IP3) in the cytoplasm and the increase of diacylglycerol (DAG) on the inner surface of the plasma membrane. The phosphoinositide signaling cascade presented here involves activation of phospholipase C (PLC) and protein kinase C (PKC), which are responsible for a multitude of biological effects after nsPEF exposure. These results expand our current knowledge of nsPEF induced physiological effects, and serve as a basis for development of novel tools for drug independent stimulation or modulation of different cellular functions.

  13. Incident reporting.

    PubMed

    Wilson, J

    Healthcare delivery is a risky business. People view the NHS in the same light as other commercial businesses such as the hotel, retail and airline industries. The White Paper 'The New NHS: Modern, Dependable' (Secretary of State for Health, 1997) places statutory responsibilities on managers and clinicians to provide a quality service and to have accountability for clinical governance and performance management. Quality and risk are two sides of the same coin, i.e. if you have good quality you have low risk, and this firmly supports the clinical effectiveness agenda. Healthcare organizations in all sectors of care delivery need to demonstrate their high levels of achievement and commitment to continuous quality improvements. Risk management is a process for identifying, assessing and evaluating risks which have adverse effects on the quality, safety and effectiveness of service delivery, and taking positive action to eliminate or reduce them. Having an open, honest and blame-free organization which is open to improving processes and systems of care is a big step towards having staff who are committed to quality and getting things right. Near-miss, incident and indicator recording and reporting are cornerstones of any quality and risk management system.

  14. Ion dose dependence of the sputtering yield: Ar{sup +}, Ne{sup +}, and Xe{sup +} bombardment of Ru(0001) and Al(111)

    SciTech Connect

    Burnett, J.W.; Pellin, M.J.; Whitten, J.E.; Gruen, D.M.; Yates, J.T. Jr.

    1994-04-01

    The sputtering yield from clean metal surfaces has long been considered to be insensitive to primary ion dose at moderate ion fluences (< 10{sup 18} ions/cm{sup 2}). Using carefully cleaned and well-characterized targets, the ion dose dependence of the sputtering yield of Ru(0001) and Al(111) has been investigated. The sputtering yield of Ru(0001) is found to decrease substantially following primary ion bombardment at low fluences, while the sputtering yield of Al(111) exhibits no fluence dependence at low primary ion dose. Using secondary neutral mass spectrometry (SNMS), the sputtering yield of ruthenium was observed to decrease following ion bombardment by argon, xenon, and neon. High-detection-efficiency time-of-flight mass spectrometry was coupled with nonresonant laser ionization to allow real-time sputtering yield measurements and to minimize target damage during data collection. The experiments show that the sputtering yield of Ru(0001) decreases by 50%, following a primary ion fluence of, less than 10{sup 16} ions/cm{sup 2} for sputtering by either argon or neon ions and by 25%, following primary ion fluences of less than 10{sup 14} ions/cm{sup 2} for sputtering by xenon. The small size of the experimentally determined damage cross section suggests that microscopic changes in the surface structure cause the observed sputtering yield depression. In contrast to the ruthenium results, the sputtering yield of Al(111) appears to be insensitive to primary ion fluence at low fluences. Calculations using the TRansport of Ions in Matter (TRIM) Monte Carlo sputtering simulation were carried out to investigate the effect of primary ion implantation upon the sputtering yield of ruthenium as well as the effect of a reduced surface binding energy of ruthenium surface atoms. The TRIM results indicate that neither of these mechanisms can explain the experimentally observed fluence dependence of the sputtering yield of ruthenium.

  15. Dose-Dependent Effects of L-Arginine on PROP Bitterness Intensity and Latency and Characteristics of the Chemical Interaction between PROP and L-Arginine

    PubMed Central

    Melis, Melania; Arca, Massimiliano; Aragoni, Maria Carla; Cabras, Tiziana; Caltagirone, Claudia; Castagnola, Massimo; Crnjar, Roberto; Messana, Irene; Tepper, Beverly J.; Tomassini Barbarossa, Iole

    2015-01-01

    Genetic variation in the ability to taste the bitterness of 6-n-propylthiouracil (PROP) is a complex trait that has been used to predict food preferences and eating habits. PROP tasting is primarily controlled by polymorphisms in the TAS2R38 gene. However, a variety of factors are known to modify the phenotype. Principle among them is the salivary protein Ps-1 belonging to the basic proline-rich protein family (bPRP). Recently, we showed that oral supplementation with Ps-1 as well as its related free amino acids (L-Arg and L-Lys) enhances PROP bitterness perception, especially for PROP non-tasters who have low salivary levels of Ps-1. Here, we show that salivary L-Arg levels are higher in PROP super-tasters compared to medium tasters and non-tasters, and that oral supplementation with free L-Arg enhances PROP bitterness intensity as well as reduces bitterness latency in a dose-dependent manner, particularly in individuals with low salivary levels of both free L-Arg and Ps-1 protein. Supplementation with L-Arg also enhanced the bitterness of caffeine. We also used 1H-NMR spectroscopy and quantum-mechanical calculations carried out by Density Functional Theory (DFT) to characterize the chemical interaction between free L-Arg and the PROP molecule. Results showed that the –NH2 terminal group of the L-ArgH+ side chain interacts with the carbonyl or thiocarbonyl groups of PROP by forming two hydrogen bonds with the resulting charged adduct. The formation of this PROP•ArgH+ hydrogen-bonded adduct could enhance bitterness intensity by increasing the solubility of PROP in saliva and its availability to receptor sites. Our data suggest that L-Arg could act as a ‘carrier’ of various bitter molecules in saliva. PMID:26103639

  16. Low-dose glimepiride with sitagliptin improves glycemic control without dose-dependency in patients with type 2 diabetes inadequately controlled on high-dose glimepiride.

    PubMed

    Umayahara, Rieko; Yonemoto, Takako; Kyou, Chika; Morishita, Kae; Ogawa, Tatsuo; Taguchi, Yoshitaka; Inoue, Tatsuhide

    2014-01-01

    This randomized, prospective study was conducted in 76 subjects to assess whether low-dose (0.5-2 mg/day) glimepiride, in combination therapy with sitagliptin, improves glycemic control in a dose-dependent manner in Japanese patients with type 2 diabetes. Eligible subjects had been treated with glimepiride at doses of 3-6 mg/day for at least 3 months and had a HbA1c level of ≥6.9%. Subjects were randomly assigned to three treatment groups of reduced doses of glimepiride (0.5 mg/day, 1 mg/day, or 2 mg/day) in addition to sitagliptin for 24 weeks. The primary efficacy analysis evaluated the change in HbA1c from baseline to week 24. Secondary efficacy endpoints included the changes in fasting plasma glucose, insulin secretion capacity, and β-cell function. Safety endpoints included hypoglycemia and any adverse event. Despite dose reduction of glimepiride, combination therapy with sitagliptin induced significant improvements in HbA1c levels (-0.8%, p < 0.001). Insulin secretion parameters (CPI, SUIT) also increased significantly. There were no significant differences between groups in changes from baseline HbA1c, insulin secretion capacity, and β-cell function (proinsulin/insulin) at 24 weeks of combination therapy. Multivariate analysis showed that baseline HbA1c was the only predictor for efficacy of combination therapy with sitagliptin and low-dose glimeripide. No changes in body weight were noted and no symptomatic hypoglycemia was documented. These findings indicate that combination therapy with sitagliptin and low-dose glimepiride (0.5 mg/day) is both effective for glycemic control and safe in Japanese patients with type 2 diabetes inadequately controlled with high-dose glimepiride. PMID:25168659

  17. Sphingosine-1-Phosphate Induces Dose-Dependent Chemotaxis or Fugetaxis of T-ALL Blasts through S1P1 Activation

    PubMed Central

    Messias, Carolina V.; Santana-Van-Vliet, Eliane; Lemos, Julia P.; Moreira, Otacilio C.; Cotta-de-Almeida, Vinicius; Savino, Wilson; Mendes-da-Cruz, Daniella Arêas

    2016-01-01

    Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid involved in several physiological processes including cell migration and differentiation. S1P signaling is mediated through five G protein-coupled receptors (S1P1-S1P5). S1P1 is crucial to the exit of T-lymphocytes from the thymus and peripheral lymphoid organs through a gradient of S1P. We have previously observed that T-ALL and T-LBL blasts express S1P1. Herein we analyzed the role of S1P receptors in the migratory pattern of human T-cell neoplastic blasts. S1P-triggered cell migration was directly related to S1P1 expression. T-ALL blasts expressing low levels of S1P1 mRNA (HPB-ALL) did not migrate toward S1P, whereas those expressing higher levels of S1P1 (MOLT-4, JURKAT and CEM) did migrate. The S1P ligand induced T-ALL cells chemotaxis in concentrations up to 500 nM and induced fugetaxis in higher concentrations (1000–10000 nM) through interactions with S1P1. When S1P1 was specifically blocked by the W146 compound, S1P-induced migration at lower concentrations was reduced, whereas higher concentrations induced cell migration. Furthermore, we observed that S1P/S1P1 interactions induced ERK and AKT phosphorylation, and modulation of Rac1 activity. Responding T-ALL blasts also expressed S1P3 mRNA but blockage of this receptor did not modify migratory responses. Our results indicate that S1P is involved in the migration of T-ALL/LBL blasts, which is dependent on S1P1 expression. Moreover, S1P concentrations in the given microenvironment might induce dose-dependent chemotaxis or fugetaxis of T-ALL blasts. PMID:26824863

  18. Sphingosine-1-Phosphate Induces Dose-Dependent Chemotaxis or Fugetaxis of T-ALL Blasts through S1P1 Activation.

    PubMed

    Messias, Carolina V; Santana-Van-Vliet, Eliane; Lemos, Julia P; Moreira, Otacilio C; Cotta-de-Almeida, Vinicius; Savino, Wilson; Mendes-da-Cruz, Daniella Arêas

    2016-01-01

    Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid involved in several physiological processes including cell migration and differentiation. S1P signaling is mediated through five G protein-coupled receptors (S1P1-S1P5). S1P1 is crucial to the exit of T-lymphocytes from the thymus and peripheral lymphoid organs through a gradient of S1P. We have previously observed that T-ALL and T-LBL blasts express S1P1. Herein we analyzed the role of S1P receptors in the migratory pattern of human T-cell neoplastic blasts. S1P-triggered cell migration was directly related to S1P1 expression. T-ALL blasts expressing low levels of S1P1 mRNA (HPB-ALL) did not migrate toward S1P, whereas those expressing higher levels of S1P1 (MOLT-4, JURKAT and CEM) did migrate. The S1P ligand induced T-ALL cells chemotaxis in concentrations up to 500 nM and induced fugetaxis in higher concentrations (1000-10000 nM) through interactions with S1P1. When S1P1 was specifically blocked by the W146 compound, S1P-induced migration at lower concentrations was reduced, whereas higher concentrations induced cell migration. Furthermore, we observed that S1P/S1P1 interactions induced ERK and AKT phosphorylation, and modulation of Rac1 activity. Responding T-ALL blasts also expressed S1P3 mRNA but blockage of this receptor did not modify migratory responses. Our results indicate that S1P is involved in the migration of T-ALL/LBL blasts, which is dependent on S1P1 expression. Moreover, S1P concentrations in the given microenvironment might induce dose-dependent chemotaxis or fugetaxis of T-ALL blasts. PMID:26824863

  19. Dose-dependent conjugation of sulfobromophthalein and hepatic transit time in bile fistula rats: role of the microtubule-dependent vesicle pathway.

    PubMed

    Tazuma, S; Horikawa, K; Ochi, H; Nishioka, T; Sunami, Y; Yasumiba, S; Asamoto, Y; Tsuboi, K; Nakai, K; Sakomoto, M; Kanno, K; Yamaguchi, A; Numata, Y; Chayama, K

    2001-06-01

    Sulfobromophthalein (BSP) is selectively taken up by the liver and secreted into the bile as unconjugated and conjugated forms. Our previous study demonstrated that unconjugated BSP, but not conjugated BSP, caused the dissociation of biliary lipid secretion from that of bile acids, suggesting that the hepatic BSP conjugation rate partly regulated biliary lipid secretion. To evaluate the mechanisms through which biliary lipid secretion is regulated by exogenous organic anions, we intravenously administered BSP to male Sprague-Dawley rats at various doses either continuously or as a bolus. Then the relationship of the dose of BSP to its conjugation rate, hepatic transit time, and biliary lipid secretion was determined. BSP decreased biliary secretion of cholesterol and phospholipids in a dose-dependent manner without affecting bile acid secretion. In contrast, the proportion of conjugated BSP in bile was associated with the dose. Although the serum clearance of BSP after bolus infusion was constant regardless of the dose administered (50 or 200 nmol/100 g), BSP secretion was delayed with increasing doses: unconjugated BSP was secreted predominantly in the early phase (0-15 min after bolus injection), and conjugated BSP was the predominant form in the late phase (15-30 min). Pretreatment with colchicine reduced the conjugation rate and hepatic transit time of BSP, suggesting that the microtubule-dependent vesicle pathway plays a role in biliary excretion and conjugation of BSP. We conclude that biliary lipid secretion is influenced by organic anions with an affinity for bile acids such as BSP and that this effect is dependent upon the hepatic metabolic rate, i.e., conjugation rate. The hepatic transit time also plays a key role in this process by influencing metabolism.

  20. Dose-Dependent Effects of L-Arginine on PROP Bitterness Intensity and Latency and Characteristics of the Chemical Interaction between PROP and L-Arginine.

    PubMed

    Melis, Melania; Arca, Massimiliano; Aragoni, Maria Carla; Cabras, Tiziana; Caltagirone, Claudia; Castagnola, Massimo; Crnjar, Roberto; Messana, Irene; Tepper, Beverly J; Tomassini Barbarossa, Iole

    2015-01-01

    Genetic variation in the ability to taste the bitterness of 6-n-propylthiouracil (PROP) is a complex trait that has been used to predict food preferences and eating habits. PROP tasting is primarily controlled by polymorphisms in the TAS2R38 gene. However, a variety of factors are known to modify the phenotype. Principle among them is the salivary protein Ps-1 belonging to the basic proline-rich protein family (bPRP). Recently, we showed that oral supplementation with Ps-1 as well as its related free amino acids (L-Arg and L-Lys) enhances PROP bitterness perception, especially for PROP non-tasters who have low salivary levels of Ps-1. Here, we show that salivary L-Arg levels are higher in PROP super-tasters compared to medium tasters and non-tasters, and that oral supplementation with free L-Arg enhances PROP bitterness intensity as well as reduces bitterness latency in a dose-dependent manner, particularly in individuals with low salivary levels of both free L-Arg and Ps-1 protein. Supplementation with L-Arg also enhanced the bitterness of caffeine. We also used 1H-NMR spectroscopy and quantum-mechanical calculations carried out by Density Functional Theory (DFT) to characterize the chemical interaction between free L-Arg and the PROP molecule. Results showed that the -NH2 terminal group of the L-ArgH+ side chain interacts with the carbonyl or thiocarbonyl groups of PROP by forming two hydrogen bonds with the resulting charged adduct. The formation of this PROP•ArgH+ hydrogen-bonded adduct could enhance bitterness intensity by increasing the solubility of PROP in saliva and its availability to receptor sites. Our data suggest that L-Arg could act as a 'carrier' of various bitter molecules in saliva. PMID:26103639

  1. Dose-dependent hepatic transcriptional responses in Atlantic salmon (Salmo salar) exposed to sublethal doses of gamma radiation.

    PubMed

    Song, You; Salbu, Brit; Teien, Hans-Christian; Heier, Lene Sørlie; Rosseland, Bjørn Olav; Tollefsen, Knut Erik

    2014-11-01

    Due to the production of free radicals, gamma radiation may pose a hazard to living organisms. The high-dose radiation effects have been extensively studied, whereas the ecotoxicity data on low-dose gamma radiation is still limited. The present study was therefore performed using Atlantic salmon (Salmo salar) to characterize effects of low-dose (15, 70 and 280 mGy) gamma radiation after short-term (48h) exposure. Global transcriptional changes were studied using a combination of high-density oligonucleotide microarrays and quantitative real-time reverse transcription polymerase chain reaction (qPCR). Differentially expressed genes (DEGs; in this article the phrase gene expression is taken as a synonym of gene transcription, although it is acknowledged that gene expression can also be regulated, e.g., at protein stability and translational level) were determined and linked to their biological meanings predicted using both Gene Ontology (GO) and mammalian ortholog-based functional analyses. The plasma glucose level was also measured as a general stress biomarker at the organism level. Results from the microarray analysis revealed a dose-dependent pattern of global transcriptional responses, with 222, 495 and 909 DEGs regulated by 15, 70 and 280 mGy gamma radiation, respectively. Among these DEGs, only 34 were commonly regulated by all radiation doses, whereas the majority of differences were dose-specific. No GO functions were identified at low or medium doses, but repression of DEGs associated with GO functions such as DNA replication, cell cycle regulation and response to reactive oxygen species (ROS) were observed after 280mGy gamma exposure. Ortholog-based toxicity pathway analysis further showed that 15mGy radiation affected DEGs associated with cellular signaling and immune response; 70mGy radiation affected cell cycle regulation and DNA damage repair, cellular energy production; and 280mGy radiation affected pathways related to cell cycle regulation and DNA

  2. Proposed Mechanistic Description of Dose-Dependent BDE-47 Urinary Elimination in Mice Using a Physiologically Based Pharmacokinetic Model

    PubMed Central

    Emond, Claude; Sanders, J. Michael; Wikoff, Daniele; Birnbaum, Linda S.

    2014-01-01

    Polybrominated diphenyl ethers (PBDEs) have been used in a wide variety of consumer applications as additive flame retardants. In North America, scientists have noted continuing increases in the levels of PBDE congeners measured in human serum. Some recent studies have found that PBDEs are associated with adverse health effects in humans, in experimental animals, and wildlife. This laboratory previously demonstrated that urinary elimination of 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) is saturable at high doses in mice; however, this dose-dependent urinary elimination has not been observed in adult rats or immature mice. Thus, the primary objective of this study was to examine the mechanism of urinary elimination of BDE-47 in adult mice using a physiologically based pharmacokinetic (PBPK) model. To support this objective, additional laboratory data were collected to evaluate the predictions of the PBPK model using novel information from adult multi-drug resistance 1a/b knockout mice. Using the PBPK model, the roles of mouse major urinary protein (a blood protein carrier) and P-glycoprotein (an apical membrane transporter in proximal tubule cells in the kidneys, brain, intestines, and liver) were investigated in BDE-47 elimination. The resulting model and new data supported the major role of m-MUP in excretion of BDE-47 in the urine of adult mice, and a lesser role of P-gp as a transporter of BDE-47 in mice. This work expands the knowledge of BDE-47 kinetics between species and provides information for determining the relevancy of these data for human risk assessment purposes. PMID:24055880

  3. Dose-dependent consumption of farmed Atlantic salmon (Salmo salar) increases plasma phospholipid n-3 fatty acids differentially

    PubMed Central

    Raatz, Susan K.; Rosenberger, Thad A.; Johnson, LuAnn K.; Wolters, William W.; Burr, Gary S; Picklo, Matthew J.

    2013-01-01

    Enhanced omega-3 fatty acid (n-3) intake benefits cardiovascular disease (CVD) risk reduction. Increasing consumption at a population level may be better addressed by diet than through supplementation. However, limited data are available on the effect of the dose response to fish intake on plasma levels of n-3 fatty acids. To compare the effects of different doses of farmed Atlantic salmon on plasma phospholipid fatty acid (PLFA) proportions and CVD risk biomarkers (glucose, insulin, HOMAIR, hsCRP, and IL-6) in healthy subjects we performed a randomized 3-period cross-over designed trial (4 wk treatment, 4-8 wk washout) to compare the effects of twice/wk consumption of farmed Atlantic salmon at doses of 90, 180, and 270 g in 19 apparently healthy men and women with a mean age of aged 40-65 years and a BMI between 25-34.9 kg/m2. All study visits were conducted at the USDA, ARS Grand Forks Human Nutrition Research Center. EPA and total n-3 were increased (p<0.05) by all treatments in a dose response manner, with total n-3 of 8.03 ± 0.26 and 9.21 ± 0.26 % for 180 and 270 g doses, respectively. Linoleic acid did not change in response to treatment while arachidonic acid (P<0.05) and total omega-6 fatty acids (n-6) decreased dose dependently (<0.0001). The addition of farmed Atlantic salmon to the diet twice/wk for 4 wk at portions of 180g and 270g modifies PLFA proportions of n-3 and n-6 in a level associated with decreased risk for CVD. PMID:23351633

  4. Dose-dependent effects of the clinical anesthetic isoflurane on Octopus vulgaris: a contribution to cephalopod welfare.

    PubMed

    Polese, Gianluca; Winlow, William; Di Cosmo, Anna

    2014-12-01

    Recent progress in animal welfare legislation relating to invertebrates has provoked interest in methods for the anesthesia of cephalopods, for which different approaches to anesthesia have been tried but in most cases without truly anesthetizing the animals. For example, several workers have used muscle relaxants or hypothermia as forms of "anesthesia." Several inhalational anesthetics are known to act in a dose-dependent manner on the great pond snail Lymnaea stagnalis, a pulmonate mollusk. Here we report, for the first time, on the effects of clinical doses of the well-known inhalational clinical anesthetic isoflurane on the behavioral responses of the common octopus Octopus vulgaris. In each experiment, isoflurane was equilibrated into a well-aerated seawater bath containing a single adult O. vulgaris. Using a web camera, we recorded each animal's response to touch stimuli eliciting withdrawal of the arms and siphon and observed changes in the respiratory rate and the chromatophore pattern over time (before, during, and after application of the anesthetic). We found that different animals of the same size responded with similar behavioral changes as the isoflurane concentration was gradually increased. After gradual application of 2% isoflurane for a maximum of 5 min (at which time all the responses indicated deep anesthesia), the animals recovered within 45-60 min in fresh aerated seawater. Based on previous findings in gastropods, we believe that the process of anesthesia induced by isoflurane is similar to that previously observed in Lymnaea. In this study we showed that isoflurane is a good, reversible anesthetic for O. vulgaris, and we developed a method for its use. PMID:25369208

  5. Dose-Dependent Mutation Rates Determine Optimum Erlotinib Dosing Strategies for EGFR Mutant Non-Small Cell Lung Cancer Patients

    PubMed Central

    Liu, Lin L.; Li, Fei; Pao, William; Michor, Franziska

    2015-01-01

    Background The advent of targeted therapy for cancer treatment has brought about a paradigm shift in the clinical management of human malignancies. Agents such as erlotinib used for EGFR-mutant non-small cell lung cancer or imatinib for chronic myeloid leukemia, for instance, lead to rapid tumor responses. Unfortunately, however, resistance often emerges and renders these agents ineffective after a variable amount of time. The FDA-approved dosing schedules for these drugs were not designed to optimally prevent the emergence of resistance. To this end, we have previously utilized evolutionary mathematical modeling of treatment responses to elucidate the dosing schedules best able to prevent or delay the onset of resistance. Here we expand on our approaches by taking into account dose-dependent mutation rates at which resistant cells emerge. The relationship between the serum drug concentration and the rate at which resistance mutations arise can lead to non-intuitive results about the best dose administration strategies to prevent or delay the emergence of resistance. Methods We used mathematical modeling, available clinical trial data, and different considerations of the relationship between mutation rate and drug concentration to predict the effectiveness of different dosing strategies. Results We designed several distinct measures to interrogate the effects of different treatment dosing strategies and found that a low-dose continuous strategy coupled with high-dose pulses leads to the maximal delay until clinically observable resistance. Furthermore, the response to treatment is robust against different assumptions of the mutation rate as a function of drug concentration. Conclusions For new and existing targeted drugs, our methodology can be employed to compare the effectiveness of different dose administration schedules and investigate the influence of changing mutation rates on outcomes. PMID:26536620

  6. Macrophage Bactericidal Activities against Staphylococcus aureus Are Enhanced In Vivo by Selenium Supplementation in a Dose-Dependent Manner

    PubMed Central

    Aribi, Mourad; Meziane, Warda; Habi, Salim; Boulatika, Yasser

    2015-01-01

    Background Dietary selenium is of fundamental importance to maintain optimal immune function and enhance immunity during infection. To this end, we examined the effect of selenium on macrophage bactericidal activities against Staphylococcus aureus. Methods Assays were performed in golden Syrian hamsters and peritoneal macrophages cultured with S. aureus and different concentrations of selenium. Results Infected and selenium-supplemented animals have significantly decreased levels of serum nitric oxide (NO) production when compared with infected but non-selenium-supplemented animals at day 7 post-infection (p < 0.05). A low dose of 5 ng/mL selenium induced a significant decrease in macrophage NO production, but significant increase in hydrogen peroxide (H2O2) levels (respectively, p = 0.009, p < 0.001). The NO production and H2O2 levels were significantly increased with increasing concentrations of selenium; the optimal macrophage activity levels were reached at 20 ng/mL. The concentration of 5 ng/mL of selenium induced a significant decrease in the bacterial arginase activity but a significant increase in the macrophage arginase activity. The dose of 20 ng/mL selenium induced a significant decrease of bacterial growth (p < 0.0001) and a significant increase in macrophage phagocytic activity, NO production/arginase balance and S. aureus killing (for all comparisons, p < 0.001). Conclusions Selenium acts in a dose-dependent manner on macrophage activation, phagocytosis and bacterial killing suggesting that inadequate doses may cause a loss of macrophage bactericidal activities and that selenium supplementation could enhance the in vivo control of immune response to S. aureus. PMID:26340099

  7. Dose-dependent compensation responses of the hypothalamic-pituitary-gonadal-liver axis of zebrafish exposed to the fungicide prochloraz.

    PubMed

    Dang, Yao; Giesy, John P; Wang, Jianghua; Liu, Chunsheng

    2015-03-01

    Compensation responses and adaptability of hypothalamic-pituitary-gonadal (HPG) axis have been reported in fish exposed to model chemicals, however due to its importance in predictive toxicology further study was needed to elucidate details of the integrated responses to model chemicals. Transcriptional profiles of the hypothalamic-pituitary-gonadal (HPG) axis and concentrations of 17β-estradiol (E2) in plasma were measured in male and female zebrafish that had been exposed to one of seven concentrations of the fungicide, prochloraz: low (1, 3 or 10μg/L), medium (30 or 100μg/L) or high concentrations (300 or 1000μg/L) for 4 days. In zebrafish exposed to the low and medium concentrations of prochloraz, compensation responses of the HPG axis through transcription, occurred in brain (up-regulation of gnrh, gnrhr and lhβ) and both brain and gonad (up-regulation of steroidogenic genes), respectively. Concentrations of E2 in plasma and expression of estrogen receptor 1 (er1) and vitellogenins (vtgs) in liver did not change. This result suggested that compensatory responses were successful in maintaining homeostasis. In zebrafish exposed to the two greatest concentrations, compensatory responses occurred in brain, gonad and liver through up-regulation of er2β, but it failed to maintain concentration of E2 in blood plasma and expression of er1 and vtgs in liver. Collectedly, the results observed in this study allowed characterization of dose-dependent compensatory responses along the HPG axis and liver and identified key linkages between compensatory responses occurring in brain, gonad and liver after exposure to prochloraz.

  8. Proposed mechanistic description of dose-dependent BDE-47 urinary elimination in mice using a physiologically based pharmacokinetic model

    SciTech Connect

    Emond, Claude; Sanders, J. Michael; Wikoff, Daniele; Birnbaum, Linda S.

    2013-12-01

    Polybrominated diphenyl ethers (PBDEs) have been used in a wide variety of consumer applications as additive flame retardants. In North America, scientists have noted continuing increases in the levels of PBDE congeners measured in human serum. Some recent studies have found that PBDEs are associated with adverse health effects in humans, in experimental animals, and wildlife. This laboratory previously demonstrated that urinary elimination of 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) is saturable at high doses in mice; however, this dose-dependent urinary elimination has not been observed in adult rats or immature mice. Thus, the primary objective of this study was to examine the mechanism of urinary elimination of BDE-47 in adult mice using a physiologically based pharmacokinetic (PBPK) model. To support this objective, additional laboratory data were collected to evaluate the predictions of the PBPK model using novel information from adult multi-drug resistance 1a/b knockout mice. Using the PBPK model, the roles of mouse major urinary protein (a blood protein carrier) and P-glycoprotein (an apical membrane transporter in proximal tubule cells in the kidneys, brain, intestines, and liver) were investigated in BDE-47 elimination. The resulting model and new data supported the major role of m-MUP in excretion of BDE-47 in the urine of adult mice, and a lesser role of P-gp as a transporter of BDE-47 in mice. This work expands the knowledge of BDE-47 kinetics between species and provides information for determining the relevancy of these data for human risk assessment purposes. - Highlights: • We report the first study on PBPK model on flame retardant in mice for BDE-47. • We examine mechanism of urinary elimination of BDE-47 in mice using a PBPK model. • We investigated roles of m-MUP and P-gp as transporters in urinary elimination.

  9. Dose-dependent regulation of the early promoter of human papillomavirus type 18 by the viral E2 protein.

    PubMed

    Steger, G; Corbach, S

    1997-01-01

    The activity of the E6/E7 promoter of genital human papillomaviruses (HPVs) is positively and negatively modulated by a complex interplay between a variety of cellular transcription factors and the virally encoded E2 protein. The long control region of genital HPVs contains four E2 binding sites in conserved positions, two of which are very close to the TATA box. Binding of E2 to these two sites has been shown to repress the promoter. To carefully analyze the effect of E2 on the activity of the early promoter P105 of HPV18, we used an in vitro transcription system, which allowed titration of the amount of E2 protein. We found that low amounts of HPV18 E2 stimulated the promoter, whereas increasing amounts resulted in promoter repression. When the affinity was analyzed, it became obvious that E2 bound with highest affinity to E2 binding site 4 (BS-4), located 500 bp upstream of the promoter. The promoter most proximal binding site (BS-1) was the weakest site. Transient transfection assays confirmed that small amounts of HPV type (HPV18) E2 and also of bovine papillomavirus type 1 (BPV1) E2 were able to activate the P105, which was dependent on an intact BS-4. The positive role of BS-4 was also obvious at higher E2 concentrations, since mutation of BS-4 enhanced repression. In contrast to HPV18 E2, BPV1 E2 bound better to BS-1 and, in correlation, was able to more strongly repress the P105 in vivo. Our results suggest a dose-dependent regulation of the HPV18 E6/E7 promoter by E2 due to variable occupancy of its binding sites, which have antagonizing effects on the activity of the E6/E7 promoter.

  10. Dose-dependent effects of the clinical anesthetic isoflurane on Octopus vulgaris: a contribution to cephalopod welfare.

    PubMed

    Polese, Gianluca; Winlow, William; Di Cosmo, Anna

    2014-12-01

    Recent progress in animal welfare legislation relating to invertebrates has provoked interest in methods for the anesthesia of cephalopods, for which different approaches to anesthesia have been tried but in most cases without truly anesthetizing the animals. For example, several workers have used muscle relaxants or hypothermia as forms of "anesthesia." Several inhalational anesthetics are known to act in a dose-dependent manner on the great pond snail Lymnaea stagnalis, a pulmonate mollusk. Here we report, for the first time, on the effects of clinical doses of the well-known inhalational clinical anesthetic isoflurane on the behavioral responses of the common octopus Octopus vulgaris. In each experiment, isoflurane was equilibrated into a well-aerated seawater bath containing a single adult O. vulgaris. Using a web camera, we recorded each animal's response to touch stimuli eliciting withdrawal of the arms and siphon and observed changes in the respiratory rate and the chromatophore pattern over time (before, during, and after application of the anesthetic). We found that different animals of the same size responded with similar behavioral changes as the isoflurane concentration was gradually increased. After gradual application of 2% isoflurane for a maximum of 5 min (at which time all the responses indicated deep anesthesia), the animals recovered within 45-60 min in fresh aerated seawater. Based on previous findings in gastropods, we believe that the process of anesthesia induced by isoflurane is similar to that previously observed in Lymnaea. In this study we showed that isoflurane is a good, reversible anesthetic for O. vulgaris, and we developed a method for its use.

  11. Proposed mechanistic description of dose-dependent BDE-47 urinary elimination in mice using a physiologically based pharmacokinetic model.

    PubMed

    Emond, Claude; Sanders, J Michael; Wikoff, Daniele; Birnbaum, Linda S

    2013-12-01

    Polybrominated diphenyl ethers (PBDEs) have been used in a wide variety of consumer applications as additive flame retardants. In North America, scientists have noted continuing increases in the levels of PBDE congeners measured in human serum. Some recent studies have found that PBDEs are associated with adverse health effects in humans, in experimental animals, and wildlife. This laboratory previously demonstrated that urinary elimination of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) is saturable at high doses in mice; however, this dose-dependent urinary elimination has not been observed in adult rats or immature mice. Thus, the primary objective of this study was to examine the mechanism of urinary elimination of BDE-47 in adult mice using a physiologically based pharmacokinetic (PBPK) model. To support this objective, additional laboratory data were collected to evaluate the predictions of the PBPK model using novel information from adult multi-drug resistance 1a/b knockout mice. Using the PBPK model, the roles of mouse major urinary protein (a blood protein carrier) and P-glycoprotein (an apical membrane transporter in proximal tubule cells in the kidneys, brain, intestines, and liver) were investigated in BDE-47 elimination. The resulting model and new data supported the major role of m-MUP in excretion of BDE-47 in the urine of adult mice, and a lesser role of P-gp as a transporter of BDE-47 in mice. This work expands the knowledge of BDE-47 kinetics between species and provides information for determining the relevancy of these data for human risk assessment purposes. PMID:24055880

  12. Dose-dependent food allergy induction against ovalbumin under acid-suppression: A murine food allergy model

    PubMed Central

    Diesner, S.C.; Knittelfelder, R.; Krishnamurthy, D.; Pali-Schöll, I.; Gajdzik, L.; Jensen-Jarolim, E.; Untersmayr, E.

    2010-01-01

    Background Animal models are essential for analyzing the allergenic potential of food proteins and for investigating mechanisms underlying food allergy. Based on previous studies revealing acid-suppression medication as risk factor for food allergy induction, we aimed to establish a mouse model mimicking the natural route of sensitization in patients. Methods The effect of acid-suppressing medication on murine gastric pH was assessed by intragastric pH measurements after two injections of a proton pump inhibitor (PPI). To investigate dose-dependency, mice were fed different concentrations of ovalbumin (OVA; 0.2, 0.5, 1.0, 2.5 or 5.0 mg) either with or without anti-ulcer medication. Additionally, different routes of exposure (i.p. vs. oral) were compared in a second immunization experiment. Sera were screened for OVA-specific antibody titers (IgG1, IgG2a and IgE) in ELISA and RBL assay. Clinical reactivity was evaluated by measuring rectal temperature after oral challenge and by type I skin tests. Results Two intravenous injections of PPI significantly elevated the gastric pH from 2.97 to 5.3. Only oral immunization with 0.2 mg OVA under anti-acid medication rendered elevated IgG1, IgG2a and IgE titers compared to all other concentrations. Protein feeding alone altered antibody titers only marginally. Even though also i.p. immunizations induced high levels of specific IgE, only oral immunizations under anti-acids induced anaphylactic reactions evidenced by a significant decrease of body temperature. Conclusion Only low-dosage ovalbumin feedings under anti-acid medication resulted in IgE mediated food allergy. Based on this knowledge we have established a suitable food allergy model for further investigations of food adverse reactions. PMID:18824031

  13. Dose-dependent compensation responses of the hypothalamic-pituitary-gonadal-liver axis of zebrafish exposed to the fungicide prochloraz.

    PubMed

    Dang, Yao; Giesy, John P; Wang, Jianghua; Liu, Chunsheng

    2015-03-01

    Compensation responses and adaptability of hypothalamic-pituitary-gonadal (HPG) axis have been reported in fish exposed to model chemicals, however due to its importance in predictive toxicology further study was needed to elucidate details of the integrated responses to model chemicals. Transcriptional profiles of the hypothalamic-pituitary-gonadal (HPG) axis and concentrations of 17β-estradiol (E2) in plasma were measured in male and female zebrafish that had been exposed to one of seven concentrations of the fungicide, prochloraz: low (1, 3 or 10μg/L), medium (30 or 100μg/L) or high concentrations (300 or 1000μg/L) for 4 days. In zebrafish exposed to the low and medium concentrations of prochloraz, compensation responses of the HPG axis through transcription, occurred in brain (up-regulation of gnrh, gnrhr and lhβ) and both brain and gonad (up-regulation of steroidogenic genes), respectively. Concentrations of E2 in plasma and expression of estrogen receptor 1 (er1) and vitellogenins (vtgs) in liver did not change. This result suggested that compensatory responses were successful in maintaining homeostasis. In zebrafish exposed to the two greatest concentrations, compensatory responses occurred in brain, gonad and liver through up-regulation of er2β, but it failed to maintain concentration of E2 in blood plasma and expression of er1 and vtgs in liver. Collectedly, the results observed in this study allowed characterization of dose-dependent compensatory responses along the HPG axis and liver and identified key linkages between compensatory responses occurring in brain, gonad and liver after exposure to prochloraz. PMID:25625521

  14. Dose-Dependent Effects of Theta Burst rTMS on Cortical Excitability and Resting-State Connectivity of the Human Motor System

    PubMed Central

    Nettekoven, Charlotte; Volz, Lukas J.; Kutscha, Martha; Pool, Eva-Maria; Rehme, Anne K.; Eickhoff, Simon B.; Fink, Gereon R.

    2014-01-01

    Theta burst stimulation (TBS), a specific protocol of repetitive transcranial magnetic stimulation (rTMS), induces changes in cortical excitability that last beyond stimulation. TBS-induced aftereffects, however, vary between subjects, and the mechanisms underlying these aftereffects to date remain poorly understood. Therefore, the purpose of this study was to investigate whether increasing the number of pulses of intermittent TBS (iTBS) (1) increases cortical excitability as measured by motor-evoked potentials (MEPs) and (2) alters functional connectivity measured using resting-state fMRI, in a dose-dependent manner. Sixteen healthy, human subjects received three serially applied iTBS blocks of 600 pulses over the primary motor cortex (M1 stimulation) and the parieto-occipital vertex (sham stimulation) to test for dose-dependent iTBS effects on cortical excitability and functional connectivity (four sessions in total). iTBS over M1 increased MEP amplitudes compared with sham stimulation after each stimulation block. Although the increase in MEP amplitudes did not differ between the first and second block of M1 stimulation, we observed a significant increase after three blocks (1800 pulses). Furthermore, iTBS enhanced resting-state functional connectivity between the stimulated M1 and premotor regions in both hemispheres. Functional connectivity between M1 and ipsilateral dorsal premotor cortex further increased dose-dependently after 1800 pulses of iTBS over M1. However, no correlation between changes in MEP amplitudes and functional connectivity was detected. In summary, our data show that increasing the number of iTBS stimulation blocks results in dose-dependent effects at the local level (cortical excitability) as well as at a systems level (functional connectivity) with a dose-dependent enhancement of dorsal premotor cortex-M1 connectivity. PMID:24828639

  15. Dose-dependent effect of N'-Nitrosodiethylamine on hepatic architecture, RBC rheology and polypeptide repertoire in Wistar rats

    PubMed Central

    Mukherjee, Devoshree

    2015-01-01

    N'-Nitrosodiethylamine (NDEA) is an effective hepatotoxicant, carcinogen and mutagen. NDEA-induced hepatic necrosis, through metabolic activation by CYP2E1, is an extensively used experimental model. In the present study, we analysed the dose- and time-dependent effect of NDEA on hepatic damage, RBC rheology and proteomic profile in male Wistar rats. The rats, 5–6 weeks old, were divided into four groups: Group-1 served as control and received normal saline, Group-2 received a single dose of 200 mg/kg body weight NDEA intraperitoneally (i.p.) and the animals were sacrificed after one week; the rats of Group-3 received a single dose of 100 mg/kg body weight NDEA and were sacrificed after one week; Group-4 received 100 mg/kg body weight/wk NDEA for two weeks and were then sacrificed. Various biochemical parameters such as ALT, AST, ALP and bilirubin were determined. Further, RBC rheology, histopathology (H&E staining) of liver biopsies and polypeptide profiling (SDS-PAGE) in sera and liver sections were also carried out both in control and NDEA treated groups. Our results showed a significant increase in all the biochemical parameters of the liver function test (p<0.05). In NDEA treated categories dacryocytes (tear drop cells), schistocytes (fragmented cells), codocytes (target cells), acanthocytes (spur cells) and ovalocytes (oval cells) were observed. H & E stained liver biopsies treated with NDEA showed abnormal liver architecture with severe haemorrhage, neutrophilic infiltration and dysplastic hepatocytes manifested in a dose-dependent manner. Software analysis of SDS-PAGE of control and NDEA treated rat sera and liver revealed qualitative and quantitative differences in polypeptide composition. Based on the presence/absence, polypeptides were classified in three different categories: (1) house-keeping, present in all the groups investigated; (2) novel, present in either control or NDEA treated group at any given time; (3) differential expression, showing

  16. Dose-dependent effects of dietary zinc oxide on bacterial communities and metabolic profiles in the ileum of weaned pigs.

    PubMed

    Pieper, R; Vahjen, W; Neumann, K; Van Kessel, A G; Zentek, J

    2012-10-01

    Pharmacological levels of zinc oxide (ZnO) can improve the health of weaning piglets and influence the intestinal microbiota. This experiment aimed at studying the dose-response effect of five dietary concentrations of ZnO on small intestinal bacteria and metabolite profiles. Fifteen piglets, weaned at 25 ± 1 days of age, were allocated into five groups according to body weight and litter. Diets were formulated to contain 50 (basal diet), 150, 250, 1000 and 2500 mg zinc/kg by adding analytical-grade (>98% purity) ZnO to the basal diet and fed ad libitum for 14 days after a 7-day adaptation period on the basal diet. Ileal bacterial community profiles were analysed by denaturing gradient gel electrophoresis and selected bacterial groups quantified by real-time PCR. Concentrations of ileal volatile fatty acids (VFA), D- and L-lactate and ammonia were determined. Species richness, Shannon diversity and evenness were significantly higher at high ZnO levels. Quantitative PCR revealed lowest total bacterial counts in the 50 mg/kg group. Increasing ZnO levels led to an increase (p = 0.017) in enterobacteria from log 4.0 cfu/g digesta (50 mg/kg) to log 6.7 cfu/g digesta (2500 mg/kg). Lactic acid bacteria were not influenced (p = 0.687) and clostridial cluster XIVa declined (p = 0.035) at highest ZnO level. Concentration of total, D- and L-lactate and propionate was not affected (p = 0.736, p = 0.290 and p = 0.630), but concentrations of ileal total VFA, acetate and butyrate increased markedly from 50 to 150 mg/kg and decreased with further increasing zinc levels and reached low levels again at 2500 mg/kg (p = 0.048, p = 0.048 and p = 0.097). Ammonia decreased (p < 0.006) with increasing dietary ZnO level. In conclusion, increasing levels of dietary ZnO had strong and dose-dependent effects on ileal bacterial community composition and activity, suggesting taxonomic variation in metabolic response to ZnO. PMID:21929727

  17. Prolonged Subdural Infusion of Kynurenic Acid Is Associated with Dose-Dependent Myelin Damage in the Rat Spinal Cord

    PubMed Central

    Dabrowski, Wojciech; Kwiecien, Jacek M.; Rola, Radoslaw; Klapec, Michal; Stanisz, Greg J.; Kotlinska-Hasiec, Edyta; Oakden, Wendy; Janik, Rafal; Coote, Margaret; Frey, Benicio N.; Turski, Waldemar A.

    2015-01-01

    Background Kynurenic acid (KYNA) is the end stage metabolite of tryptophan produced mainly by astrocytes in the central nervous system (CNS). It has neuroprotective activities but can be elevated in the neuropsychiatric disorders. Toxic effects of KYNA in the CNS are unknown. The aim of this study was to assess the effect of the subdural KYNA infusion on the spinal cord in adult rats. Methods A total of 42 healthy adult rats were randomly assigned into six groups and were infused for 7 days with PBS (control) or 0.0002 pmol/min, 0.01 nmol/min, 0.1 nmol/min, 1 nmol/min, and 10 nmol/min of KYNA per 7 days. The effect of KYNA on spinal cord was determined using histological and electron microscopy examination. Myelin oligodendrocyte glycoprotein (MOG) was measured in the blood serum to assess a degree of myelin damage. Result In all rats continuous long-lasting subdural KYNA infusion was associated with myelin damage and myelin loss that was increasingly widespread in a dose-depended fashion in peripheral, sub-pial areas. Damage to myelin sheaths was uniquely related to the separation of lamellae at the intraperiod line. The damaged myelin sheaths and areas with complete loss of myelin were associated with limited loss of scattered axons while vast majority of axons in affected areas were morphologically intact. The myelin loss-causing effect of KYNA occurred with no necrosis of oligodendrocytes, with locally severe astrogliosis and no cellular inflammatory response. Additionally, subdural KYNA infusion increased blood MOG concentration. Moreover, the rats infused with the highest doses of KYNA (1 and 10 nmol/min) demonstrated adverse neurological signs including weakness and quadriplegia. Conclusions We suggest, that subdural infusion of high dose of KYNA can be used as an experimental tool for the study of mechanisms of myelin damage and regeneration. On the other hand, the administration of low, physiologically relevant doses of KYNA may help to discover the role

  18. Safety and Effectiveness of two treatment regimes with tranexamic acid to minimize inflammatory response in elective cardiopulmonary bypass patients: a randomized double-blind, dose-dependent, phase IV clinical trial

    PubMed Central

    2011-01-01

    Background In cardiopulmonary bypass (CPB) patients, fibrinolysis may enhance postoperative inflammatory response. We aimed to determine whether an additional postoperative dose of antifibrinolytic tranexamic acid (TA) reduced CPB-mediated inflammatory response (IR). Methods We performed a randomized, double-blind, dose-dependent, parallel-groups study of elective CPB patients receiving TA. Patients were randomly assigned to either the single-dose group (40 mg/Kg TA before CPB and placebo after CPB) or the double-dose group (40 mg/Kg TA before and after CPB). Results 160 patients were included, 80 in each group. The incident rate of IR was significantly lower in the double-dose-group TA2 (7.5% vs. 18.8% in the single-dose group TA1; P = 0.030). After adjusting for hypertension, total protamine dose and temperature after CPB, TA2 showed a lower risk of IR compared with TA1 [OR: 0.29 (95% CI: 0.10-0.83), (P = 0.013)]. Relative risk for IR was 2.5 for TA1 (95% CI: 1.02 to 6.12). The double-dose group had significantly lower chest tube bleeding at 24 hours [671 (95% CI 549-793 vs. 826 (95% CI 704-949) mL; P = 0.01 corrected-P significant] and lower D-dimer levels at 24 hours [489 (95% CI 437-540) vs. 621(95% CI: 563-679) ng/mL; P = 0.01 corrected-P significant]. TA2 required lower levels of norepinephrine at 24 h [0.06 (95% CI: 0.03-0.09) vs. 0.20(95 CI: 0.05-0.35) after adjusting for dobutamine [F = 6.6; P = 0.014 corrected-P significant]. We found a significant direct relationship between IL-6 and temperature (rho = 0.26; P < 0.01), D-dimer (rho = 0.24; P < 0.01), norepinephrine (rho = 0.33; P < 0.01), troponin I (rho = 0.37; P < 0.01), Creatine-Kinase (rho = 0.37; P < 0.01), Creatine Kinase-MB (rho = 0.33; P < 0.01) and lactic acid (rho = 0.46; P < 0.01) at ICU arrival. Two patients (1.3%) had seizure, 3 patients (1.9%) had stroke, 14 (8.8%) had acute kidney failure, 7 (4.4%) needed dialysis, 3 (1.9%) suffered myocardial infarction and 9 (5.6%) patients died. We

  19. COMPLEMENTARY FEEDING WITH FORTIFIED SPREAD IS LIKELY TO REDUCE THE INCIDENCE OF SEVERE STUNTING AMONG 6–18 MONTH OLD RURAL MALAWIAN INFANTS

    PubMed Central

    Phuka, John C.; Maleta, Kenneth; Thakwalakwa, Chrissie; Cheung, Yin Bun; Briend, André; Manary, Mark J.; Ashorn, Per

    2013-01-01

    Objective To compare growth and incidence of malnutrition among infants receiving long-term dietary complementation with ready-to-use fortified spread (FS) or micronutrient fortified maize-soy flour (LP). Design Randomized, controlled, single-blind trial Setting Rural Malawian population with high incidence of malnutrition Participants 182 six-month-old infants. Intervention Participants were randomized to receive 1-year-long daily supplementation with either 71g of LP (282 kcal energy / day), 50g FS50 (256 kcal), or 25g FS25 (127 kcal). Main outcome measures Weight and length gain, incidence of severe stunting, underweight, and wasting. Results The mean weight and length gains in LP, FS50 and FS25 groups were 2.37, 2.47, and 2.37 kg (p= 0.658) and 12.7, 13.5, and 13.2 cm (p=0.234), respectively. In the same groups, cumulative 12-month incidence of severe stunting was 14.0%, 0.0% and 4.0% (p=0.011), severe underweight 15.0%, 22.5% and 16.9% (p=0.706), and severe wasting 1.8%, 1.9% and 1.8% (p=0.999). Compared to LP-supplemented infants, those given FS50 gained on average (95%CI;p) 100 g (−143 to 343; p=0.419) more weight and 0.8 cm (−0.1 to 1.7; p=0.091) more length. There was a significant interaction between baseline length and intervention (p=0.042); among children with below-median length at enrolment, those given FS50 gained on average 1.9 cm (0.3 to 3.5; p=0.020) more than individuals receiving LP. Conclusions One-year-long complementary feeding with FS does not have significantly larger effect than maize-soy flour on the average weight gain of all infants, but it seems to boost linear growth in the disadvantaged individuals and hence decrease the incidence of severe stunting. PMID:18606932

  20. Incidence, risk factors and outcome of de novo tumors in liver transplant recipients focusing on alcoholic cirrhosis.

    PubMed

    Jiménez-Romero, Carlos; Justo-Alonso, Iago; Cambra-Molero, Félix; Calvo-Pulido, Jorge; García-Sesma, Álvaro; Abradelo-Usera, Manuel; Caso-Maestro, Oscar; Manrique-Municio, Alejandro

    2015-05-01

    Orthotopic liver transplantation (OLT) is an established life-saving procedure for alcoholic cirrhotic (AC) patients, but the incidence of de novo tumors ranges between 2.6% and 15.7% and is significantly increased in comparison with patients who undergo OLT for other etiologies. Tobacco, a known carcinogen, has been reported to be between 52% and 83.3% in AC patients before OLT. Other risk factors that contribute to the development of malignancies are dose-dependent immunosuppression, advanced age, viral infections, sun exposure, and premalignant lesions (inflammatory bowel disease, Barrett's esophagus). A significantly more frequent incidence of upper aerodigestive (UAD) tract, lung, skin, and kidney-bladder tumors has been found in OLT recipients for AC in comparison with other etiologies. Liver transplant recipients who develop de novo non-skin tumors have a decreased long-term survival rate compared with controls. This significantly lower survival rate is more evident in AC recipients who develop UAD tract or lung tumors after OLT mainly because the diagnosis is usually performed at an advanced stage. All transplant candidates, especially AC patients, should be encouraged to cease smoking and alcohol consumption in the pre- and post-OLT periods, use skin protection, avoid sun exposure and over-immunosuppression, and have a yearly otopharyngolaryngeal exploration and chest computed tomography scan in order to prevent or reduce the incidence of de novo malignancies. Although still under investigation, substitution of calcineurin inhibitors for sirolimus or everolimus may reduce the incidence of de novo tumors after OLT.

  1. Intestinal invasion of Salmonella enterica serovar Typhimurium in the avian host is dose dependent and does not depend on motility and chemotaxis.

    PubMed

    Olsen, John Elmerdahl; Hoegh-Andersen, Kirsten Hobolt; Rosenkrantz, Jesper Tjørnholt; Schroll, Casper; Casadesús, Josep; Aabo, Søren; Christensen, Jens Peter

    2013-08-30

    Salmonella enterica serotype Typhimurium (S. Typhimurium) can invade in the intestine of the avian host, and knowledge on the mechanisms that govern this is potentially important for prevention of disease. This study investigated the invasion of S. Typhimurium in the avian host and to which extent it depended on motility and chemotaxis. Wild type and previously well-characterized transposon mutants in flagella genes fliC and fljB and in chemotaxis genes cheA, cheB and cheR were used as challenge strains in intestinal loop experiments. Invasion was shown to be dose dependent, but did not require functional flagella or chemotaxis genes. In support of the results from intestinal loop experiments, flagella and chemotaxis genes were not significantly important to the outcome of an oral infection. The results showed that S. Typhimurium invasion in the avian host was dose dependent and was not affected by the loss of flagella and chemotaxis genes.

  2. The 30 degree tilt position vs the 90 degree lateral and supine positions in reducing the incidence of non-blanching erythema in a hospital inpatient population: a randomised controlled trial.

    PubMed

    Young, Trudie

    2004-07-01

    Manual repositioning of patients by nursing staff is a recognised technique for preventing pressure ulcer formation. The 30 degree tilt is a method of positioning patients that, in the laboratory setting, reduced the contact pressure between the patient and the support surface. A randomised controlled trial was used to examine the effects of the 30 degree tilt position in reducing the incidence of non-blanching erythema (i.e. established pressure damage) in a hospital inpatient population (n=23) when compared to the use of the 90 degree lateral and supine position (n=23). The primary outcome of the trial was the incidence of pressure damage, defined as non-blanching erythema. In this study no subject developed pressure damage that presented with visible breaks in the epidermis, but all damage was restricted to areas of non-blanching erythema (five of the 39 subjects who completed the study exhibited such injury). The main findings of this study were that patient positioning using the 30 degree tilt method did not reduce the incidence of pressure damage compared with either the 90 degree lateral or supine positions. This study also investigated the feasibility of using the 30 degree tilt position with medical inpatients; it found that 78% of subjects experienced difficulty in adopting and maintaining the position. This finding seriously questions the practicality of using the 30 degree tilt method with a predominantly ill population.

  3. Reduced incidence and severity of acute mountain sickness in Qinghai-Tibet railroad construction workers after repeated 7-month exposures despite 5-month low altitude periods.

    PubMed

    Wu, Tian Yi; Ding, Shou Quan; Liu, Jin Liang; Yu, Man Tang; Jia, Jian Hou; Duan, Jun Qing; Chai, Zuo Chuan; Dai, Rui Chen; Zhang, Sheng Lin; Liang, Bao Zhu; Zhao, Ji Zhui; Qi, De Tang; Sun, Yong Fu; Kayser, Bengt

    2009-01-01

    The construction of the Qinghai-Tibet railroad provided a unique opportunity to study the relation between intermittent altitude exposure and acute mountain sickness (AMS). For 5 yr, workers spent 7-month periods at altitude interspaced with 5-month periods at sea level; the incidence, severity, and risk factors of AMS were prospectively investigated. Six hundred lowlanders commuted for 5 yr between near sea level and approximately 4500 m and were compared to 600 other lowland workers, recruited each year upon their first ascent to high altitude as newcomers, and to 200 Tibetan workers native to approximately 4500 m. AMS was assessed with the Lake Louise Scoring System. The incidence and severity of AMS in commuters were lower upon each subsequent exposure, whereas they remained similar in newcomers each year. AMS susceptibility was thus lowered by repeated exposure to altitude. Repeated exposure increased resting Sao(2) and decreased resting heart rate. Tibetans had no AMS, higher Sao(2), and lower heart rates. In conclusion, repetitive 7-month exposures increasingly protect lowlanders against AMS, even when interspaced with 5-month periods spent at low altitude, but do not allow attaining the level of adaptation of altitude natives.

  4. 1-Bromopropane, an alternative to ozone layer depleting solvents, is dose-dependently neurotoxic to rats in long-term inhalation exposure.

    PubMed

    Ichihara, G; Kitoh, J; Yu, X; Asaeda, N; Iwai, H; Kumazawa, T; Shibata, E; Yamada, T; Wang, H; Xie, Z; Takeuchi, Y

    2000-05-01

    1-Bromopropane has been newly introduced as an alternative to ozone layer-depleting solvents. We aimed to clarify the dose-dependent effects of 1-bromopropane on the nervous system. Forty-four Wistar male rats were randomly divided into 4 groups of 11 each. The groups were exposed to 200, 400, or 800 ppm of 1-bromopropane or only fresh air 8 h per day for 12 weeks. Grip strength of forelimbs and hind limbs, maximum motor nerve conduction velocity (MCV), and distal latency (DL) of the tail nerve were measured in 9 rats of each group every 4 weeks. The other 2 rats of each group were perfused at the end of the experiment for morphological examinations. The rats of the 800-ppm group showed poor kicking and were not able to stand still on the slope. After a 12-week exposure, forelimb grip strength decreased significantly at 800 ppm and hind limb grip strength decreased significantly at both 400 and 800 ppm or after a 12-week exposure. MCV and DL of the tail nerve deteriorated significantly at 800 ppm. Ovoid or bubble-like debris of myelin sheaths was prominent in the unraveled muscular branch of the posterior tibial nerve in the 800-ppm group. Swelling of preterminal axons in the gracile nucleus increased in a dose-dependent manner. Plasma creatine phosphokinase (CPK) decreased dose-dependently with significant changes at 400 and 800 ppm. 1-Bromopropane induced weakness in the muscle strength of rat limbs and deterioration of MCV and DL in a dose-dependent manner, with morphological changes in peripheral nerve and preterminal axon in the gracile nucleus. 1-Bromopropane may be seriously neurotoxic to humans and should thus be used carefully in the workplace.

  5. A dose-dependent relationship between mercury exposure from dental amalgams and urinary mercury levels: a further assessment of the Casa Pia Children's Dental Amalgam Trial.

    PubMed

    Geier, D A; Carmody, T; Kern, J K; King, P G; Geier, Mark R

    2012-01-01

    Dental amalgams are a commonly used dental restorative material, and amalgams are about 50% mercury (Hg). In our study, urinary Hg levels was examined in children of age 8-18 years, with and without dental amalgam fillings, from a completed clinical trial (parent study) that was designed to evaluate the potential health consequences of prolonged exposure to Hg from dental amalgam fillings. Our study was designed to determine whether there was a significant dose-dependent correlation between increasing Hg exposure from dental amalgams and urinary Hg levels. Hg exposure depends on the size and number of teeth with dental amalgams. Overall, consistent with the results observed in the parent study, there was a statistically significant dose-dependent correlation between cumulative exposure to Hg from dental amalgams and urinary Hg levels, after covariate adjustment. Further, it was observed that urinary Hg levels increased by 18% to 52% among 8 to 18 year old individuals, respectively, with an average exposure to amalgams, in comparison to study subjects with no exposure to amalgams. The results of our study suggest that dental amalgams contribute to ongoing Hg exposure in a dose-dependent fashion.

  6. Dose-Dependent Change in Elimination Kinetics of Ethanol due to Shift of Dominant Metabolizing Enzyme from ADH 1 (Class I) to ADH 3 (Class III) in Mouse.

    PubMed

    Haseba, Takeshi; Kameyama, Kouji; Mashimo, Keiko; Ohno, Youkichi

    2012-01-01

    ADH 1 and ADH 3 are major two ADH isozymes in the liver, which participate in systemic alcohol metabolism, mainly distributing in parenchymal and in sinusoidal endothelial cells of the liver, respectively. We investigated how these two ADHs contribute to the elimination kinetics of blood ethanol by administering ethanol to mice at various doses, and by measuring liver ADH activity and liver contents of both ADHs. The normalized AUC (AUC/dose) showed a concave increase with an increase in ethanol dose, inversely correlating with β. CL(T) (dose/AUC) linearly correlated with liver ADH activity and also with both the ADH-1 and -3 contents (mg/kg B.W.). When ADH-1 activity was calculated by multiplying ADH-1 content by its V(max⁡)/mg (4.0) and normalized by the ratio of liver ADH activity of each ethanol dose to that of the control, the theoretical ADH-1 activity decreased dose-dependently, correlating with β. On the other hand, the theoretical ADH-3 activity, which was calculated by subtracting ADH-1 activity from liver ADH activity and normalized, increased dose-dependently, correlating with the normalized AUC. These results suggested that the elimination kinetics of blood ethanol in mice was dose-dependently changed, accompanied by a shift of the dominant metabolizing enzyme from ADH 1 to ADH 3.

  7. Dose-Dependent Change in Elimination Kinetics of Ethanol due to Shift of Dominant Metabolizing Enzyme from ADH 1 (Class I) to ADH 3 (Class III) in Mouse

    PubMed Central

    Haseba, Takeshi; Kameyama, Kouji; Mashimo, Keiko; Ohno, Youkichi

    2012-01-01

    ADH 1 and ADH 3 are major two ADH isozymes in the liver, which participate in systemic alcohol metabolism, mainly distributing in parenchymal and in sinusoidal endothelial cells of the liver, respectively. We investigated how these two ADHs contribute to the elimination kinetics of blood ethanol by administering ethanol to mice at various doses, and by measuring liver ADH activity and liver contents of both ADHs. The normalized AUC (AUC/dose) showed a concave increase with an increase in ethanol dose, inversely correlating with β. CLT (dose/AUC) linearly correlated with liver ADH activity and also with both the ADH-1 and -3 contents (mg/kg B.W.). When ADH-1 activity was calculated by multiplying ADH-1 content by its Vmax⁡/mg (4.0) and normalized by the ratio of liver ADH activity of each ethanol dose to that of the control, the theoretical ADH-1 activity decreased dose-dependently, correlating with β. On the other hand, the theoretical ADH-3 activity, which was calculated by subtracting ADH-1 activity from liver ADH activity and normalized, increased dose-dependently, correlating with the normalized AUC. These results suggested that the elimination kinetics of blood ethanol in mice was dose-dependently changed, accompanied by a shift of the dominant metabolizing enzyme from ADH 1 to ADH 3. PMID:22164338

  8. [Dose-dependent tazepam modulation of amplitude-temporal characteristics of thalamocortical responses and the constant potential of the sensorimotor cortex in rabbits at eye opening].

    PubMed

    Shimko, I A; Fokin, V F

    2000-01-01

    The pronounced benzodiazepine (antiphobic) modulation of the amplitude-temporal parameters of different components of the thalamocortical responses (TCR) of the sensorimotor cortex is observed in rabbits in their early postnatal ontogeny. This modulation is of a dose-dependent character and is registered not after the injection of tazepam in a concentration of the "therapeutic tranquilizing window" but also in the psychotoxic plasma range. A gradual increase in blood tazepam concentration in a young rabbit pup is accompanied by the wave-like and differential decrease in the amplitude of the second and third positive (P2 and P3) and third negative (N3) TCR components, while the second negative (N2) and fourth positive (P4) components tend to a wave-like increase. The dose-dependent dynamics of tazepam modulation of the P2, P3, and N3 latencies is characterized by a wave-like and differential increase. The latency of P4 decreases slightly and that of the N2 increases with a low degree of significance. The selective dynamics of benzodiazepine modulation appears to be related with peculiarities of the electrogenesis of each of the components. The dose-dependent modulation of the level of cortical DC potential is of the same character as the respective amplitude changes in P2, P3, and N3, but its fluctiatuons are more pronounced.

  9. In utero exposure to di(n)butyl phthalate reduces testicular testosterone and testis size in a dose-dependent manner in Harlan Sprague Dawley fetal rats

    EPA Science Inventory

    Phthalate esters are widely used to impart flexibility to plastics (e.g. plastic medical devices and children’s toys) as well as other uses in health and beauty products and some pharmaceuticals. Certain phthalate esters cause reproductive malformations and decrease androgen-dep...

  10. Acoustic plane waves normally incident on a clamped panel in a rectangular duct. [to explain noise reduction curves for reducing interior noise in aircraft

    NASA Technical Reports Server (NTRS)

    Unz, H.; Roskam, J.

    1979-01-01

    The theory of acoustic plane wave normally incident on a clamped panel in a rectangular duct is developed. The coupling theory between the elastic vibrations of the panel (plate) and the acoustic wave propagation in infinite space and in the rectangular duct is considered. The partial differential equation which governs the vibration of the panel (plate) is modified by adding to its stiffness (spring) forces and damping forces, and the fundamental resonance frequency and the attenuation factor are discussed. The noise reduction expression based on the theory is found to agree well with the corresponding experimental data of a sample aluminum panel in the mass controlled region, the damping controlled region, and the stiffness controlled region. All the frequency positions of the upward and downward resonance spikes in the sample experimental data are identified theoretically as resulting from four cross interacting major resonance phenomena: the cavity resonance, the acoustic resonance, the plate resonance, and the wooden back panel resonance.

  11. Infants fed formula with added long chain polyunsaturated fatty acids have reduced incidence of respiratory illnesses and diarrhea during the first year of life

    PubMed Central

    2014-01-01

    Background Long chain polyunsaturated fatty acids (LCPUFAs) may influence the immune system. Our objective was to compare the frequency of common illnesses in infants who received formula with or without added LCPUFAs. Methods In this observational, multi-center, prospective study, infants consumed formula with 17 mg DHA and 34 mg ARA/100 kcal (n = 233) or with no added DHA or ARA (n = 92). Pediatricians recorded respiratory illnesses, otitis media, eczema, and diarrhea through 1 year of age. Results Infants who consumed formula with DHA/ARA had lower incidence of bronchitis/bronchiolitis (P = 0.004), croup (P = 0.044), nasal congestion (P = 0.001), cough (P = 0.014), and diarrhea requiring medical attention (P = 0.034). The odds ratio (OR) of having at least one episode of bronchitis/bronchiolitis (0.41, 95% CI 0.24, 0.70; P = 0.001), croup (0.23, 95% CI 0.05, 0.97; P = 0.045), nasal congestion (0.37, 95% CI 0.20, 0.66; P = 0.001), cough (0.52, 95% CI 0.32, 0.86; P = 0.011), and diarrhea requiring medical attention (0.51, 95% CI 0.28, 0.92; P = 0.026) was lower in infants fed DHA/ARA. The OR of an increased number of episodes of bronchitis/bronchiolitis, croup, nasal congestion, cough, and diarrhea, as well as the hazard ratio for shorter time to first episode of bronchitis/bronchiolitis, nasal congestion, cough, and diarrhea were also significantly lower in the DHA/ARA group. Conclusions In healthy infants, formula with DHA/ARA was associated with lower incidence of common respiratory symptoms and illnesses, as well as diarrhea. PMID:24989353

  12. Strict adherence to a blood bank specimen labeling policy by all clinical laboratories significantly reduces the incidence of "wrong blood in tube".

    PubMed

    O'Neill, Edward; Richardson-Weber, Leslie; McCormack, Gina; Uhl, Lynne; Haspel, Richard L

    2009-08-01

    Phlebotomy errors leading to incompatible transfusions are a leading cause of transfusion-related morbidity and mortality. Our institution's specimen-labeling policy requires the collection date, 2 unique patient identifiers, and the ability to identify the phlebotomist. This policy, however, was initially strictly enforced only by the blood bank. In fiscal year 2005, following an educational campaign on proper specimen labeling, all clinical laboratories began strictly adhering to the specimen-labeling policy. Compared with the preceding 4 years, in the 3 years following policy implementation, the incidence of wrong blood in tube (WBIT) and mislabeled specimens detected by the blood bank decreased by 73.5% (0.034% to 0.009%; P < or = .0001) and by 84.6% (0.026% to 0.004%; P < or = .0001), respectively. During a short period, a simple, low-cost educational initiative and policy change can lead to statistically significant decreases in WBIT and mislabeled specimens received by the blood bank. PMID:19605809

  13. Heme oxygenase-1 gene promoter polymorphism is associated with reduced incidence of acute chest syndrome among children with sickle cell disease

    PubMed Central

    Bean, Christopher J.; Boulet, Sheree L.; Ellingsen, Dorothy; Pyle, Meredith E.; Barron-Casella, Emily A.; Casella, James F.; Payne, Amanda B.; Driggers, Jennifer; Trau, Heidi A.; Yang, Genyan; Jones, Kimberly; Ofori-Acquah, Solomon F.; Hooper, W. Craig

    2012-01-01

    Sickle cell disease is a common hemolytic disorder with a broad range of complications, including vaso-occlusive episodes, acute chest syndrome (ACS), pain, and stroke. Heme oxygenase-1 (gene HMOX1; protein HO-1) is the inducible, rate-limiting enzyme in the catabolism of heme and might attenuate the severity of outcomes from vaso-occlusive and hemolytic crises. A (GT)n dinucleotide repeat located in the promoter region of the HMOX1 gene is highly polymorphic, with long repeat lengths linked to decreased activity and inducibility. We examined this polymorphism to test the hypothesis that short alleles are associated with a decreased risk of adverse outcomes (hospitalization for pain or ACS) among a cohort of 942 children with sickle cell disease. Allele lengths varied from 13 to 45 repeats and showed a trimodal distribution. Compared with children with longer allele lengths, children with 2 shorter alleles (4%; ≤ 25 repeats) had lower rates of hospitalization for ACS (incidence rate ratio 0.28, 95% confidence interval, 0.10-0.81), after adjusting for sex, age, asthma, percentage of fetal hemoglobin, and α-globin gene deletion. No relationship was identified between allele lengths and pain rate. We provide evidence that genetic variation in HMOX1 is associated with decreased rates of hospitalization for ACS, but not pain. This study is registered at www.clinicaltrials.gov as #NCT00072761. PMID:22966170

  14. Improved compliance with venous thromboembolism (VTE) pharmacologic prophylaxis for patients with gynecologic malignancies hospitalized for nonsurgical indications did not reduce VTE incidence

    PubMed Central

    Prescott, Lauren S.; Kidin, Lisa M.; Downs, Rebecca L.; Cleveland, David J.; Wilson, Ginger L.; Munsell, Mark F.; DeJesus, Alma Y.; Cain, Katherine E.; Ramirez, Pedro T.; Kroll, Michael H.; Levenback, Charles F.; Schmeler, Kathleen M.

    2014-01-01

    Objective National guidelines recommend prophylactic anticoagulation for all hospitalized patients with cancer to prevent hospital-acquired venous thromboembolism (VTE). However, adherence to these evidence-based recommended practice patterns remains low. We performed a quality improvement project to increase VTE pharmacologic prophylaxis rates among patients with gynecologic malignancies hospitalized for nonsurgical indications and evaluated the resulting effect on rates of development of VTE. Methods/materials In June 2011, departmental VTE practice guidelines were implemented for patients with gynecologic malignancies who were hospitalized for nonsurgical indications. A standardized VTE prophylaxis module was added to the admission electronic order sets. Outcome measures included: number of admissions receiving VTE pharmacologic prophylaxis within 24 hours of admission; and number of potentially preventable hospital-acquired VTEs diagnosed within 30 and 90 days of discharge. Outcomes were compared between a pre-guideline implementation cohort (N=99), a post-guideline implementation cohort (N=127), and a sustainability cohort assessed 2 years after implementation (N=109). Patients were excluded if upon admission they had a VTE, were considered low risk for VTE, or had a documented contraindication to pharmacologic prophylaxis. Results Administration of pharmacologic prophylaxis within 24 hours of admission increased from 20.8% to 88.2% immediately following the implementation of guidelines, but declined to 71.8% in our sustainability cohort (p<0.001). There was no difference in VTE incidence among the three cohorts (n=2 (4.2%) v. n=3 (3.9%) v. n=3 (4.2%), respectively; p=1.00). Conclusions Our quality improvement project improved pharmacologic VTE prophylaxis rates. A small decrease in prophylaxis over the subsequent 2 years suggests a need for continued surveillance to optimize quality improvement initiatives. Despite increased adherence to guidelines, VTE rates

  15. A significant dose-dependent relationship between mercury exposure from dental amalgams and kidney integrity biomarkers: a further assessment of the Casa Pia children's dental amalgam trial.

    PubMed

    Geier, D A; Carmody, T; Kern, J K; King, P G; Geier, M R

    2013-04-01

    Dental amalgams are a commonly used dental restorative material. Amalgams are about 50% mercury (Hg), and Hg is known to significantly accumulate in the kidney. It was hypothesized that because Hg accumulates in the proximal tubules (PTs), glutathione-S-transferases (GST)-α (suggestive of kidney damage at the level of PT) would be expected to be more related to Hg exposure than GST-π (suggestive of kidney damage at the level of the distal tubules). Urinary biomarkers of kidney integrity were examined in children of 8-18 years old, with and without dental amalgam fillings, from a completed clinical trial (parent study). Our study determined whether there was a significant dose-dependent correlation between increasing Hg exposure from dental amalgams and GST-α and GST-π as biomarkers of kidney integrity. Overall, the present study, using a different and more sensitive statistical model than the parent study, revealed a statistically significant dose-dependent correlation between cumulative exposure to Hg from dental amalgams and urinary levels of GST-α, after covariate adjustment; where as, a nonsignificant relationship was observed with urinary levels of GST-π. Furthermore, it was observed that urinary GST-α levels increased by about 10% over the 8-year course of the study among individuals with an average exposure to amalgams among the study subjects from the amalgam group, in comparison with study subjects with no exposure to dental amalgams. The results of our study suggest that dental amalgams contribute to ongoing kidney damage at the level of the PTs in a dose-dependent fashion.

  16. Soy diets containing varying amounts of genistein stimulate growth of estrogen-dependent (MCF-7) tumors in a dose-dependent manner.

    PubMed

    Allred, C D; Allred, K F; Ju, Y H; Virant, S M; Helferich, W G

    2001-07-01

    We have demonstrated that the isoflavone, genistein, stimulates growth of estrogen-dependent human breast cancer (MCF-7) cells in vivo (C. Y. Hsieh et al., Cancer Res., 58: 3833-3838, 1998). The isoflavones are a group of phytoestrogens that are present in high concentrations in soy. Whether consumption of genistein from soy protein will have similar effects on estrogen-dependent tumor growth as pure genistein has not been investigated in the athymic mouse tumor implant model. Depending on processing, soy protein isolates vary widely in concentrations of genistein. We hypothesize that soy isolates containing different concentrations of genistein will stimulate the growth of estrogen-dependent cells in vivo in a dose-dependent manner. To test this hypothesis we conducted experiments in which these soy protein isolates were fed to athymic mice implanted s.c. with estrogen-dependent tumors. Genistein content (aglycone equivalent) of the soy isolate diets were 15, 150, or 300 ppm. Positive (with 17beta-estradiol pellet implant) and negative (no 17beta-estradiol) control groups received casein-based (isoflavone-free) diets. Tumor size was measured weekly. At completion of the study animals were killed and tumors collected for evaluation of cellular proliferation and estrogen-dependent gene expression. Incorporation of bromodeoxyuridine into cellular DNA was used as an indicator of cell proliferation, and pS2 mRNA was used as an estrogen-responsive gene. Soy protein diets containing varying amounts of genistein increased estrogen-dependent tumor growth in a dose-dependent manner. Cell proliferation was greatest in tumors of animals given estrogen or dietary genistein (150 and 300 ppm). Expression of pS2 was increased in tumors from animals consuming dietary genistein (150 and 300 ppm). Here we present new information that soy protein isolates containing increasing concentrations of genistein stimulate the growth of estrogen-dependent breast cancer cells in vivo in a dose-dependent

  17. The Dose-Dependent Organ-Specific Effects of a Dipeptidyl Peptidase-4 Inhibitor on Cardiovascular Complications in a Model of Type 2 Diabetes

    PubMed Central

    Seo, Jung-Woo; Lee, Arah; Kim, Dong Jin; Kim, Yang-Gyun; Kim, Se-Yeun; Lee, Kyung Hye; Lim, Sung-Jig; Cheng, Xian Wu; Lee, Sang-Ho; Kim, Weon

    2016-01-01

    Objective Although dipeptidyl peptidase-4 (DPP-4) inhibitors have been suggested to have a non-glucoregulatory protective effect in various tissues, the effects of long-term inhibition of DPP-4 on the micro- and macro-vascular complications of type 2 diabetes remain uncertain. The aim of the present study was to investigate the organ-specific protective effects of DPP-4 inhibitor in rodent model of type 2 diabetes. Methods Eight-week-old diabetic and obese db/db mice and controls (db/m mice) received vehicle or one of two doses of gemigliptin (0.04 and 0.4%) daily for 12 weeks. Urine albumin excretion and echocardiography measured at 20 weeks of age. Heart and kidney tissue were subjected to molecular analysis and immunohistochemical evaluation. Results Gemigliptin effectively suppressed plasma DPP-4 activation in db/db mice in a dose-dependent manner. The HbA1c level was normalized in the 0.4% gemigliptin, but not in the 0.04% gemigliptin group. Gemigliptin showed a dose-dependent protective effect on podocytes, anti-apoptotic and anti-oxidant effects in the diabetic kidney. However, the dose-dependent effect of gemigliptin on diabetic cardiomyopathy was ambivalent. The lower dose significantly attenuated left ventricular (LV) dysfunction, apoptosis, and cardiac fibrosis, but the higher dose could not protect the LV dysfunction and cardiac fibrosis. Conclusion Gemigliptin exerted non-glucoregulatory protective effects on both diabetic nephropathy and cardiomyopathy. However, high-level inhibition of DPP-4 was associated with an organ-specific effect on cardiovascular complications in type 2 diabetes. PMID:26959365

  18. Glucose and insulin do not decrease in a dose-dependent manner after increasing doses of mixed fibers that are consumed in muffins for breakfast.

    PubMed

    Willis, Holly J; Thomas, William; Eldridge, Alison L; Harkness, Laura; Green, Hilary; Slavin, Joanne L

    2011-01-01

    Conventional wisdom suggests that fiber consumption leads to lower postprandial glucose and insulin response. We hypothesized that increasing doses of mixed, viscous fiber would lower glucose and insulin levels in a dose-dependent manner. Healthy men (n = 10) and women (n = 10) with a body mass index of 24 ± 2 (mean ± SEM) participated in this double-blind, crossover study. On 4 separate visits, fasting subjects consumed an approximately 2093 kJ (500 calorie) muffin with 0, 4, 8, or 12 g of mixed fibers. Blood was drawn to measure glucose and insulin at regular intervals throughout a 3-hour test period. Area under the curve (AUC) glucose was significantly lower after 0 g of fiber than after 4, 8, or 12 g of fiber (arbitrary AUC units ± SEM: 25.3 ± 5.2 vs 44.6 ± 7.7, 49.7 ± 7.9, 51.5 ± 6.6, respectively; P < .006). Area under the curve glucose increased with increasing fiber doses (P for trend = .0003). Area under the curve insulin was higher after the 4-g dose than after the 0-, 8-, and 12-g doses (arbitrary AUC units ± SEM: 84.4 ± 8.0 vs 60.1 ± 6.5, 69.4 ± 8.7, 69.7 ± 8.5, respectively; P < .05); it did not change in a dose-dependent manner. Area under the curve glucose and AUC insulin did not correlate with each other. Glucose and insulin did not decrease in a dose-dependent manner after 0, 4, 8, and 12 g of mixed fibers were consumed in muffins for breakfast. The lack of differences was largely based on the individual variation in glucose response. Caution should be used when making general claims about the expected impact of fiber on glucose and insulin levels.

  19. Lactobacillus reuteri strains reduce incidence and severity of experimental necrotizing enterocolitis via modulation of TLR4 and NF-κB signaling in the intestine

    PubMed Central

    Liu, Yuying; Fatheree, Nicole Y.; Mangalat, Nisha

    2012-01-01

    Necrotizing enterocolitis (NEC) is the leading gastrointestinal cause of mortality and morbidity in the premature infant. Premature infants have a delay in intestinal colonization by commensal bacteria and colonization with potentially pathogenic organisms. Lactobacillus reuteri is a probiotic that inhibits enteric infections, modulates the immune system, and may be beneficial to prevent NEC. In previous studies, L. reuteri strains DSM 17938 and ATCC PTA 4659 differentially modulated inflammation in vitro; however, the strains had equivalent anti-inflammatory responses in LPS feeding-induced ileitis in neonatal rats in vivo. The impact of these two strains in the prevention of NEC has not been previously investigated. NEC was induced in newborn rats by orogastric formula feeding and exposure to hypoxia. L. reuteri was added to the formula to prevent NEC. NEC score, Toll-like receptor (TLR)-signaling genes, phospho-IκB activity, and cytokine levels in the intestine were examined. Both strains significantly increased survival rate and decreased the incidence and severity of NEC, with optimal effects from DSM 17938. In response to probiotic, mRNA expression of IL-6, TNF-α, TLR4, and NF-κB was significantly downregulated, while mRNA levels of anti-inflammatory cytokine IL-10 were significantly upregulated. In parallel, L. reuteri treatment led to decrease intestinal protein levels of TLR4 and cytokine levels of TNF-α and IL-1β in newborn rats with NEC. Both strains significantly inhibited not only intestinal LPS-induced phospho-IκB activity in an ex vivo study but also decreased the levels of phospho-IκB in the intestines of NEC rat model. Cow milk formula feeding produced a similar but milder proinflammatory profile in the intestine that was also ameliorated by 17938. Our studies demonstrate that each of the two L. reuteri strains has potential therapeutic value in our NEC model and in enteritis associated with cow milk feeding. These results support the

  20. Medium chain triglycerides dose-dependently prevent liver pathology in a rat model of nonalcoholic fatty liver disease

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Obesity is often associated with a cluster of increased health risks collectively known as "Metabolic Syndrome" (MS). MS is often accompanied by development of fatty liver. Sometimes fatty liver results in damage leading to reduced liver function, and need for a transplant. This condition is known...

  1. Dose dependency of fermentation and the extent of renal excretion of palatinit (isomalt) in rats with respect to its energy value.

    PubMed

    Herfarth, H; Klingebiel, L; Juhr, N C; Grossklaus, R

    1994-09-01

    The impact of dose-dependent caloric salvage by microbial fermentation processes in the lower gut and the extent of renal excretion for the overall energetic availability of the alternative bulk sweetener Palatinit were investigated in rats. To evaluate the extent of dose-dependent fermentation a conventional and a germ-free rat model were used and fecal excretions of Palatinit after intragastric application were compared. Because of the lack of bacterial colonization in the gastrointestinal tract in germ-free rat the difference in fecal excretion of Palatinit between germ-free and conventional rat is mainly due to bacterial fermentation. To determine the amount of renal excretion of Palatinit the urine was collected. The experiments were conducted using different amounts of Palatinit (300 and 1,200 mg/kg body weight = mg/kg b.w.). Fecal excretions of Palatinit and its monomers (sorbitol and mannitol) were measured by high-performance liquid chromatography (HPLC) and for the determination of renal excretions a gas chromatography system was used. After the application of 300 mg/kg b.w. Palatinit only the breakdown product sorbitol could be recovered in the feces of germ-free rats (29% of the applied dose). No intact Palatinit could be found. In contrast, neither Palatinit nor the breakdown products sorbitol or mannitol could be detected in the feces of conventional rats after application of the same dose. After the application of the higher dose only small amounts of intact Palatinit were found in the feces of germ-free rats (average 12%). There was no intact measurable Palatinit in the feces of conventional rats. The fecal excretions of sorbitol and mannitol in the feces of the germ-free rats were 55% and 39%; in conventional rats only 21% sorbitol was excreted. Only traces of Palatinit, sorbitol or mannitol were found in the urine of conventional and germ-free rats after application of the low as well as the high dose. In conclusion, this study clearly shows the

  2. Statins Attenuate Helicobacter pylori CagA Translocation and Reduce Incidence of Gastric Cancer: In Vitro and Population-Based Case-Control Studies.

    PubMed

    Lin, Chun-Jung; Liao, Wei-Chih; Lin, Hwai-Jeng; Hsu, Yuan-Man; Lin, Cheng-Li; Chen, Yu-An; Feng, Chun-Lung; Chen, Chih-Jung; Kao, Min-Chuan; Lai, Chih-Ho; Kao, Chia-Hung

    2016-01-01

    Gastric cancer is the second leading cause of cancer-related death worldwide. The correlation of Helicobacter pylori and the etiology of gastric cancer was substantially certain. Cholesterol-rich microdomains (also called lipid rafts), which provide platforms for signaling, are associated with H. pylori-induced pathogenesis leading to gastric cancer. Patients who have been prescribed statins, inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase, have exhibited a reduced risk of several types of cancer. However, no studies have addressed the effect of statins on H. pylori-associated gastric cancer from the antineoplastic perspective. In this study, we showed that treatment of gastric epithelial cells with simvastatin reduced the level of cellular cholesterol and led to attenuation of translocation and phosphorylation of H. pylori cytotoxin-associated gene A (CagA), which is recognized as a major determinant of gastric cancer development. Additionally, a nationwide case-control study based on data from the Taiwanese National Health Insurance Research Database (NHIRD) was conducted. A population-based case-control study revealed that patients who used simvastatin exhibited a significantly reduced risk of gastric cancer (adjusted odds ratio (OR) = 0.76, 95% confidence interval (CI) = 0.70-0.83). In patients exhibiting H. pylori infection who were prescribed simvastatin, the adjusted OR for gastric cancer was 0.25 (95% CI = 0.12-0.50). Our results combined an in vitro study with a nationwide population analysis reveal that statin use might be a feasible approach to prevent H. pylori-associated gastric cancer.

  3. Statins Attenuate Helicobacter pylori CagA Translocation and Reduce Incidence of Gastric Cancer: In Vitro and Population-Based Case-Control Studies

    PubMed Central

    Hsu, Yuan-Man; Lin, Cheng-Li; Chen, Yu-An; Feng, Chun-Lung; Chen, Chih-Jung; Kao, Min-Chuan; Lai, Chih-Ho; Kao, Chia-Hung

    2016-01-01

    Gastric cancer is the second leading cause of cancer-related death worldwide. The correlation of Helicobacter pylori and the etiology of gastric cancer was substantially certain. Cholesterol-rich microdomains (also called lipid rafts), which provide platforms for signaling, are associated with H. pylori-induced pathogenesis leading to gastric cancer. Patients who have been prescribed statins, inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase, have exhibited a reduced risk of several types of cancer. However, no studies have addressed the effect of statins on H. pylori-associated gastric cancer from the antineoplastic perspective. In this study, we showed that treatment of gastric epithelial cells with simvastatin reduced the level of cellular cholesterol and led to attenuation of translocation and phosphorylation of H. pylori cytotoxin-associated gene A (CagA), which is recognized as a major determinant of gastric cancer development. Additionally, a nationwide case-control study based on data from the Taiwanese National Health Insurance Research Database (NHIRD) was conducted. A population-based case-control study revealed that patients who used simvastatin exhibited a significantly reduced risk of gastric cancer (adjusted odds ratio (OR) = 0.76, 95% confidence interval (CI) = 0.70–0.83). In patients exhibiting H. pylori infection who were prescribed simvastatin, the adjusted OR for gastric cancer was 0.25 (95% CI = 0.12–0.50). Our results combined an in vitro study with a nationwide population analysis reveal that statin use might be a feasible approach to prevent H. pylori-associated gastric cancer. PMID:26730715

  4. An oral DNA vaccine against infectious haematopoietic necrosis virus (IHNV) encapsulated in alginate microspheres induces dose-dependent immune responses and significant protection in rainbow trout (Oncorrhynchus mykiss).

    PubMed

    Ballesteros, Natalia A; Alonso, Marta; Saint-Jean, Sylvia Rodríguez; Perez-Prieto, Sara I

    2015-08-01

    Administered by intramuscular injection, a DNA vaccine (pIRF1A-G) containing the promoter regions upstream of the rainbow trout interferon regulatory factor 1A gene (IRF1A) driven the expression of the infectious hematopoietic necrosis virus (IHNV) glycoprotein (G) elicited protective immune responses in rainbow trout (Oncorhynchus mykiss). However, less laborious and cost-effective routes of DNA vaccine delivery are required to vaccinate large numbers of susceptible farmed fish. In this study, the pIRF1A-G vaccine was encapsulated into alginate microspheres and orally administered to rainbow trout. At 1, 3, 5, and 7 d post-vaccination, IHNV G transcripts were detected by quantitative real-time PCR in gills, spleen, kidney and intestinal tissues of vaccinated fish. This result suggested that the encapsulation of pIRF1A-G in alginate microparticles protected the DNA vaccine from degradation in the fish stomach and ensured vaccine early delivery to the hindgut, vaccine passage through the intestinal mucosa and its distribution thought internal and external organs of vaccinated fish. We also observed that the oral route required approximately 20-fold more plasmid DNA than the injection route to induce the expression of significant levels of IHNV G transcripts in kidney and spleen of vaccinated fish. Despite this limitation, increased IFN-1, TLR-7 and IgM gene expression was detected by qRT-PCR in kidney of vaccinated fish when a 10 μg dose of the oral pIRF1A-G vaccine was administered. In contrast, significant Mx-1, Vig-1, Vig-2, TLR-3 and TLR-8 gene expression was only detected when higher doses of pIRF1A-G (50 and 100 μg) were orally administered. The pIRF1A-G vaccine also induced the expression of several markers of the adaptive immune response (CD4, CD8, IgM and IgT) in kidney and spleen of immunized fish in a dose-dependent manner. When vaccinated fish were challenged by immersion with live IHNV, evidence of a dose-response effect of the oral vaccine could also

  5. The impact of resveratrol and hydrogen peroxide on muscle cell plasticity shows a dose-dependent interaction.

    PubMed

    Bosutti, Alessandra; Degens, Hans

    2015-01-01

    While reactive oxygen species (ROS) play a role in muscle repair, excessive amounts of ROS for extended periods may lead to oxidative stress. Antioxidants, as resveratrol (RS), may reduce oxidative stress, restore mitochondrial function and promote myogenesis and hypertrophy. However, RS dose-effectiveness for muscle plasticity is unclear. Therefore, we investigated RS dose-response on C2C12 myoblast and myotube plasticity 1. in the presence and 2. absence of different degrees of oxidative stress. Low RS concentration (10 μM) stimulated myoblast cell cycle arrest, migration and sprouting, which were inhibited by higher doses (40-60 μM). RS did not increase oxidative capacity. In contrast, RS induced mitochondria loss, reduced cell viability and ROS production, and activated stress response pathways [Hsp70 and pSer36-p66(ShcA) proteins]. However, the deleterious effects of H2O2 (1000 µM) on cell migration were alleviated after preconditioning with 10 µM-RS. This dose also enhanced cell motility mediated by 100 µM-H2O2, while higher RS-doses augmented the H2O2-induced impaired myoblast regeneration and mitochondrial dehydrogenase activity. In conclusion, low resveratrol doses promoted in vitro muscle regeneration and attenuated the impact of ROS, while high doses augmented the reduced plasticity and metabolism induced by oxidative stress. Thus, the effects of resveratrol depend on its dose and degree of oxidative stress. PMID:25627702

  6. A retinoic acid receptor alpha antagonist counteracts retinoid teratogenicity in vitro and reduced incidence and/or severity of malformations in vivo.

    PubMed

    Eckhardt, K; Schmitt, G

    1994-02-15

    The role of retinoic acid receptors (RAR) in retinoid-induced teratogenesis is mainly unknown. The aim of the present studies was to demonstrate the effect of a RAR alpha antagonist on retinoid-induced teratogenic effects in vitro and in vivo. In micromass cultures of rat limb bud cells a RAR alpha antagonist was able to counteract differentiation inhibiting effects of a RAR alpha agonist. In mouse studies, the selective RAR alpha antagonist reduced frequency and/or severity of major malformations. Our observations indicate the potentiality of selective RAR agonists and antagonists in dissecting the function of nuclear receptors and in particular cases of retinoid teratogenesis, to assign to the different receptors a primary role in determining one or another of the multiple malformations.

  7. A high dietary concentration of inulin is necessary to reduce the incidence of swine dysentery in pigs experimentally challenged with Brachyspira hyodysenteriae.

    PubMed

    Hansen, Christian F; Hernández, Aracely; Mansfield, Josie; Hidalgo, Álvaro; La, Tom; Phillips, Nyree D; Hampson, David J; Pluske, John R

    2011-11-01

    A total of sixty surgically castrated male pigs (Large White × Landrace) weighing 31·2 (sd 4·3) kg were used in a randomised block experiment to examine the effect of added dietary inulin (0, 20, 40 and 80 g/kg) on the occurrence of swine dysentery (SD) and on fermentation characteristics in the large intestine after experimental challenge with the causative spirochaete Brachyspira hyodysenteriae. The pigs were allowed to adapt to the diets for 2 weeks before each pig was challenged orally four times with a broth culture containing B. hyodysenteriae on consecutive days. Increasing dietary levels of inulin linearly (P = 0·001) reduced the risk of pigs developing SD; however, eight out of fifteen pigs fed the diet with 80 g/kg inulin still developed the disease. The pH values in the caecum (P = 0·072) tended to decrease, and in the upper colon, the pH values did decrease (P = 0·047) linearly with increasing inulin levels in the diets, most probably due to a linear increase in the concentration of total volatile fatty acids in the caecum (P = 0·018), upper colon (P = 0·001) and lower colon (P = 0·013). In addition, there was a linear reduction in the proportion of the branched-chain fatty acids isobutyric acid and isovaleric acid in the caecum (P = 0·015 and 0·026) and upper colon (P = 0·011 and 0·013) with increasing levels of dietary inulin. In conclusion, the present study showed that a diet supplemented with a high level of inulin (80 g/kg) but not lower levels reduced the risk of pigs developing SD, possibly acting through a modification of the microbial fermentation patterns in the large intestine.

  8. Anatomy of an incident

    DOE PAGES

    Cournoyer, Michael E.; Trujillo, Stanley; Lawton, Cindy M.; Land, Whitney M.; Schreiber, Stephen B.

    2016-03-23

    A traditional view of incidents is that they are caused by shortcomings in human competence, attention, or attitude. It may be under the label of “loss of situational awareness,” procedure “violation,” or “poor” management. A different view is that human error is not the cause of failure, but a symptom of failure – trouble deeper inside the system. In this perspective, human error is not the conclusion, but rather the starting point of investigations. During an investigation, three types of information are gathered: physical, documentary, and human (recall/experience). Through the causal analysis process, apparent cause or apparent causes are identifiedmore » as the most probable cause or causes of an incident or condition that management has the control to fix and for which effective recommendations for corrective actions can be generated. A causal analysis identifies relevant human performance factors. In the following presentation, the anatomy of a radiological incident is discussed, and one case study is presented. We analyzed the contributing factors that caused a radiological incident. When underlying conditions, decisions, actions, and inactions that contribute to the incident are identified. This includes weaknesses that may warrant improvements that tolerate error. Measures that reduce consequences or likelihood of recurrence are discussed.« less

  9. Early B-cell Factor 1 Regulates the Expansion of B-cell Progenitors in a Dose-dependent Manner*

    PubMed Central

    Åhsberg, Josefine; Ungerbäck, Jonas; Strid, Tobias; Welinder, Eva; Stjernberg, Jenny; Larsson, Malin; Qian, Hong; Sigvardsson, Mikael

    2013-01-01

    Transcription factor doses are of importance for normal and malignant B-lymphocyte development; however, the understanding of underlying mechanisms and functional consequences of reduced transcription factor levels is limited. We have analyzed progenitor and B-lineage compartments in mice carrying heterozygote mutations in the E2a, Ebf1, or Pax5 gene. Although lymphoid progenitors from Ebf1 or Pax5 heterozygote mice were specified and lineage-restricted in a manner comparable with Wt progenitors, this process was severely impaired in E2a heterozygote mutant mice. This defect was not significantly enhanced upon combined deletion of E2a with Ebf1 or Pax5. Analysis of the pre-B-cell compartment in Ebf1 heterozygote mice revealed a reduction in cell numbers. These cells expressed Pax5 and other B-lineage-associated genes, and global gene expression analysis suggested that the reduction of the pre-B-cell compartment was a result of impaired pre-B-cell expansion. This idea was supported by a reduction in IL2Rα-expressing late pre-B-cells as well as by cell cycle analysis and by the finding that the complexity of the VDJ rearrangement patterns was comparable in Wt and Ebf1+/− pre-B-cells, although the number of progenitors was reduced. Heterozygote deletion of Ebf1 resulted in impaired response to IL7 in vitro and reduced expression levels of pre-BCR on the cell surface, providing possible explanations for the observed stage-specific reduction in cellular expansion. Thus, transcription factor doses are critical for specification as well as expansion of B-lymphoid progenitors, providing increased insight into the molecular regulation of B-cell development. PMID:24078629

  10. Sperm Oxidative Stress Is Detrimental to Embryo Development: A Dose-Dependent Study Model and a New and More Sensitive Oxidative Status Evaluation

    PubMed Central

    de Castro, Letícia S.; de Assis, Patrícia M.; Siqueira, Adriano F. P.; Hamilton, Thais R. S.; Mendes, Camilla M.; Losano, João D. A.; Nichi, Marcílio; Visintin, José A.; Assumpção, Mayra E. O. A.

    2016-01-01

    Our study aimed to assess the impact of sperm oxidative stress on embryo development by means of a dose-dependent model. In experiment 1, straws from five bulls were subjected to incubation with increasing H2O2 doses (0, 12.5, 25, and 50 μM). Motility parameters were evaluated by Computed Assisted System Analysis (CASA). Experiment 2 was designed to study a high (50 μM) and low dose (12.5 μM) of H2O2 compared to a control (0 μM). Samples were incubated and further used for in vitro fertilization. Analyses of motility (CASA), oxidative status (CellROX green and 2'-7' dichlorofluorescein diacetate), mitochondrial potential (JC-1), chromatin integrity (AO), and sperm capacitation status (chlortetracycline) were performed. Embryos were evaluated based on fast cleavage (30 h.p.i.), cleavage (D = 3), development (D = 5), and blastocyst rates (D = 8). We observed a dose-dependent deleterious effect of H2O2 on motility and increase on the percentages of positive cells for CellROX green, capacitated sperm, and AO. A decrease on cleavage and blastocyst rates was observed as H2O2 increased. Also, we detected a blockage on embryo development. We concluded that sperm when exposed to oxidative environment presents impaired motility traits, prooxidative status, and premature capacitation; such alterations resulting in embryo development fail. PMID:26770658

  11. Sperm Oxidative Stress Is Detrimental to Embryo Development: A Dose-Dependent Study Model and a New and More Sensitive Oxidative Status Evaluation.

    PubMed

    de Castro, Letícia S; de Assis, Patrícia M; Siqueira, Adriano F P; Hamilton, Thais R S; Mendes, Camilla M; Losano, João D A; Nichi, Marcílio; Visintin, José A; Assumpção, Mayra E O A

    2016-01-01

    Our study aimed to assess the impact of sperm oxidative stress on embryo development by means of a dose-dependent model. In experiment 1, straws from five bulls were subjected to incubation with increasing H2O2 doses (0, 12.5, 25, and 50 μM). Motility parameters were evaluated by Computed Assisted System Analysis (CASA). Experiment 2 was designed to study a high (50 μM) and low dose (12.5 μM) of H2O2 compared to a control (0 μM). Samples were incubated and further used for in vitro fertilization. Analyses of motility (CASA), oxidative status (CellROX green and 2'-7' dichlorofluorescein diacetate), mitochondrial potential (JC-1), chromatin integrity (AO), and sperm capacitation status (chlortetracycline) were performed. Embryos were evaluated based on fast cleavage (30 h.p.i.), cleavage (D = 3), development (D = 5), and blastocyst rates (D = 8). We observed a dose-dependent deleterious effect of H2O2 on motility and increase on the percentages of positive cells for CellROX green, capacitated sperm, and AO. A decrease on cleavage and blastocyst rates was observed as H2O2 increased. Also, we detected a blockage on embryo development. We concluded that sperm when exposed to oxidative environment presents impaired motility traits, prooxidative status, and premature capacitation; such alterations resulting in embryo development fail. PMID:26770658

  12. A dose-dependent decrease in the fraction of cases harboring M6P/IGF2R mutations in hepatocellular carcinomas from the atomic bomb survivors.

    PubMed

    Iwamoto, Keisuke S; Yano, Shiho; Barber, Chad L; MacPhee, Donald G; Tokuoka, Shoji

    2006-12-01

    The risk for hepatocellular carcinoma (HCC) development is significantly heightened in the atomic bomb survivors, but the mechanism is unclear. We have previously reported finding a radiation dose-dependent increase in HCCs with TP53 mutations from the survivors. We now show that, in the same HCC samples, the frequency of 3'-untranslated region (3'UTR) mutations in M6P/IGF2R, a candidate HCC tumor suppressor gene, decreases with dose (P = 0.0091), implying a radiation dose-dependent negative selection of cells harboring such mutations. The fact that they were in the 3'UTR implicates changes in transcript stability rather than in protein function as the mechanism. Moreover, these M6P/IGF2R 3'UTR mutations and the TP53 mutations detected previously were mutually exclusive in most of the tumors, suggesting two independent pathways to HCC development, with the TP53 pathway being more favored with increasing radiation dose than the M6P/IGF2R pathway. These results suggest that tumors attributable to radiation may be genotypically different from tumors of other etiologies and hence may provide a way of distinguishing radiation-induced cancers from "background" cancers--a shift from the current paradigm.

  13. The dose-dependent effect on protection and humoral response to a DNA vaccine against Infectious Hematopoietic Necrosis (IHN) virus in subyearling rainbow trout

    USGS Publications Warehouse

    LaPatra, Scott E.; Corbeil, Serge; Jones, Gerald R.; Shewmaker, William D.; Kurath, Gael

    2000-01-01

    A dose–response study that used the DNA vaccine pIHNw-G against infectious hematopoietic necrosis virus (IHNV) showed that complete and highly significant (P < 0.001) protection against a virus injection challenge can be attained in subyearling rainbow trout Oncorhynchus mykiss (145–160 g, 8- to 10-months-old) 6 weeks after a single intramuscular injection with doses as low as 1 μg. Complete protection was also reproducibly demonstrated at higher vaccine doses; however, no protection was observed with a 0.1-μg dose. Virus-neutralizing antibody titers were detected in fish that had been vaccinated with different doses of the DNA vaccine and then sham-infected; there appeared to be a dose-dependent effect, with higher titers obtained with higher doses of vaccine. The DNA-vaccinated animals that survived virus challenge had significantly (P < 0.05) higher neutralizing antibody titers than sham-infected, DNA-vaccinated control fish. Additionally, the titers detected in the IHN survivors exhibited a significant (P < 0.05) dose-dependent effect, with the highest titers being present in fish that received the highest vaccine doses.

  14. Development of a Computational High-Throughput Tool for the Quantitative Examination of Dose-Dependent Histological Features

    PubMed Central

    Nault, Rance; Colbry, Dirk; Brandenberger, Christina; Harkema, Jack R.; Zacharewski, Timothy R.

    2015-01-01

    High-resolution digitalizing of histology slides facilitates the development of computational alternatives to manual quantitation of features of interest. We developed a MATLAB-based quantitative histological analysis tool (QuHAnT) for the high-throughput assessment of distinguishable histological features. QuHAnT validation was demonstrated by comparison with manual quantitation using liver sections from mice orally gavaged with sesame oil vehicle or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 0.001–30 µg/kg) every 4 days for 28 days, which elicits hepatic steatosis with mild fibrosis. A quality control module of QuHAnT reduced the number of quantifiable Oil Red O (ORO)-stained images from 3,123 to 2,756. Increased ORO staining was measured at 10 and 30 µg/kg TCDD with a high correlation between manual and computational volume densities (Vv), although the dynamic range of QuHAnT was 10-fold greater. Additionally, QuHAnT determined the size of each ORO vacuole, which could not be accurately quantitated by visual examination or manual point counting. PicroSirius Red quantitation demonstrated superior collagen deposition detection due to the ability to consider all images within each section. QuHAnT dramatically reduced analysis time and facilitated the comprehensive assessment of features improving accuracy and sensitivity and represents a complementary tool for tissue/cellular features that are difficult and tedious to assess via subjective or semiquantitative methods. PMID:25274660

  15. Reaching the poor with health interventions: programme-incidence analysis of seven randomised trials of women's groups to reduce newborn mortality in Asia and Africa

    PubMed Central

    Houweling, Tanja A J; Morrison, Joanna; Alcock, Glyn; Azad, Kishwar; Das, Sushmita; Hossen, Munir; Kuddus, Abdul; Lewycka, Sonia; Looman, Caspar W; Magar, Bharat Budhathoki; Manandhar, Dharma S; Akter, Mahfuza; Dube, Albert Lazarous Nkhata; Rath, Shibanand; Saville, Naomi; Sen, Aman; Tripathy, Prasanta; Costello, Anthony

    2016-01-01

    Background Efforts to end preventable newborn deaths will fail if the poor are not reached with effective interventions. To understand what works to reach vulnerable groups, we describe and explain the uptake of a highly effective community-based newborn health intervention across social strata in Asia and Africa. Methods We conducted a secondary analysis of seven randomised trials of participatory women's groups to reduce newborn mortality in India, Bangladesh, Nepal and Malawi. We analysed data on 70 574 pregnancies. Socioeconomic and sociodemographic differences in group attendance were tested using logistic regression. Qualitative data were collected at each trial site (225 focus groups, 20 interviews) to understand our results. Results Socioeconomic differences in women's group attendance were small, except for occasional lower attendance by elites. Sociodemographic differences were large, with lower attendance by young primigravid women in African as well as in South Asian sites. The intervention was considered relevant and interesting to all socioeconomic groups. Local facilitators ensured inclusion of poorer women. Embarrassment and family constraints on movement outside the home restricted attendance among primigravid women. Reproductive health discussions were perceived as inappropriate for them. Conclusions Community-based women's groups can help to reach every newborn with effective interventions. Equitable intervention uptake is enhanced when facilitators actively encourage all women to attend, organise meetings at the participants’ convenience and use approaches that are easily understandable for the less educated. Focused efforts to include primigravid women are necessary, working with families and communities to decrease social taboos. PMID:26246540

  16. Dose-dependent influence of buspirone on the activities of selective serotonin reuptake inhibitors in the mouse forced swimming test.

    PubMed

    Redrobe, J P; Bourin, M

    1998-07-01

    Recent clinical data suggest that buspirone may enhance the efficacy and/or reduce the latency to therapeutic effect of selective serotonin reuptake inhibitors (SSRIs) in unipolar major depressive disorder. The present study, using the mouse forced swimming test, was performed to investigate further the mechanisms involved in the potential antidepressant-enhancing effects of buspirone. Prior administration of buspirone (0.06 mg kg(-1), i.p.) significantly enhanced the anti-immobility effects of subactive doses of fluvoxamine (4 mg kg(-1), i.p.; P < 0.01), paroxetine (4 mg kg(-1), i.p.; P < 0.01), citalopram (4 mg kg(-1), i.p.; P < 0.01) and sertraline (2 mg kg(-1), i.p.; P < 0.01) in the forced swimming test. However, pretreatment with buspirone did not induce antidepressant-like effects when tested in combination with fluoxetine (4 mg kg(-1), i.p.). Each antidepressant tested reduced immobility time in the forced swimming test [citalopram (16 mg kg(-1), i.p.; P < 0.01), fluoxetine (32 mg kg(-1), i.p.; P < 0.01), fluvoxamine (32 mg kg(-1), i.p.; P < 0.01), paroxetine (16 mg kg(-1), i.p.; P < 0.01) and sertraline (16 mg kg(-1), i.p.; P < 0.01)]. Pretreatment with buspirone (0.5 mg kg(-1), i.p.), or its major metabolite 1-PP (0.5 mg kg(-1), i.p.), attenuated all SSRI-induced anti-immobility effects (P < 0.01). Concomitant studies of locomotor activity ruled out any stimulant or sedative effects of the interactions. The results of the present study suggested that low dose buspirone enhanced the activity of subactive doses of SSRIs in the mouse forced swimming test, probably via an action at 5-HT1A receptors. On the other hand, a high dose of buspirone attenuated the antidepressant-like effects of active doses of these drugs, possibly via the generation of an active metabolite (1-PP) acting at alpha2-adrenoreceptors.

  17. Effects of ethanol on gene expression in rat bone: transient dose-dependent changes in mRNA levels for matrix proteins, skeletal growth factors, and cytokines are followed by reductions in bone formation.

    PubMed

    Turner, R T; Wronski, T J; Zhang, M; Kidder, L S; Bloomfield, S A; Sibonga, J D

    1998-10-01

    Several studies were performed in female rats to determine dose and time course changes in mRNA levels for matrix proteins in bone after a single administration of ethanol. As expected, dose-dependent transient increases in blood ethanol were measured. Additionally, there was mild hypocalcemia with no change in immunoreactive parathyroid hormone. Coordinated dose-dependent increases in mRNA for type 1 collagen, osteonectin, and osteocalcin were noted in the proximal tibial metaphysis 6 hr after ethanol was given, with the peak values occurring at a dose of 1.2 g/kg (0.4 ml). Similar increases in mRNA levels for matrix proteins were noted in lumbar vertebrae after ethanol treatment. The changes were specific for bone; ethanol had no effect on mRNA levels for matrix proteins in the uterus or liver, although the mRNA concentrations tended to be reduced in uterus. Message levels for several cytokines implicated in the regulation of bone turnover were also assayed; mRNA levels for transforming growth factor-beta1, transforming growth factor-beta2, interferon-gamma, and interleukin-6 were unchanged at doses ranging from 0.14 to 1.7 g/kg. At the highest dose of ethanol, the mRNA level for tumor necrosis factor-alpha was elevated while the level for insulin-like growth factor-1 was reduced. The time course effects of ethanol (0.4 ml dose) were determined in a separate experiment. Ethanol resulted in a transient increase in mRNA levels for the three bone matrix proteins assayed. However, matrix protein synthesis, as determined by incorporation of 3H-proline into the proximal tibial metaphysis, was not changed after 6 hr. The changes in mRNA levels for the matrix proteins were preceded by brief, transient decreases in mRNA levels for interleukin-1beta, interferon-gamma, and migration inhibitory factor, and followed by a more prolonged decrease in the mRNA level for insulin-like growth factor-1. A subsequent study was performed to determine the effects of repetitive daily

  18. Dose-dependent inhibition of Gag cellular immunity by Env in SIV/HIV DNA vaccinated macaques

    PubMed Central

    Valentin, Antonio; Li, Jinyao; Rosati, Margherita; Kulkarni, Viraj; Patel, Vainav; Jalah, Rashmi; Alicea, Candido; Reed, Steven; Sardesai, Niranjan; Berkower, Ira; Pavlakis, George N; Felber, Barbara K

    2015-01-01

    The induction of a balanced immune response targeting the major structural proteins, Gag and Env of HIV, is important for the development of an efficacious vaccine. The use of DNA plasmids expressing different antigens offers the opportunity to test in a controlled manner the influence of different vaccine components on the magnitude and distribution of the vaccine-induced cellular and humoral immune responses. Here, we show that increasing amounts of env DNA results in greatly enhanced Env antibody titers without significantly affecting the levels of anti-Env cellular immune responses. Co-immunization with Env protein further increased antibody levels, indicating that vaccination with DNA only is not sufficient for eliciting maximal humoral responses against Env. In contrast, under high env:gag DNA plasmid ratio, the development of Gag cellular responses was significantly reduced by either SIV or HIV Env, whereas Gag humoral responses were not affected. Our data indicate that a balanced ratio of the 2 key HIV/SIV vaccine components, Gag and Env, is important to avoid immunological interference and to achieve both maximal humoral responses against Env to prevent virus acquisition and maximal cytotoxic T cell responses against Gag to prevent virus spread. PMID:26125521

  19. Dose-dependent effects of cannabis on the neural correlates of error monitoring in frequent cannabis users.

    PubMed

    Kowal, Mikael A; van Steenbergen, Henk; Colzato, Lorenza S; Hazekamp, Arno; van der Wee, Nic J A; Manai, Meriem; Durieux, Jeffrey; Hommel, Bernhard

    2015-11-01

    Cannabis has been suggested to impair the capacity to recognize discrepancies between expected and executed actions. However, there is a lack of conclusive evidence regarding the acute impact of cannabis on the neural correlates of error monitoring. In order to contribute to the available knowledge, we used a randomized, double-blind, between-groups design to investigate the impact of administration of a low (5.5 mg THC) or high (22 mg THC) dose of vaporized cannabis vs. placebo on the amplitudes of the error-related negativity (ERN) and error positivity (Pe) in the context of the Flanker task, in a group of frequent cannabis users (required to use cannabis minimally 4 times a week, for at least 2 years). Subjects in the high dose group (n=18) demonstrated a significantly diminished ERN in comparison to the placebo condition (n=19), whereas a reduced Pe amplitude was observed in both the high and low dose (n=18) conditions, as compared to placebo. The results suggest that a high dose of cannabis may affect the neural correlates of both the conscious (late), as well as the initial automatic processes involved in error monitoring, while a low dose of cannabis might impact only the conscious (late) processing of errors.

  20. Bi-modal dose-dependent cardiac response to tetrahydrobiopterin in pressure-overload induced hypertrophy and heart failure.

    PubMed

    Moens, An L; Ketner, Elizabeth A; Takimoto, Eiki; Schmidt, Tim S; O'Neill, Charles A; Wolin, Michael S; Alp, Nicholas J; Channon, Keith M; Kass, David A

    2011-10-01

    The exogenous administration of tetrahydrobiopterin (BH4), an essential cofactor of nitric oxide synthase (NOS), has been shown to reduce left ventricular hypertrophy, fibrosis, and cardiac dysfunction in mice with pre-established heart disease induced by pressure-overload. In this setting, BH4 re-coupled endothelial NOS (eNOS), with subsequent reduction of NOS-dependent oxidative stress and reversal of maladaptive remodeling. However, recent studies suggest the effective BH4 dosing may be narrower than previously thought, potentially due to its oxidation upon oral consumption. Accordingly, we assessed the dose response of daily oral synthetic sapropterin dihydrochloride (6-R-l-erythro-5,6,7,8-tetrahydrobiopterin, 6R-BH4) on pre-established pressure-overload cardiac disease. Mice (n=64) were administered 0-400mg/kg/d BH4 by ingesting small pre-made pellets (consumed over 15-30 min). In a dose range of 36-200mg/kg/d, 6R-BH4 suppressed cardiac chamber remodeling, hypertrophy, fibrosis, and oxidative stress with pressure-overload. However, at both lower and higher doses, BH4 had less or no ameliorative effects. The effective doses correlated with a higher myocardial BH4/BH2 ratio. However, BH2 rose linearly with dose, and at the 400mg/kg/d, this lowered the BH4/BH2 ratio back toward control. These results expose a potential limitation for the clinical use of BH4, as variability of cellular redox and perhaps heart disease could produce a variable therapeutic window among individuals. This article is part of a special issue entitled ''Key Signaling Molecules in Hypertrophy and Heart Failure.'' PMID:21645517

  1. Brefeldin A induced dose-dependent changes to Golgi structure and function in the rat exocrine pancreas.

    PubMed

    Kömhoff, M; Hollinshead, M; Tooze, J; Kern, H F

    1994-04-01

    We have studied the effect of increasing concentrations of Brefeldin A (BfA) on the rate of secretion in vitro of pulse-labeled proteins and individual enzymes and on the fine structure of the Golgi apparatus in pancreatic acinar cells derived from control rats and from animals stimulated in vivo by feeding a synthetic proteinase inhibitor (FOY 305). A half-maximal inhibition of intracellular transport of newly synthesized proteins was observed at 0.125 microgram/ml BfA which in FOY-stimulated pancreatic lobules was more pronounced. The Golgi apparatus at this low dose of BfA was still preserved and consisted of stacks of narrow cisternae devoid of secretory material. Granule formation from the trans-Golgi network (TGN) was greatly reduced. A nearly complete inhibition of both total protein and individual enzyme transport was observed at 0.5 microgram/ml BfA. This inhibitory effect was more pronounced with enzyme proteins which are transported slowly through the cellular compartments (e.g. lipase) as compared to faster moving proteins (e.g. chymotrypsinogen). The Golgi apparatus at 0.5 microgram/ml BfA was fragmented into clouds of small uniform vesicles which were stained with an antibody directed against TGN 38 and which were surrounded by a network of tubular membranes reacting with an antibody against p58, a marker protein of the intermediate compartment between rough endoplasmic reticulum (RER) and Golgi. Incubation of pancreatic lobules in 10 micrograms/ml BfA led to a disappearance of the small vesicles and a relocation of TGN 38 into the RER, while the tubuloreticular membranes of the intermediate compartment remained unaffected. Aggregates of clathrin cages devoid of membranes accumulated in the area of the previous Golgi vesicles. The inhibitory effect of 0.5 microgram/ml BfA on both intracellular transport and Golgi fine structure was readily reversible within 15 to 30 min upon removal of the drug, but took 1 h or longer after incubation in 5 or 10

  2. Time and Dose-Dependent Effects of Labisia pumila on Bone Oxidative Status of Postmenopausal Osteoporosis Rat Model

    PubMed Central

    Mohd Effendy, Nadia; Shuid, Ahmad Nazrun

    2014-01-01

    Postmenopausal osteoporosis can be associated with oxidative stress and deterioration of antioxidant enzymes. It is mainly treated with estrogen replacement therapy (ERT). Although effective, ERT may cause adverse effects such as breast cancer and pulmonary embolism. Labisia pumila var. alata (LP), a herb used traditionally for women’s health was found to protect against estrogen-deficient osteoporosis. An extensive study was conducted in a postmenopausal osteoporosis rat model using several LP doses and duration of treatments to determine if anti-oxidative mechanisms were involved in its bone protective effects. Ninety-six female Sprague-Dawley rats were randomly divided into six groups; baseline group (BL), sham-operated (Sham), ovariectomised control (OVXC), ovariectomised (OVX) and given 64.5 μg/kg of Premarin (ERT), ovariectomised and given 20 mg/kg of LP (LP20) and ovariectomised and given 100 mg/kg of LP (LP100). The groups were further subdivided to receive their respective treatments via daily oral gavages for three, six or nine weeks of treatment periods. Following euthanization, the femora were dissected out for bone oxidative measurements which include superoxide dismutase (SOD), glutathione peroxidase (GPx) and malondialdehyde (MDA) levels. Results: The SOD levels of the sham-operated and all the treatment groups were significantly higher than the OVX groups at all treatment periods. The GPx level of ERT and LP100 groups at the 9th week of treatment were significantly higher than the baseline and OVX groups. MDA level of the OVX group was significantly higher than all the other groups at weeks 6 and 9. The LP20 and LP100 groups at the 9th week of treatment had significantly lower MDA levels than the ERT group. There were no significant differences between LP20 and LP100 for all parameters. Thus, LP supplementations at both doses, which showed the best results at 9 weeks, may reduce oxidative stress which in turn may prevent bone loss via its anti

  3. BPA exposure during in vitro oocyte maturation results in dose-dependent alterations to embryo development rates, apoptosis rate, sex ratio and gene expression.

    PubMed

    Ferris, Jacqueline; Mahboubi, Kiana; MacLusky, Neil; King, W Allan; Favetta, Laura A

    2016-01-01

    Alterations in the oocyte's environment can negatively affect embryo development. Oocyte quality, which can determine embryonic viability, is easily perturbed, thus factors affecting normal oocyte maturation are a concern. Bisphenol A (BPA) is an endocrine disrupting chemical that elicits a variety of reproductive effects. BPA has previously been found to disrupt meiosis, however the embryonic effects in mammals are not well documented. Here, bovine oocytes were matured in vitro with and without BPA treatment. Resulting embryos exhibited decreased embryonic development rates, increased apoptosis, and a skewed sex ratio. Gene expression in blastocysts was not altered, whereas treatment with 15ng/mL BPA resulted in increased expression of several of the genes studies, however this increase was largely due to a vehicle effect. BPA exposure during oocyte maturation in vitro can therefore, in a dose-dependent way, decrease oocyte and embryo quality and developmental potential and affect gene expression of developmentally important transcripts.

  4. Hepatic lipid profiling of deer mice fed ethanol using {sup 1}H and {sup 31}P NMR spectroscopy: A dose-dependent subchronic study

    SciTech Connect

    Fernando, Harshica; Bhopale, Kamlesh K.; Boor, Paul J.; Ansari, G.A. Shakeel; Kaphalia, Bhupendra S.

    2012-11-01

    Chronic alcohol abuse is a 2nd major cause of liver disease resulting in significant morbidity and mortality. Alcoholic liver disease (ALD) is characterized by a wide spectrum of pathologies starting from fat accumulation (steatosis) in early reversible stage to inflammation with or without fibrosis and cirrhosis in later irreversible stages. Previously, we reported significant steatosis in the livers of hepatic alcohol dehydrogenase (ADH)-deficient (ADH{sup −}) vs. hepatic ADH-normal (ADH{sup +}) deer mice fed 4% ethanol daily for 2 months [Bhopale et al., 2006, Alcohol 39, 179–188]. However, ADH{sup −} deer mice fed 4% ethanol also showed a significant mortality. Therefore, a dose-dependent study was conducted to understand the mechanism and identify lipid(s) involved in the development of ethanol-induced fatty liver. ADH{sup −} and ADH{sup +} deer mice fed 1, 2 or 3.5% ethanol daily for 2 months and fatty infiltration in the livers were evaluated by histology and by measuring dry weights of extracted lipids. Lipid metabolomic changes in extracted lipids were determined by proton ({sup 1}H) and {sup 31}phosphorus ({sup 31}P) nuclear magnetic resonance (NMR) spectroscopy. The NMR data was analyzed by hierarchical clustering (HC) and principle component analysis (PCA) for pattern recognition. Extensive vacuolization by histology and significantly increased dry weights of total lipids found only in the livers of ADH{sup −} deer mice fed 3.5% ethanol vs. pair-fed controls suggest a dose-dependent formation of fatty liver in ADH{sup −} deer mouse model. Analysis of NMR data of ADH{sup −} deer mice fed 3.5% ethanol vs. pair-fed controls shows increases for total cholesterol, esterified cholesterol, fatty acid methyl esters (FAMEs), triacylglycerides and unsaturation, and decreases for free cholesterol, phospholipids and allylic and diallylic protons. Certain classes of neutral lipids (cholesterol esters, fatty acyl chain (-COCH{sub 2}-) and FAMEs) were

  5. The efficacy and safety profile of albumin administration for patients with cirrhosis at high risk of hepatorenal syndrome is dose dependent

    PubMed Central

    Afinogenova, Yuliya; Tapper, Elliot B.

    2015-01-01

    Background: Albumin is a critical component in the standard therapeutic approach to acute renal failure (ARF) and spontaneous bacterial peritonitis (SBP) in the setting of ascites. However, data regarding the safety and minimum effective dose are limited. Methods: We conducted a retrospective review of patients with decompensated cirrhosis who received albumin within the first 48 hours of hospitalization at Beth Israel Deaconess Medical Center between 2010 and 2013. Outcomes included 90-day risk of death or transplantation (primary) and (secondary) complications of albumin infusion (length of stay (LOS) and need for critical care)), all adjusted for comorbidity and severity of illness. Results: We included 169 patients with ARF and 88 patients with SBP. The optimal doses of albumin for a survival benefit were found to be 87.5 g and 100 g in the ARF and SBP cohorts, respectively. The odds ratio (OR) for the 90-day risk of death or liver transplantation associated with the optimal loading dose was 0.36 (95% CI: 0.17–0.76, P = 0.008) and 0.28 (95% CI: 0.07–0.97, P = 0.04) for the ARF and SBP cohorts, respectively. This effect persisted for patients with ARF who had neither hepatorenal syndrome (HRS) nor SBP (OR: 0.13, 95% CI: 0.007–0.79, P = 0.02). LOS (beta coefficient per log albumin dose: 1.69; 95% CI: 0.14–3.24, P = 0.03) and risk of critical care (OR/g albumin: 1.03; 95% CI: 1.01–1.05, P = 0.01) were also dose dependent. Conclusion: Albumin has a dose-dependent effect on both survival and complications in patients with cirrhosis with ARF (HRS and otherwise) and/or SBP. PMID:26178624

  6. Prebiotic fibres dose-dependently increase satiety hormones and alter Bacteroidetes and Firmicutes in lean and obese JCR:LA-cp rats

    PubMed Central

    Parnell, Jill A.; Reimer, Raylene A.

    2013-01-01

    There is a growing interest in modulating gut microbiota with diet in the context of obesity. The purpose of the present study was to evaluate the dose-dependent effects of prebiotics (inulin and oligofructose) on gut satiety hormones, energy expenditure, gastric emptying and gut microbiota. Male lean and obese JCR:LA-cp rats were randomised to either of the following: lean 0 % fibre (LC), lean 10 % fibre (LF), lean 20 % fibre (LHF), obese 0 % fibre (OC), obese 10 % fibre (OF) or obese 20 % fibre (OHF). Body composition, gastric emptying, energy expenditure, plasma satiety hormone concentrations and gut microbiota (using quantitative PCR) were measured. Caecal proglucagon and peptide YY mRNA levels were up-regulated 2-fold in the LF, OF and OHF groups and 3-fold in the LHF group. Ghrelin O-acyltransferase mRNA levels were higher in obese v. lean rats and decreased in the OHF group. Plasma ghrelin response was attenuated in the LHF group. Microbial species measured in the Bacteroidetes division decreased, whereas those in the Firmicutes increased in obese v. lean rats and improved with prebiotic intake. Bifidobacterium and Lactobacillus increased in the OHF v. OC group. Bacteroides and total bacteria negatively correlated with percentage of body fat and body weight. Enterobacteriaceae increased in conjunction with glucose area under the curve (AUC) and glucagon-like peptide-1 AUC. Bacteroides and total bacteria correlated positively with ghrelin AUC yet negatively with insulin AUC and energy intake (P<0·05). Several of the mechanisms through which prebiotics act (food intake, satiety hormones and alterations in gut microbiota) are regulated in a dose-dependent manner. The combined effects of prebiotics may have therapeutic potential for obesity. PMID:21767445

  7. Dose-dependent, Saturable Occupancy of the Metabotropic Glutamate Subtype 5 Receptor by Fenobam as Measured with [11C]ABP688 PET Imaging

    PubMed Central

    KUWABARA, HIROTO; STANSFIELD, KIRSTIE; VALENTINE, HEATHER; ALEXANDER, MOHAB; KUMAR, ANIL; HILTON, JOHN; DANNALS, ROBERT F.; WONG, DEAN F.; GASPARINI, FABRIZIO

    2014-01-01

    Fenobam is a negative allosteric modulator of the metabotropic glutamate receptor subtype 5 (mGluR5) with inverse agonist activity and is expected to contribute to the treatment of neuropsychiatric disorders involving dysfunction of mGluR5 including Fragile × syndrome. This study examined whether [11C]ABP688, an antagonist PET radioligand, competes with fenobam for the same binding site in the non-human primate brain and would allow examination of occupancy-plasma concentration relationships in the evaluation of the drug for target disorders in the human brain. Four paired PET studies with [11C]ABP688 were performed in baboons at a baseline condition and after intravenous treatment with fenobam at different dose levels (0.3 - 1.33 mg/kg). Total distribution volume (VT) and binding potential (BPND) using the cerebellum as a reference region were obtained by the plasma reference graphical method. Then it was examined whether occupancy follows a dose-dependent, saturating pattern that was predicted by a modified first-order Hill equation in individual regions. Baseline regional VT and BPND values agreed with previously published data. Occupancy showed dose-dependent and saturating patterns in individual regions, reaching >90% occupancy at 1.33 mg/kg dose of fenobam in the majority of regions. To our knowledge, this is the first use of PET to characterize the mGluR5 therapeutic drug fenobam. This study demonstrates a proof of principle for determining the in vivo occupancy of fenobam in primates. The results indicate that [11C]ABP688 and PET may be useful for examination of occupancy of mGluR5 by fenobam, which should prove to be useful for designing future studies and treatment of human disease states. PMID:25098663

  8. Prebiotic fibres dose-dependently increase satiety hormones and alter Bacteroidetes and Firmicutes in lean and obese JCR:LA-cp rats.

    PubMed

    Parnell, Jill A; Reimer, Raylene A

    2012-02-01

    There is a growing interest in modulating gut microbiota with diet in the context of obesity. The purpose of the present study was to evaluate the dose-dependent effects of prebiotics (inulin and oligofructose) on gut satiety hormones, energy expenditure, gastric emptying and gut microbiota. Male lean and obese JCR:LA-cp rats were randomised to either of the following: lean 0 % fibre (LC), lean 10 % fibre (LF), lean 20 % fibre (LHF), obese 0 % fibre (OC), obese 10 % fibre (OF) or obese 20 % fibre (OHF). Body composition, gastric emptying, energy expenditure, plasma satiety hormone concentrations and gut microbiota (using quantitative PCR) were measured. Caecal proglucagon and peptide YY mRNA levels were up-regulated 2-fold in the LF, OF and OHF groups and 3-fold in the LHF group. Ghrelin O-acyltransferase mRNA levels were higher in obese v. lean rats and decreased in the OHF group. Plasma ghrelin response was attenuated in the LHF group. Microbial species measured in the Bacteroidetes division decreased, whereas those in the Firmicutes increased in obese v. lean rats and improved with prebiotic intake. Bifidobacterium and Lactobacillus increased in the OHF v. OC group. Bacteroides and total bacteria negatively correlated with percentage of body fat and body weight. Enterobacteriaceae increased in conjunction with glucose area under the curve (AUC) and glucagon-like peptide-1 AUC. Bacteroides and total bacteria correlated positively with ghrelin AUC yet negatively with insulin AUC and energy intake (P < 0·05). Several of the mechanisms through which prebiotics act (food intake, satiety hormones and alterations in gut microbiota) are regulated in a dose-dependent manner. The combined effects of prebiotics may have therapeutic potential for obesity.

  9. Prebiotic fibres dose-dependently increase satiety hormones and alter Bacteroidetes and Firmicutes in lean and obese JCR:LA-cp rats.

    PubMed

    Parnell, Jill A; Reimer, Raylene A

    2012-02-01

    There is a growing interest in modulating gut microbiota with diet in the context of obesity. The purpose of the present study was to evaluate the dose-dependent effects of prebiotics (inulin and oligofructose) on gut satiety hormones, energy expenditure, gastric emptying and gut microbiota. Male lean and obese JCR:LA-cp rats were randomised to either of the following: lean 0 % fibre (LC), lean 10 % fibre (LF), lean 20 % fibre (LHF), obese 0 % fibre (OC), obese 10 % fibre (OF) or obese 20 % fibre (OHF). Body composition, gastric emptying, energy expenditure, plasma satiety hormone concentrations and gut microbiota (using quantitative PCR) were measured. Caecal proglucagon and peptide YY mRNA levels were up-regulated 2-fold in the LF, OF and OHF groups and 3-fold in the LHF group. Ghrelin O-acyltransferase mRNA levels were higher in obese v. lean rats and decreased in the OHF group. Plasma ghrelin response was attenuated in the LHF group. Microbial species measured in the Bacteroidetes division decreased, whereas those in the Firmicutes increased in obese v. lean rats and improved with prebiotic intake. Bifidobacterium and Lactobacillus increased in the OHF v. OC group. Bacteroides and total bacteria negatively correlated with percentage of body fat and body weight. Enterobacteriaceae increased in conjunction with glucose area under the curve (AUC) and glucagon-like peptide-1 AUC. Bacteroides and total bacteria correlated positively with ghrelin AUC yet negatively with insulin AUC and energy intake (P < 0·05). Several of the mechanisms through which prebiotics act (food intake, satiety hormones and alterations in gut microbiota) are regulated in a dose-dependent manner. The combined effects of prebiotics may have therapeutic potential for obesity. PMID:21767445

  10. School Bus Accidents: Reducing Incidents and Injuries

    ERIC Educational Resources Information Center

    Mahoney, Daniel

    2009-01-01

    The number of children injured in nonfatal school bus accidents annually is more than double the number previously estimated. In Ohio alone, approximately 20,800 children younger than 18 were occupants of school buses that were involved in crashes in 2003 and 2004 (McGeehan 2007). Among those children, most had minor or no injuries. However, there…

  11. Ultraviolet radiation cataract: dose dependence

    NASA Astrophysics Data System (ADS)

    Soderberg, Per G.; Loefgren, Stefan

    1994-07-01

    Current safety limits for cataract development after acute exposure to ultraviolet radiation (UVR) are based on experiments analyzing experimental data with a quantal, effect-no effect, dose-response model. The present study showed that intensity of forward light scattering is better described with a continuous dose-response model. It was found that 3, 30 and 300 kJ/m2UVR300nm induces increased light scattering within 6 h. For all three doses the intensity of forward light scattering was constant after 6 h. The intensity of forward light scattering was proportional to the log dose of UVR300nm. There was a slight increase of the intensity of forward light scattering on the contralateral side in animals that received 300 kJ/m2. Altogether 72 Sprague-Dawley male rats were included. Half of the rats were exposed in vivo on one side to UVR300nm. The other half was kept as a control group, receiving the same treatment as exposed rats but without delivery of UVR300nm to the eye. Subgroups of the rats received either of the three doses. Rats were sacrificed at varying intervals after the exposure. The lenses were extracted and the forward light scattering was estimated. It is concluded that intensity of forward light scattering in the lens after exposure to UVR300nm should be described with a continuous dose-reponse model.

  12. Evaluating the Effectiveness of an Antimicrobial Stewardship Program on Reducing the Incidence Rate of Healthcare-Associated Clostridium difficile Infection: A Non-Randomized, Stepped Wedge, Single-Site, Observational Study

    PubMed Central

    McArthur, Leslie

    2016-01-01

    Background The incidence rate of healthcare-associated Clostridium difficile infection (HA-CDI) is estimated at 1 in 100 patients. Antibiotic exposure is the most consistently reported risk factor for HA-CDI. Strategies to reduce the risk of HA-CDI have focused on reducing antibiotic utilization. Prospective audit and feedback is a commonly used antimicrobial stewardship intervention (ASi). The impact of this ASi on risk of HA-CDI is equivocal. This study examines the effectiveness of a prospective audit and feedback ASi on reducing the risk of HA-CDI. Methods Single-site, 339 bed community-hospital in Barrie, Ontario, Canada. Primary outcome is HA-CDI incidence rate. Daily prospective and audit ASi is the exposure variable. ASi implemented across 6 wards in a non-randomized, stepped wedge design. Criteria for ASi; any intravenous antibiotic use for ≥ 48 hrs, any oral fluoroquinolone or oral second generation cephalosporin use for ≥ 48 hrs, or any antimicrobial use for ≥ 5 days. HA-CDI cases and model covariates were aggregated by ward, year and month starting September 2008 and ending February 2016. Multi-level mixed effect negative binomial regression analysis was used to model the primary outcome, with intercept and slope coefficients for ward-level random effects estimated. Other covariates tested for inclusion in the final model were derived from previously published risk factors. Deviance residuals were used to assess the model’s goodness-of-fit. Findings The dataset included 486 observation periods, of which 350 were control periods and 136 were intervention periods. After accounting for all other model covariates, the estimated overall ASi incidence rate ratio (IRR) was 0.48 (95% 0.30, 0.79). The ASi effect was independent of antimicrobial utilization. The ASi did not seem to reduce the risk of Clostridium difficile infection on the surgery wards (IRR 0.87, 95% CI 0.45, 1.69) compared to the medicine wards (IRR 0.42, 95% CI 0.28, 0.63). The ward

  13. HDL and CER-001 Inverse-Dose Dependent Inhibition of Atherosclerotic Plaque Formation in apoE-/- Mice: Evidence of ABCA1 Down-Regulation

    PubMed Central

    Tardy, Claudine; Goffinet, Marine; Boubekeur, Nadia; Cholez, Guy; Ackermann, Rose; Sy, Gavin; Keyserling, Constance; Lalwani, Narendra; Paolini, John F.; Dasseux, Jean-Louis; Barbaras, Ronald; Baron, Rudi

    2015-01-01

    Objective CER-001 is a novel engineered HDL-mimetic comprised of recombinant human apoA-I and charged phospholipids that was designed to mimic the beneficial properties of nascent pre-ß HDL. In this study, we have evaluated the dose-dependent regulation of ABCA1 expression in vitro and in vivo in the presence of CER-001 and native HDL (HDL3). Methods and Results CER-001 induced cholesterol efflux from J774 macrophages in a dose-dependent manner similar to natural HDL. A strong down-regulation of the ATP-binding cassette A1 (ABCA1) transporter mRNA (- 50%) as well as the ABCA1 membrane protein expression (- 50%) was observed at higher doses of CER-001 and HDL3 compared to non-lipidated apoA-I. In vivo, in an apoE-/- mouse “flow cessation model,” in which the left carotid artery was ligatured to induce local inflammation, the inhibition of atherosclerotic plaque burden progression in response to a dose-range of every-other-day CER-001 or HDL in the presence of a high-fat diet for two weeks was assessed. We observed a U-shaped dose-response curve: inhibition of the plaque total cholesterol content increased with increasing doses of CER-001 or HDL3 up to a maximum inhibition (- 51%) at 5 mg/kg; however, as the dose was increased above this threshold, a progressively less pronounced inhibition of progression was observed, reaching a complete absence of inhibition of progression at doses of 20 mg/kg and over. ABCA1 protein expression in the same atherosclerotic plaque was decreased by-45% and-68% at 50 mg/kg for CER-001 and HDL respectively. Conversely, a-12% and 0% decrease in ABCA1 protein expression was observed at the 5 mg/kg dose for CER-001 and HDL respectively. Conclusions These data demonstrate that high doses of HDL and CER-001 are less effective at slowing progression of atherosclerotic plaque in apoE-/- mice compared to lower doses, following a U-shaped dose-response curve. A potential mechanism for this phenomenon is supported by the observation that

  14. Incidence, risk factors and outcome of de novo tumors in liver transplant recipients focusing on alcoholic cirrhosis

    PubMed Central

    Jiménez-Romero, Carlos; Justo-Alonso, Iago; Cambra-Molero, Félix; Calvo-Pulido, Jorge; García-Sesma, Álvaro; Abradelo-Usera, Manuel; Caso-Maestro, Oscar; Manrique-Municio, Alejandro

    2015-01-01

    Orthotopic liver transplantation (OLT) is an established life-saving procedure for alcoholic cirrhotic (AC) patients, but the incidence of de novo tumors ranges between 2.6% and 15.7% and is significantly increased in comparison with patients who undergo OLT for other etiologies. Tobacco, a known carcinogen, has been reported to be between 52% and 83.3% in AC patients before OLT. Other risk factors that contribute to the development of malignancies are dose-dependent immunosuppression, advanced age, viral infections, sun exposure, and premalignant lesions (inflammatory bowel disease, Barrett’s esophagus). A significantly more frequent incidence of upper aerodigestive (UAD) tract, lung, skin, and kidney-bladder tumors has been found in OLT recipients for AC in comparison with other etiologies. Liver transplant recipients who develop de novo non-skin tumors have a decreased long-term survival rate compared with controls. This significantly lower survival rate is more evident in AC recipients who develop UAD tract or lung tumors after OLT mainly because the diagnosis is usually performed at an advanced stage. All transplant candidates, especially AC patients, should be encouraged to cease smoking and alcohol consumption in the pre- and post-OLT periods, use skin protection, avoid sun exposure and over-immunosuppression, and have a yearly otopharyngolaryngeal exploration and chest computed tomography scan in order to prevent or reduce the incidence of de novo malignancies. Although still under investigation, substitution of calcineurin inhibitors for sirolimus or everolimus may reduce the incidence of de novo tumors after OLT. PMID:25954477

  15. IFN-τ acts in a dose-dependent manner on prostaglandin production by buffalo endometrial stromal cells cultured in vitro.

    PubMed

    Chethan, S G; Singh, S K; Nongsiej, J; Rakesh, H B; Singh, R P; Kumar, N; Agarwal, S K

    2014-06-01

    Interferon-τ (IFN-τ) has been recognized as the primary embryonic signal responsible for maternal recognition of pregnancy. Uterine endometrium produces both prostaglandin F2α (PGF2α ) and prostaglandin E2 (PGE2 ). PGF2α is responsible for the luteolysis; however, PGE2 favours establishment of pregnancy by its luteoprotective action. In this study, the dose-response effect of recombinant bovine IFN-τ (rbIFN-τ) on prostaglandin (PG) production by buffalo endometrial stromal cells cultured in vitro was studied. Buffalo endometrial stromal cells were isolated by double enzymatic digestion, initially with trypsin III followed by a cocktail of trypsin III, collagenase type II and DNase I and subsequently cultured till confluence. Further, cells were treated with different doses of rbIFN-τ (0.001, 0.01, 0.1, 1.0 and 10 μg/ml) and keeping a separate set of control. Culture supernatant was collected after 6, 12 and 24 h of treatment. PG levels in the culture supernatant were measured by enzyme immune assay (EIA) and total cellular protein estimated by Bradford method. Results indicated that buffalo endometrial stromal cells following rbIFN-τ treatment enhanced the secretion of both PGE2 and PGF2α , and also its ratio in a strict dose-dependent manner with a significant increase (p < 0.01) in PGE2 production at 1 μg/ml dose of rbIFN-τ and maximal stimulation for both PG was observed at 10 μg/ml. Further, both PG production and its ratio were increased significantly (p < 0.01) in a time-dependent fashion in all the groups at 6, 12 and 24 h post-treatment with highest level achieved at 24 h as compared with control. Absolute levels of PGE2 remained higher than PGF2α indicating PGE2 as the major PG produced by endometrial stromal cells. The dose-dependent response of rbIFN-τ signifies the importance of optimum concentration of IFN-τ for the embryonic development especially during the critical period to establish successful pregnancy.

  16. Use of a Structured Mirrors Intervention Does Not Reduce Delirium Incidence But May Improve Factual Memory Encoding in Cardiac Surgical ICU Patients Aged Over 70 Years: A Pilot Time-Cluster Randomized Controlled Trial

    PubMed Central

    Giraud, Kimberly; Pontin, Megan; Sharples, Linda D.; Fletcher, Paul; Dalgleish, Tim; Eden, Allaina; Jenkins, David P.; Vuylsteke, Alain

    2016-01-01

    Introduction: Post-operative delirium remains a significant problem, particularly in the older surgical patient. Previous evidence suggests that the provision of supplementary visual feedback about ones environment via the use of a mirror may positively impact on mental status and attention (core delirium diagnostic domains). We aimed to explore whether use of an evidence-based mirrors intervention could be effective in reducing delirium and improving post-operative outcomes such as factual memory encoding of the Intensive Care Unit (ICU) environment in older cardiac surgical patients. Methods: This was a pilot time-cluster randomized controlled trial at a 32-bed ICU, enrolling 223 patients aged 70 years and over, admitted to ICU after elective or urgent cardiac surgery from October 29, 2012 to June 23, 2013. The Mirrors Group received a structured mirrors intervention at set times (e.g., following change in mental status). The Usual Care Group received the standard care without mirrors. Primary outcome was ICU delirium incidence; secondary outcomes were ICU delirium days, ICU days with altered mental status or inattention, total length of ICU stay, physical mobilization (balance confidence) at ICU discharge, recall of factual and delusional ICU memories at 12 weeks, Health-Related Quality of Life at 12 weeks, and acceptability of the intervention. Results: The intervention was not associated with a significant reduction in ICU delirium incidence [Mirrors: 20/115 (17%); Usual Care: 17/108 (16%)] or duration [Mirrors: 1 (1–3); Usual Care: 2 (1–8)]. Use of the intervention on ICU was predictive of significantly higher recall of factual (but not delusional) items at 12 weeks after surgery (p = 0.003) and acceptability was high, with clinicians using mirrors at 86% of all recorded hourly observations. The intervention did not significantly impact on other secondary outcomes. Conclusion: Use of a structured mirrors intervention on the post-operative ICU does not

  17. Phenotype and Hierarchy of Two Transgenic T Cell Lines Targeting the Respiratory Syncytial Virus KdM282-90 Epitope Is Transfer Dose-Dependent.

    PubMed

    Morabito, Kaitlyn M; Erez, Noam; Graham, Barney S; Ruckwardt, Tracy J

    2016-01-01

    In this study, we compared two lines of transgenic CD8+ T cells specific for the same KdM282-90 epitope of respiratory syncytial virus in the CB6F1 hybrid mouse model. Here we found that these two transgenic lines had similar in vivo abilities to control viral load after respiratory syncytial virus infection using adoptive transfer. Transfer of the TRBV13-2 line resulted in higher levels of IL-6 and MIP1-α in the lung than TRBV13-1 transfer. Interestingly, when large numbers of cells were co-transferred, the lines formed a hierarchy, with TRBV13-2 being immunodominant over TRBV13-1 in the mediastinal lymph node despite no identifiable difference in proliferation or apoptosis between the lines. This hierarchy was not established when lower cell numbers were transferred. The phenotype and frequency of proliferating cells were also cell transfer dose-dependent with higher percentages of CD127loCD62LloKLRG1lo and proliferating cells present when lower numbers of cells were transferred. These results illustrate the importance of cell number in adoptive transfer experiments and its influence on the phenotype and hierarchy of the subsequent T cell response. PMID:26752171

  18. Male Sprague-Dawley rats exposed to in utero di(n-butyl) phthalate: dose dependent and age-related morphological changes in Leydig cell smooth endoplasmic reticulum.

    PubMed

    Shirai, Masaru; Wakui, Shin; Wempe, Michael F; Mutou, Tomoko; Oyama, Noriko; Motohashi, Masaya; Takahashi, Hiroyuki; Kansaku, Norio; Asari, Masao; Hano, Hiroshi; Endou, Hitoshi

    2013-01-01

    When 100 mg/kg/day of di(n-butyl) phthalate (DBP) was intragastrically administered to pregnant Sprague-Dawley rats throughout gestation days 12 to 21, the male pups had similar body weights with no apparent physical differences (e.g., litter size, sex ratio) compared to that of the vehicle group. However, prominent age-related morphological alterations in the smooth endoplasmic reticulum (sER) of testicular Leydig cells (LCs) were observed once these animals reached puberty. At weeks 5 to 7, the abundant sER with non-dilated cisternae was distributed in LCs. Subsequently, although the number of LCs significantly increased, the amount of sER was significantly decreased at 9 to 14 weeks of age and had disappeared at 17 weeks. In contrast, the number of LCs and the amount of sER in LCs of the lower dose groups (10, 30, and 50 mg/kg/day) were similar to those of the vehicle group. Further, serum testosterone levels in the 100 mg/kg dose group were significantly lower during 5 to 17 weeks of age. While their luteinizing hormone (LH) level was significantly lower at 5 to 7 weeks of age, it became significantly higher during 9 to 17 weeks. The amount of sER in LCs decreased with age with the increase in LCs proliferation and serum LH levels in rat exposed in utero to DBP in a dose-dependent manner.

  19. Magnetic super-hydrophilic carbon nanotubes/graphene oxide composite as nanocarriers of mesenchymal stem cells: Insights into the time and dose dependences.

    PubMed

    Granato, Alessandro E C; Rodrigues, Bruno V M; Rodrigues-Junior, Dorival M; Marciano, Fernanda R; Lobo, Anderson O; Porcionatto, Marimelia A

    2016-10-01

    Among nanostructured materials, multi-walled carbon nanotubes (MWCNT) have demonstrated great potential for biomedical applications in recent years. After oxygen plasma etching, we can obtain super-hydrophilic MWCNT that contain graphene oxide (GO) at their tips. This material exhibits good dispersion in biological systems due to the presence of polar groups and its excellent magnetic properties due to metal particle residues from the catalyst that often remain trapped in its walls and tips. Here, we show for the first time a careful biological investigation using magnetic superhydrophilic MWCNT/GO (GCN composites). The objective of this study was to investigate the application of GCN for the in vitro immobilization of mesenchymal stem cells. Our ultimate goal was to develop a system to deliver mesenchymal stem cells to different tissues and organs. We show here that mesenchymal stem cells were able to internalize GCN with a consequent migration when subjected to a magnetic field. The cytotoxicity of GCN was time- and dose-dependent. We also observed that GCN internalization caused changes in the gene expression of the proteins involved in cell adhesion and migration, such as integrins, laminins, and the chemokine CXCL12, as well as its receptor CXCR4. These results suggest that GCN represents a potential new platform for mesenchymal stem cell immobilization at injury sites. PMID:27287169

  20. CTLA4 blockade expands FoxP3+ regulatory and activated effector CD4+ T cells in a dose-dependent fashion

    PubMed Central

    Kavanagh, Brian; O'Brien, Shaun; Lee, David; Hou, Yafei; Weinberg, Vivian; Rini, Brian; Allison, James P.; Small, Eric J.

    2008-01-01

    Cytotoxic T lymphocyte–associated antigen 4 (CTLA4) delivers inhibitory signals to activated T cells. CTLA4 is constitutively expressed on regulatory CD4+ T cells (Tregs), but its role in these cells remains unclear. CTLA4 blockade has been shown to induce antitumor immunity. In this study, we examined the effects of anti-CTLA4 antibody on the endogenous CD4+ T cells in cancer patients. We show that CTLA4 blockade induces an increase not only in the number of activated effector CD4+ T cells, but also in the number of CD4+ FoxP3+ Tregs. Although the effects were dose-dependent, CD4+ FoxP3+ regulatory T cells could be expanded at lower antibody doses. In contrast, expansion of effector T cells was seen only at the highest dose level studied. Moreover, these expanded CD4+ FoxP3+ regulatory T cells are induced to proliferate with treatment and possess suppressor function. Our results demonstrate that treatment with anti-CTLA4 antibody does not deplete human CD4+ FoxP3+ Tregs in vivo, but rather may mediate its effects through the activation of effector T cells. Our results also suggest that CTLA4 may inhibit Treg proliferation similar to its role on effector T cells. This study is registered at http://www.clinicaltrials.gov/ct2/show/NCT00064129, registry number NCT00064129. PMID:18523152

  1. Dose-Dependent Effects of CeO2 on Microstructure and Antibacterial Property of Plasma-Sprayed TiO2 Coatings for Orthopedic Application

    NASA Astrophysics Data System (ADS)

    Zhao, Xiaobing; Liu, Gaopeng; Zheng, Hai; Cao, Huiliang; Liu, Xuanyong

    2015-02-01

    Titanium and its alloys have been used extensively for orthopedic and dental implants. Although these devices have achieved high rates of success, two major complications may be encountered: the lack of osseointegration and the biomaterial-related infection. Accordingly, cerium oxide (CeO2)-doped titanium oxide (TiO2) materials were coated on titanium by an atmospheric plasma spraying (APS) technique. The phase structures, morphologies, and surface chemical states of the obtained coatings were characterized by x-ray diffraction, scanning electron microscopy, and x-ray photoelectron spectroscopy techniques. The in vitro antibacterial and cytocompatibility of the materials were studied with Staphylococcus aureus ( S. aureus, ATCC25923) and osteoblast precursor cell line MC3T3-E1. The results indicated that the addition of CeO2 shifts slightly the diffraction peaks of TiO2 matrix to low angles but does not change its rutile phase structure. In addition, the CeO2/TiO2 composite coatings possess dose-dependent corrosion resistance and antimicrobial properties. And doping of 10 wt.% CeO2 exhibits the highest activity against S. aureus, improved corrosion resistance, and competitive cytocompatibility, which argues a promising option for balancing the osteogenetic and antibacterial properties of titanium implants.

  2. Use of dose-dependent absorption into target tissues to more accurately predict cancer risk at low oral doses of hexavalent chromium.

    PubMed

    Haney, J

    2015-02-01

    The mouse dose at the lowest water concentration used in the National Toxicology Program hexavalent chromium (CrVI) drinking water study (NTP, 2008) is about 74,500 times higher than the approximate human dose corresponding to the 35-city geometric mean reported in EWG (2010) and over 1000 times higher than that based on the highest reported tap water concentration. With experimental and environmental doses differing greatly, it is a regulatory challenge to extrapolate high-dose results to environmental doses orders of magnitude lower in a meaningful and toxicologically predictive manner. This seems particularly true for the low-dose extrapolation of results for oral CrVI-induced carcinogenesis since dose-dependent differences in the dose fraction absorbed by mouse target tissues are apparent (Kirman et al., 2012). These data can be used for a straightforward adjustment of the USEPA (2010) draft oral slope factor (SFo) to be more predictive of risk at environmentally-relevant doses. More specifically, the evaluation of observed and modeled differences in the fraction of dose absorbed by target tissues at the point-of-departure for the draft SFo calculation versus lower doses suggests that the draft SFo be divided by a dose-specific adjustment factor of at least an order of magnitude to be less over-predictive of risk at more environmentally-relevant doses.

  3. Delay- and Dose-Dependent Effects of Δ9-Tetrahydrocannabinol Administration on Spatial and Object Working Memory Tasks in Adolescent Rhesus Monkeys

    PubMed Central

    Verrico, Christopher D; Liu, Shijing; Bitler, Elizabeth J; Gu, Hong; Sampson, Allan R; Bradberry, Charles W; Lewis, David A

    2012-01-01

    Among adolescents, the perception that cannabis can cause harm has decreased and use has increased. However, in rodents, cannabinoid administration during adolescence induces working memory (WM) deficits that are more severe than if the same exposure occurs during adulthood. As both object and spatial WM mature in a protracted manner, although apparently along different trajectories, adolescent cannabis users may be more susceptible to impairments in one type of WM. Here, we evaluate the acute effects of a range of doses (30–240 μg/kg) of intravenous Δ9-tetrahydrocannabinol (THC) administration on the performance of spatial and object WM tasks in adolescent rhesus monkeys. Accuracy on the object WM task was not significantly affected by any dose of THC. In contrast, THC administration impaired accuracy on the spatial WM task in a delay- and dose-dependent manner. Importantly, the THC-induced spatial WM deficits were not because of motor or motivational impairments. These data support the idea that immature cognitive functions are more sensitive to the acute effects of THC. PMID:22218091

  4. The local application of a flavonoid, (-)-epicatechin, increases the spiking of globus pallidus neurons in a dose-dependent manner and diminishes the catalepsy induced by haloperidol.

    PubMed

    Alatorre, Alberto; Oviedo-Chávez, Aldo; Villalobos, Nelson; Ríos, Alain; Barrientos, Rafael; Querejeta, Enrique

    2015-02-01

    Flavonoids are natural substances obtained from plants. Most flavonoids cross the blood-brain barrier and exert a wide range of effects on the central nervous system. These actions have been attributed to the modulation of GABA-A receptors. Although motor systems in the central nervous system express a high density of GABA-A receptors, physiological studies about the effects of flavonoids on motor nuclei are scarce. Among the nuclei of the basal ganglia, the globus pallidus is potentially important for the processing of information related to movement. The electrical activity of globus pallidus neurons depends on the GABAergic fibers coming from the striatum and recurrent collateral fibers. It is known that the basal activity of the globus pallidus is modified by blocking dopaminergic receptors. In the present work, we analyzed the effects of the local application of a flavonoid, (-)-epicatechin, on the spiking of globus pallidus neurons in chloral hydrate-anesthetized rats and determined whether (-)-epicatechin applied bilaterally to the globus pallidus can modify the catalepsy induced by systemic administration of haloperidol. The results showed that (-)-epicatechin increased the basal firing of globus pallidus neurons in a dose-dependent manner and antagonized the inhibitory effect of GABA. Bilateral infusion of (-)-epicatechin to the globus pallidus diminished the catalepsy induced by haloperidol. PMID:25503260

  5. The local application of a flavonoid, (-)-epicatechin, increases the spiking of globus pallidus neurons in a dose-dependent manner and diminishes the catalepsy induced by haloperidol.

    PubMed

    Alatorre, Alberto; Oviedo-Chávez, Aldo; Villalobos, Nelson; Ríos, Alain; Barrientos, Rafael; Querejeta, Enrique

    2015-02-01

    Flavonoids are natural substances obtained from plants. Most flavonoids cross the blood-brain barrier and exert a wide range of effects on the central nervous system. These actions have been attributed to the modulation of GABA-A receptors. Although motor systems in the central nervous system express a high density of GABA-A receptors, physiological studies about the effects of flavonoids on motor nuclei are scarce. Among the nuclei of the basal ganglia, the globus pallidus is potentially important for the processing of information related to movement. The electrical activity of globus pallidus neurons depends on the GABAergic fibers coming from the striatum and recurrent collateral fibers. It is known that the basal activity of the globus pallidus is modified by blocking dopaminergic receptors. In the present work, we analyzed the effects of the local application of a flavonoid, (-)-epicatechin, on the spiking of globus pallidus neurons in chloral hydrate-anesthetized rats and determined whether (-)-epicatechin applied bilaterally to the globus pallidus can modify the catalepsy induced by systemic administration of haloperidol. The results showed that (-)-epicatechin increased the basal firing of globus pallidus neurons in a dose-dependent manner and antagonized the inhibitory effect of GABA. Bilateral infusion of (-)-epicatechin to the globus pallidus diminished the catalepsy induced by haloperidol.

  6. The dose-dependent influence of zinc and cadmium contamination of soil on their uptake and glucosinolate content in white cabbage (Brassica oleracea var. capitata f. alba).

    PubMed

    Kusznierewicz, Barbara; Bączek-Kwinta, Renata; Bartoszek, Agnieszka; Piekarska, Anna; Huk, Anna; Manikowska, Anna; Antonkiewicz, Jacek; Namieśnik, Jacek; Konieczka, Piotr

    2012-11-01

    The relationship between the ability to accumulate heavy metals (represented by Cd and Zn) and to synthesize bioactive compounds (represented by glucosinolates [GLS]) was investigated in two cabbage cultivars. Plants were grown in the greenhouse of a phytotron under controlled conditions in soils spiked with two different Zn or Cd concentrations. The measurements of Cd and Zn contents in soil and cabbage (leaf) samples were performed by atomic absorption spectroscopy, whereas GLS levels in cabbage were determined by high-performance liquid chromatography. The ranges of metal contents in soil were 80 to 450 mg/kg dry weight for Zn and 0.3 to 30 mg/kg dry weight for Cd, whereas the levels of accumulated Zn and Cd in cabbage amounted to 15 to 130 and 0.02 to 3 mg/kg dry weight, respectively. After initial symptoms of toxicity, during a later stage of growth, the plants exhibited very good tolerance to both metals. Enhanced biosynthesis of GLS was observed in a dose-dependent manner following exposure to the heavy metals. The GLS content in Zn-exposed cabbage rose from 3.2 to 12 µmol/g dry weight, and the corresponding values for Cd-treated plants were 3.5 to 10 µmol/g dry weight. Thus, the increased soil contamination by metals caused greater accumulation in cabbage, as well as stimulation of GLS biosynthesis. The results obtained point to the high phytoremediation and biofumigation potential of white cabbage.

  7. The serine protease motif of Pic mediates a dose-dependent mucolytic activity after binding to sugar constituents of the mucin substrate.

    PubMed

    Gutiérrez-Jiménez, Javier; Arciniega, Ivonne; Navarro-García, Fernando

    2008-08-01

    The pic gene is harbored on the chromosomes of three important pathogens: enteroaggregative Escherichia coli (EAEC), uropathogenic E. coli (UPEC), and Shigella flexneri. Since Pic is secreted into the intestinal lumen during EAEC infection, we sought to identify intestinal-mucosal substrates for Pic. Pic did not damage epithelial cells, cleave fodrin, or degrade host defense proteins embedded in the mucus layer (sIgA, lactoferrin and lysozyme). However, by using a solid-phase assay to evaluate the mucinolytic activity of EAEC Pic, we documented a specific, dose-dependent mucinolytic activity. A serine protease inhibitor and an enzymatically inactive variant of Pic were used to show that the Pic serine protease motif is required for mucinolytic activity. Pic binds mucin, and this binding was blocked in competition assays using monosaccharide constituents of the oligosaccharide side chains of mucin. Moreover, Pic mucinolytic activity decreased when sialic acid was removed from mucin. Thus, Pic is a mucinase with lectin-like activity that can be related to its reported hemagglutinin activity. Our results suggest that EAEC may secrete Pic into the intestinal lumen as a strategy for penetrating the gel-like mucus layer during EAEC colonization.

  8. Magnetic super-hydrophilic carbon nanotubes/graphene oxide composite as nanocarriers of mesenchymal stem cells: Insights into the time and dose dependences.

    PubMed

    Granato, Alessandro E C; Rodrigues, Bruno V M; Rodrigues-Junior, Dorival M; Marciano, Fernanda R; Lobo, Anderson O; Porcionatto, Marimelia A

    2016-10-01

    Among nanostructured materials, multi-walled carbon nanotubes (MWCNT) have demonstrated great potential for biomedical applications in recent years. After oxygen plasma etching, we can obtain super-hydrophilic MWCNT that contain graphene oxide (GO) at their tips. This material exhibits good dispersion in biological systems due to the presence of polar groups and its excellent magnetic properties due to metal particle residues from the catalyst that often remain trapped in its walls and tips. Here, we show for the first time a careful biological investigation using magnetic superhydrophilic MWCNT/GO (GCN composites). The objective of this study was to investigate the application of GCN for the in vitro immobilization of mesenchymal stem cells. Our ultimate goal was to develop a system to deliver mesenchymal stem cells to different tissues and organs. We show here that mesenchymal stem cells were able to internalize GCN with a consequent migration when subjected to a magnetic field. The cytotoxicity of GCN was time- and dose-dependent. We also observed that GCN internalization caused changes in the gene expression of the proteins involved in cell adhesion and migration, such as integrins, laminins, and the chemokine CXCL12, as well as its receptor CXCR4. These results suggest that GCN represents a potential new platform for mesenchymal stem cell immobilization at injury sites.

  9. Dose-dependent effect of tamoxifen in tamoxifen-resistant breast cancer cells via stimulation by the ERK1/2 and AKT signaling pathways.

    PubMed

    Wang, Li-Juan; Han, Su-Xia; Bai, E; Zhou, Xia; Li, Meng; Jing, Gui-Hua; Zhao, Jing; Yang, An-Gang; Zhu, Qing

    2013-04-01

    The majority of breast cancers undergo progression from an initially endocrine responsive phenotype to an endocrine therapy-resistant phenotype, and acquired resistance to tamoxifen (Tam) is a major clinical problem. In the present study, we aimed to identify the function and mechanism of Tam at different concentrations in cells with acquired Tam resistance. Estrogen-dependent MCF-7 cells were cultured with Tam to generate Tam-resistant (TAM-R) breast cancer cells or in estrogen-free medium to mimic the effects of clinical treatment. In addition, we analyzed the effects of different concentrations of Tam on TAM-R cells by cell counting. Furthermore, the crosstalk between the stimulatory G protein α subunit (Gαs) and the activation of ERK1/2 and AKT in TAM-R cells was examined by small interfering RNA (siRNA) and immunoblotting methods. Low-dose Tam was found to act as an estrogen agonist via stimulation of the ERK1/2 signaling pathway, resulting in acquired resistance to Tam, whereas high-dose Tam inhibited TAM-R cell growth by blocking the activation of ERK1/2 and AKT. Moreover, Gαs was involved in Tam resistance in breast cancer cells. Taken together, our study demonstrated a dose-dependent growth response to Tam in TAM-R cells, which will promote the understanding of the importance of the appropriate use and dosage of Tam in the clinic.

  10. Dietary proanthocyanidins boost hepatic NAD+ metabolism and SIRT1 expression and activity in a dose-dependent manner in healthy rats

    PubMed Central

    Aragonès, Gerard; Suárez, Manuel; Ardid-Ruiz, Andrea; Vinaixa, Maria; Rodríguez, Miguel A.; Correig, Xavier; Arola, Lluís; Bladé, Cinta

    2016-01-01

    Proanthocyanidins (PACs) have been reported to modulate multiple targets by simultaneously controlling many pivotal metabolic pathways in the liver. However, the precise mechanism of PAC action on the regulation of the genes that control hepatic metabolism remains to be clarified. Accordingly, we used a metabolomic approach combining both nuclear magnetic resonance and mass spectrometry analysis to evaluate the changes induced by different doses of grape-seed PACs in the liver of healthy rats. Here, we report that PACs significantly increased the hepatic nicotinamide adenine dinucleotide (NAD+) content in a dose-dependent manner by specifically modulating the hepatic concentrations of the major NAD+ precursors as well as the mRNA levels of the genes that encode the enzymes involved in the cellular metabolism of NAD+. Notably, Sirtuin 1 (Sirt1) gene expression was also significantly up-regulated in a dose-response pattern. The increase in both the NAD+ availability and Sirt1 mRNA levels, in turn, resulted in the hepatic activation of SIRT1, which was significantly associated with improved protection against hepatic triglyceride accumulation. Our data clearly indicates that PAC consumption could be a valid tool to enhance hepatic SIRT1 activity through the modulation of NAD+ levels. PMID:27102823

  11. Superoxide radical-generating compounds activate a predicted promoter site for paraquat-inducible genes of the Chromobacterium violaceum bacterium in a dose-dependent manner.

    PubMed

    Gabriel, J E; Guerra-Slompo, E P; de Souza, E M; de Carvalho, F A L; Madeira, H M F; de Vasconcelos, A T R

    2015-01-01

    The purpose of the present study was to functionally evaluate the influence of superoxide radical-generating compounds on the heterologous induction of a predicted promoter region of open reading frames for paraquat-inducible genes (pqi genes) revealed during genome annotation analyses of the Chromobacterium violaceum bacterium. A 388-bp fragment corresponding to a pqi gene promoter of C. violaceum was amplified using specific primers and cloned into a conjugative vector containing the Escherichia coli lacZ gene without a promoter. Assessments of the expression of the β-galactosidase enzyme were performed in the presence of menadione (MEN) and phenazine methosulfate (PMS) compounds at different final concentrations to evaluate the heterologous activation of the predicted promoter region of interest in C. violaceum induced by these substrates. Under these experimental conditions, the MEN reagent promoted highly significant increases in the expression of the β-galactosidase enzyme modulated by activating the promoter region of the pqi genes at all concentrations tested. On the other hand, significantly higher levels in the expression of the β-galactosidase enzyme were detected exclusively in the presence of the PMS reagent at a final concentration of 50 μg/mL. The findings described in the present study demonstrate that superoxide radical-generating compounds can activate a predicted promoter DNA motif for pqi genes of the C. violaceum bacterium in a dose-dependent manner. PMID:26345950

  12. Dose-dependent impairment of inhibitory avoidance retention in rats by immediate post-training infusion of a mitogen-activated protein kinase kinase inhibitor into cortical structures.

    PubMed

    Walz, R; Roesler, R; Quevedo, J; Rockenbach, I C; Amaral, O B; Vianna, M R; Lenz, G; Medina, J H; Izquierdo, I

    1999-11-15

    Mitogen-activated protein kinase (MAPK) is a serine/threonine protein kinase abundantly expressed in postmitotic neurons of the developed nervous system. MAPK is activated in and required for both the induction of long-term potentiation (LTP) in hippocampal slices and the acquisition of fear conditioning training in rats. The present work was performed in order to test the effect of the specific inhibitor of MAPK kinase (MAPKK), PD 098059, on retention of a step-down inhibitory avoidance (IA). Adult male Wistar rats were bilaterally injected (0.5 microl/side) with PD 098059 (at 0.5, 5, or 50 microM) or vehicle into the entorhinal cortex or into the parietal cortex immediately after IA training using a 0.4 mA footshock. Retention testing was carried out 24 h after training. PD 098059 impaired retention when injected into the entorhinal cortex at the dose of 50 microM, but not at the doses of 5 or 0.5 microM. When infused into the parietal cortex, PD 098059 was amnestic at the doses of 5 and 50 microM. The drug had no effect when infused at the highest dose in either structure 6 h after training. Our results suggest that the MAPKK inhibitor impairs IA retention memory in a dose-dependent manner when injected immediately after training into entorhinal cortex or parietal cortex. The effective dose is variable according to the neocortical structure studied.

  13. Dose-dependent antioxidant responses and pathological changes in tenca (Tinca tinca) after acute oral exposure to Microcystis under laboratory conditions.

    PubMed

    Atencio, L; Moreno, I; Jos, A; Pichardo, S; Moyano, R; Blanco, A; Cameán, A M

    2008-07-01

    The effects of cyanobacterial cells containing microcystins (MCs), toxins from cyanobacteria, on oxidative stress biomarkers from liver and kidney of Tenca fish (Tinca tinca) were investigated under laboratory conditions. Moreover, a histopathological study of liver, kidney, heart and intestine tissues was performed. Fish were orally exposed to cyanobacterial cells dosing 0, 5, 11, 25 and 55 microg MC-LR/fish mixed with the food. Results showed a dose-dependent decrease of superoxide dismutase (SOD) activity, and also of catalase (CAT) in the liver. Glutathione levels and protein oxidation, however, were not altered by the exposure to the cyanobacterial material. The microscopic study revealed tissue alterations even at the lower cyanobacterial cells doses. Onion-like hepatocytes in the liver, glomerulopathy in the kidney, loss of myofibrils in the heart and vacuolated enterocytes in the gastrointestinal tract were the main changes observed. These findings suggest that this fresh water fish can be adversely affected by cyanobacterial blooms in their natural habitats. PMID:18588906

  14. Liver X receptor agonist GW3965 dose-dependently regulates lps-mediated liver injury and modulates posttranscriptional TNF-alpha production and p38 mitogen-activated protein kinase activation in liver macrophages.

    PubMed

    Wang, Yun Yong; Dahle, Maria K; Steffensen, Knut R; Reinholt, Finn P; Collins, Jon L; Thiemermann, Christoph; Aasen, Ansgar O; Gustafsson, Jan-Ake; Wang, Jacob E

    2009-11-01

    Modulation of the host inflammatory response to infection may be a key approach to improve the outcome of patients with sepsis and organ injury. We previously reported that pretreatment of rats with the liver X receptor (LXR) agonist GW3965 reduced the liver injury associated with endotoxemia and attenuated the production of TNF-alpha by rat Kupffer cells. Here, we examine the dose-dependent effect of GW3965 on liver injury and cytokine production in a rat model of endotoxemia and explore the mechanisms underlying TNF-alpha attenuation in Kupffer cells. Low doses of GW3965 (0.1 or 0.3 mg/kg) administered 30 min before infusion of LPS and peptidoglycan significantly attenuated the increase in plasma levels of the liver injury markers alanine aminotransferase and bilirubin (6 h) as well as the inflammatory mediators TNF-alpha (1 h) and prostaglandin E2 (6 h) associated with endotoxemia. In contrast, pretreatment with a higher dose of GW3965 (1.0 mg/kg) had no such effect. Studies in primary cultures of rat Kupffer cells demonstrated that LXR agonist treatment attenuated both the secreted and cell-associated levels of TNF-alpha, whereas TNF-alpha mRNA levels were not altered. Phosphorylated p38 mitogen-activated protein kinase, which plays a major role in production of TNF-alpha at the posttranscriptional level, was attenuated by GW3965 treatment in Kupffer cells. Experiments in murine LXR-deficient Kupffer cells demonstrated enhanced production of TNF-alpha in Kupffer cells from LXR-alpha(-/-) mice when challenged with LPS compared with LXR-beta(-/-) and wild-type Kupffer cells. Taken together, these results argue in favor of a novel mechanism for LXR-mediated attenuation of liver injury by interfering with posttranscriptional regulation of TNF-alpha in Kupffer cells. PMID:19295476

  15. Prevention of soya-induced enteritis in Atlantic salmon (Salmo salar) by bacteria grown on natural gas is dose dependent and related to epithelial MHC II reactivity and CD8α+ intraepithelial lymphocytes.

    PubMed

    Romarheim, Odd H; Hetland, Dyveke L; Skrede, Anders; Øverland, Margareth; Mydland, Liv T; Landsverk, Thor

    2013-03-28

    An experiment was carried out to study the preventive effect of bacterial meal (BM) produced from natural gas against plant-induced enteropathy in Atlantic salmon (Salmo salar). Salmon were fed a diet based on fish meal (FM) or seven diets with 200 g/kg solvent-extracted soyabean meal (SBM) to induce enteritis in combination with increasing levels of BM from 0 to 300 g/kg. Salmon fed a SBM-containing diet without BM developed typical SBM-induced enteritis. The enteritis gradually disappeared with increasing inclusion of BM. By morphometry, no significant (P>0.05) differences in the size of stretches stained for proliferating cell nuclear antigen were found with 150 g/kg BM compared with the FM diet. Increasing BM inclusion caused a gradual decline in the number of cluster of differentiation 8 α positive (CD8α+) intraepithelial lymphocytes, and fish fed BM at 200 g/kg or higher revealed no significant difference from the FM diet. Histological sections stained with antibody for MHC class II (MHC II) showed that fish with intestinal inflammation had more MHC II-reactive cells in the lamina propria and submucosa, but less in the epithelium and brush border, compared with fish without inflammation. There were no significant (P>0.05) differences in growth among the diets, but the highest levels of BM slightly reduced protein digestibility and increased the weight of the distal intestine. In conclusion, the prevention of SBM-induced enteritis by BM is dose dependent and related to intestinal levels of MHC II- and CD8α-reactive cells.

  16. The induction of human myeloid derived suppressor cells through hepatic stellate cells is dose-dependently inhibited by the tyrosine kinase inhibitors nilotinib, dasatinib and sorafenib, but not sunitinib.

    PubMed

    Heine, Annkristin; Schilling, Judith; Grünwald, Barbara; Krüger, Achim; Gevensleben, Heidrun; Held, Stefanie Andrea Erika; Garbi, Natalio; Kurts, Christian; Brossart, Peter; Knolle, Percy; Diehl, Linda; Höchst, Bastian

    2016-03-01

    Increased numbers of immunosuppressive myeloid derived suppressor cells (MDSCs) correlate with a poor prognosis in cancer patients. Tyrosine kinase inhibitors (TKIs) are used as standard therapy for the treatment of several neoplastic diseases. However, TKIs not only exert effects on the malignant cell clone itself but also affect immune cells. Here, we investigate the effect of TKIs on the induction of MDSCs that differentiate from mature human monocytes using a new in vitro model of MDSC induction through activated hepatic stellate cells (HSCs). We show that frequencies of monocytic CD14(+)HLA-DR(-/low) MDSCs derived from mature monocytes were significantly and dose-dependently reduced in the presence of dasatinib, nilotinib and sorafenib, whereas sunitinib had no effect. These regulatory effects were only observed when TKIs were present during the early induction phase of MDSCs through activated HSCs, whereas already differentiated MDSCs were not further influenced by TKIs. Neither the MAPK nor the NFκB pathway was modulated in MDSCs when any of the TKIs was applied. When functional analyses were performed, we found that myeloid cells treated with sorafenib, nilotinib or dasatinib, but not sunitinib, displayed decreased suppressive capacity with regard to CD8+ T cell proliferation. Our results indicate that sorafenib, nilotinib and dasatinib, but not sunitinib, decrease the HSC-mediated differentiation of monocytes into functional MDSCs. Therefore, treatment of cancer patients with these TKIs may in addition to having a direct effect on cancer cells also prevent the differentiation of monocytes into MDSCs and thereby differentially modulate the success of immunotherapeutic or other anti-cancer approaches. PMID:26786874

  17. Long-term Results of Carbon Ion Radiation Therapy for Locally Advanced or Unfavorably Located Choroidal Melanoma: Usefulness of CT-based 2-Port Orthogonal Therapy for Reducing the Incidence of Neovascular Glaucoma

    SciTech Connect

    Toyama, Shingo; Tsuji, Hiroshi; Mizoguchi, Nobutaka; Nomiya, Takuma; Kamada, Tadashi; Tokumaru, Sunao; Mizota, Atsushi; Ohnishi, Yoshitaka; Tsujii, Hirohiko

    2013-06-01

    Purpose: To determine the long-term results of carbon ion radiation therapy (C-ion RT) in patients with choroidal melanoma, and to assess the usefulness of CT-based 2-port irradiation in reducing the risk of neovascular glaucoma (NVG). Methods and Materials: Between January 2001 and February 2012, a total of 116 patients with locally advanced or unfavorably located choroidal melanoma received CT-based C-ion RT. Of these patients, 114 were followed up for more than 6 months and their data analyzed. The numbers of T3 and T2 patients (International Union Against Cancer [UICC], 5th edition) were 106 and 8, respectively. The total dose of C-ion RT varied from 60 to 85 GyE, with each dose given in 5 fractions. Since October 2005, 2-port therapy (51 patients) has been used in an attempt to reduce the risk of NVG. A dose-volume histogram analysis was also performed in 106 patients. Results: The median follow-up was 4.6 years (range, 0.5-10.6 years). The 5-year overall survival, cause-specific survival, local control, distant metastasis-free survival, and eye retention rates were 80.4% (95% confidence interval 89.0%-71.8%), 82.2% (90.6%-73.8%), 92.8% (98.5%-87.1%), 72.1% (81.9%-62.3%), and 92.8% (98.1%-87.5%), respectively. The overall 5-year NVG incidence rate was 35.9% (25.9%-45.9%) and that of 1-port group and 2-port group were 41.6% (29.3%-54.0%) and 13.9% (3.2%-24.6%) with statistically significant difference (P<.001). The dose-volume histogram analysis showed that the average irradiated volume of the iris-ciliary body was significantly lower in the non-NVG group than in the NVG group at all dose levels, and significantly lower in the 2-port group than in the 1-port group at high dose levels. Conclusions: The long-term results of C-ion RT for choroidal melanoma are satisfactory. CT-based 2-port C-ion RT can be used to reduce the high-dose irradiated volume of the iris-ciliary body and the resulting risk of NVG.

  18. Dose-Dependent Effects on Sphingoid Bases and Cytokines in Chickens Fed Diets Prepared with Fusarium Verticillioides Culture Material Containing Fumonisins

    PubMed Central

    Grenier, Bertrand; Schwartz-Zimmermann, Heidi E.; Caha, Sylvia; Moll, Wulf Dieter; Schatzmayr, Gerd; Applegate, Todd J.

    2015-01-01

    In chickens, the effect of mycotoxins, especially fumonisins (FB), in the gastrointestinal tract (GIT) is not well documented. Thus, this study in broiler chicks determined the effects of consuming diets prepared with Fusarium verticillioides culture material containing FB on intestinal gene expression and on the sphinganine (Sa)/sphingosine (So) ratio (Sa/So; a biomarker of FB effect due to disruption of sphingolipid metabolism). Male broilers were assigned to 6 diets (6 cages/diet; 6 birds/cage) from hatch to 20 days containing 0.4, 5.6, 11.3, 17.5, 47.8, or 104.8 mg FB/kg diet. Exposure to FB altered the Sa/So ratio in all tissues analyzed, albeit to varying extents. Linear dose-responses were observed in the kidney, jejunum and cecum. The liver and the ileum were very sensitive and data fit a cubic and quadratic polynomial model, respectively. Gene expression in the small intestine revealed low but significant upregulations of cytokines involved in the pro-inflammatory, Th1/Th17 and Treg responses, especially at 10 days of age. Interestingly, the cecal tonsils exhibited a biphasic response. Unlike the sphingolipid analysis, the effects seen on gene expression were not dose dependent, even showing more effects when birds were exposed to 11.3 mg FB/kg. In conclusion, this is the first report on the disruption of the sphingolipid metabolism by FB in the GIT of poultry. Further studies are needed to reach conclusions on the biological meaning of the immunomodulation observed in the GIT, but the susceptibility of chickens to intestinal pathogens when exposed to FB, at doses lower than those that would cause overt clinical symptoms, should be addressed. PMID:25871822

  19. Cigarette smoking leads to persistent and dose-dependent alterations of brain activity and connectivity in anterior insula and anterior cingulate.

    PubMed

    Zanchi, Davide; Brody, Arthur L; Montandon, Marie-Louise; Kopel, Rotem; Emmert, Kirsten; Preti, Maria Giulia; Van De Ville, Dimitri; Haller, Sven

    2015-11-01

    Although many smokers try to quit smoking, only about 20-25 percent will achieve abstinence despite 6 months or more of gold-standard treatment. This low success rate suggests long-term changes in the brain related to smoking, which remain poorly understood. We compared ex-smokers to both active smokers and non-smokers using functional magnetic resonance imaging (fMRI) to explore persistent modifications in brain activity and network organization. This prospective and consecutive study includes 18 non-smokers (29.5 ± 6.7 years of age, 11 women), 14 smokers (≥10 cigarettes a day >2 years of smoking, 29.3 ± 6.0 years of age, 10 women) and 14 ex-smokers (>1 year of quitting 30.5 ± 5.7 years of age, 10 women). Participants underwent a block-design fMRI study contrasting smoking cue with control (neutral cue) videos. Data analyses included task-related general linear model, seed-based functional connectivity, voxel-based morphometry (VBM) of gray matter and tract-based spatial statistics (TBSS) of white matter. Smoking cue videos versus control videos activated the right anterior insula in ex-smokers compared with smokers, an effect correlating with cumulative nicotine intake (pack-years). Moreover, ex-smokers had a persistent decrease in functional connectivity between right anterior insula and anterior cingulate cortex (ACC) compared with control participants, but similar to active smokers. Potentially confounding alterations in gray or white matter were excluded in VBM and TBSS analyses. In summary, ex-smokers with long-term nicotine abstinence have persistent and dose-dependent brain network changes notably in the right anterior insula and its connection to the ACC.

  20. Dose-dependent effects of a soluble dietary fibre (pectin) on food intake, adiposity, gut hypertrophy and gut satiety hormone secretion in rats.

    PubMed

    Adam, Clare L; Williams, Patricia A; Garden, Karen E; Thomson, Lynn M; Ross, Alexander W

    2015-01-01

    Soluble fermentable dietary fibre elicits gut adaptations, increases satiety and potentially offers a natural sustainable means of body weight regulation. Here we aimed to quantify physiological responses to graded intakes of a specific dietary fibre (pectin) in an animal model. Four isocaloric semi-purified diets containing 0, 3.3%, 6.7% or 10% w/w apple pectin were offered ad libitum for 8 or 28 days to young adult male rats (n = 8/group). Measurements were made of voluntary food intake, body weight, initial and final body composition by magnetic resonance imaging, final gut regional weights and histology, and final plasma satiety hormone concentrations. In both 8- and 28-day cohorts, dietary pectin inclusion rate was negatively correlated with food intake, body weight gain and the change in body fat mass, with no effect on lean mass gain. In both cohorts, pectin had no effect on stomach weight but pectin inclusion rate was positively correlated with weights and lengths of small intestine and caecum, jejunum villus height and crypt depth, ileum crypt depth, and plasma total glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY) concentrations, and at 8 days was correlated with weight and length of colon and with caecal mucosal depth. Therefore, the gut's morphological and endocrine adaptations were dose-dependent, occurred within 8 days and were largely sustained for 28 days during continued dietary intervention. Increasing amounts of the soluble fermentable fibre pectin in the diet proportionately decreased food intake, body weight gain and body fat content, associated with proportionately increased satiety hormones GLP-1 and PYY and intestinal hypertrophy, supporting a role for soluble dietary fibre-induced satiety in healthy body weight regulation. PMID:25602757

  1. U-shaped dose-dependent effects of BmK AS, a unique scorpion polypeptide toxin, on voltage-gated sodium channels

    PubMed Central

    Zhu, Mang-Mang; Tao, Jie; Tan, Miao; Yang, Hong-tian; Ji, Yong-Hua

    2009-01-01

    Background and purpose: Buthus martensi Karsch (BmK) AS is a scorpion polypeptide toxin, said to target the voltage-gated sodium channels (VGSCs). However, the mechanism of action of BmK AS on the VGSCs has yet to be defined. Experimental approach: We examined the electrophysiological effects of BmK AS in a wide dose range on the rat brain-type VGSC α-subunit, rNav1.2a, heterologously expressed in Xenopus oocytes and on the VGSCs endogenously expressed in the dorsal root ganglion neuroblastoma ND7-23 cell line. Key results: In the oocytes, BmK AS depolarized the voltage dependence of activation and inactivation of rNav1.2a at 0.1 and 500 nM whereas these parameters were hyperpolarized at 1 nM. In ND7-23 cells, BmK AS hyperpolarized the voltage dependence of activation and inactivation at 0.1, 1 and 100 nM but not 10 nM. BmK AS also hyperpolarized the voltage dependence of recovery from inactivation at 0.1 and 100 nM and slowed the recovery kinetics at all concentrations, but the effects of 1 and 10 nM were relatively smaller than those at 0.1 and 100 nM. Moreover, the inactivation of VGSCs was potentiated by 10 nM BmK AS in both systems, whereas it was inhibited by 0.1 or 100 nM BmK AS in the oocytes or ND7-23 cells respectively. Conclusions and implications: BmK AS modulated the VGSCs in a unique U-shaped dose-dependent manner, which could be due to the opposing effects of binding to two distinct receptor sites on the VGSCs. PMID:19912232

  2. Chronic aspirin via dose-dependent and selective inhibition of cardiac proteasome possibly contributed a potential risk to the ischemic heart.

    PubMed

    Tan, Chunjiang; Chen, Wenlie; Wu, Yanbin; Lin, Jiumao; Lin, Ruhui; Tan, Xuerui; Chen, Songming

    2013-08-01

    Impaired cardiac proteasome has been reported in ischemic heart and heart failure. Recent data highlighted aspirin as an inhibitor of the ubiquitin-proteasome system, however, it's unclear whether it affects cardiac proteasome functions. Myocardial infarction (MI), sham or normal male SD rats were injected intraperitoneally with high (300 mg/kg), low (5 mg/kg) aspirin or saline (control) once a day for seven weeks. Parallel experiments were performed in the hypoxia/reoxygenated human ventricular myocytes. Dose-related increases in heart and ventricular weight, and impaired cardiac functions, were found more exacerbated in the aspirin-treated MI rat hearts than the saline-treated MI counterparts. The activity of 26S, 20S and 19S declined by about 30%, or the 20S proteasome subunits β5, β2 and β1 decreased by 40%, 20% and 30%, respectively, in the MI rats compared with the non-MI rats (P<0.05). Compared with the saline-treated MI rats, 26S and 20S in high or low dose aspirin-treated MI rats further decreased by 30% and 20%, β5 by 30% and 12%, and β1 by 40% and 30%, respectively, and the lost activity was correlated with the compromised cardiac functions or the decreased cell viability. The dose-related and selective inhibition of 26S and 20S proteasome, or the 20S proteasome subunits β5 and β1 by aspirin was comparable to their protein expressions in the MI rats and in the cultured cells. The impaired cardiac proteasome, enhanced by chronic aspirin treatment, attenuated the removal of oxidative and ubiquitinated proteins, and chronic aspirin treatment via selective and dose-dependent inhibition of cardiac proteasome possibly constituted a potential risk to ischemic heart.

  3. Dose-dependent testosterone sensitivity of the steroidal passport and GC-C-IRMS analysis in relation to the UGT2B17 deletion polymorphism.

    PubMed

    Strahm, Emmanuel; Mullen, Jenny E; Gårevik, Nina; Ericsson, Magnus; Schulze, Jenny J; Rane, Anders; Ekström, Lena

    2015-01-01

    The newly implemented Steroid Module of the Athlete Biological Passport has improved doping tests for steroids. A biomarker included in this passport is the urinary testosterone glucuronide to epitestosterone glucuronide (T/E) ratio, a ratio greatly affected by a deletion polymorphism in UGT2B17. Suspect urine doping tests are further analyzed with gas chromatography-combustion-isotope ratio mass spectrometry (GC-C-IRMS) to determine the origin of the androgen. In this study, we investigated the sensitivity of the steroidal module and the IRMS analysis, in subjects administered with three doses of testosterone enanthate (500, 250, and 125 mg), in relation to the UGT2B17 polymorphism. All subjects carrying the UGT2B17 enzyme reached the traditionally used threshold, a T/E ratio of 4, after all three administered doses, whereas none of the subjects devoid of this enzyme reached a T/E of 4. On the other hand, using the athlete biological passport and IRMS analysis, all three doses could be detected to a high degree of sensitivity. The concentrations of all steroids included in the steroidal module were dose dependently increased, except for epitestosterone which decreased independent of dose. The decrease in epitestosterone was significantly associated with circulatory levels of testosterone post dose (rs =0.60 and p=0.007). In conclusion, these results demonstrate that administration of a single dose of 125-500 mg testosterone enanthate could be detected using the athlete biological passport, together with IRMS. Since IRMS is sensitive to testosterone doping independent of UGT2B17 genotype, also very small changes in the steroidal passport should be investigated with IRMS.

  4. Arsenic-induced dose-dependent modulation of the NF-κB/IL-6 axis in thymocytes triggers differential immune responses.

    PubMed

    Choudhury, Sreetama; Gupta, Payal; Ghosh, Sayan; Mukherjee, Sudeshna; Chakraborty, Priyanka; Chatterji, Urmi; Chattopadhyay, Sreya

    2016-05-16

    Arsenic contamination of drinking water is a matter of global concern. Arsenic intake impairs immune responses and leads to a variety of pathological conditions including cancer. In order to understand the intricate tuning of immune responses elicited by chronic exposure to arsenic, a mouse model was established by subjecting mice to different environmentally relevant concentrations of arsenic in drinking water for 30days. Detailed study of the thymus, a primary immune organ, revealed arsenic-mediated tissue damage in both histological specimens and scanning electron micrographs. Analysis of molecular markers of apoptosis by Western blot revealed a dose-dependent activation of the apoptotic cascade. Enzymatic assays supported oxidative stress as an instigator of cell death. Interestingly, assessment of inflammatory responses revealed disparity in the NF-κB/IL-6/STAT3 axis, where it was found that in animals consuming higher amounts of arsenic NF-κB activation did not lead to the classical IL-6 upregulation response. This deviation from the canonical pathway was accompanied with a significant rise in numbers of CD4+ CD25+ FoxP3 expressing cells in the thymus. The cytokine profile of the animals exposed to higher doses of arsenic also indicated an immune-suppressed milieu, thus validating that arsenic shapes the immune environment in context to its dose of exposure and that at higher doses it leads to immune-suppression. Our study establishes a novel role of arsenic in regulating immune homeostasis in context to its dose, where, at higher doses, arsenic related upregulation of NF-κB cascade takes on an alternative role that is correlated with increased immune-suppression.

  5. Dose-dependent testosterone sensitivity of the steroidal passport and GC-C-IRMS analysis in relation to the UGT2B17 deletion polymorphism.

    PubMed

    Strahm, Emmanuel; Mullen, Jenny E; Gårevik, Nina; Ericsson, Magnus; Schulze, Jenny J; Rane, Anders; Ekström, Lena

    2015-01-01

    The newly implemented Steroid Module of the Athlete Biological Passport has improved doping tests for steroids. A biomarker included in this passport is the urinary testosterone glucuronide to epitestosterone glucuronide (T/E) ratio, a ratio greatly affected by a deletion polymorphism in UGT2B17. Suspect urine doping tests are further analyzed with gas chromatography-combustion-isotope ratio mass spectrometry (GC-C-IRMS) to determine the origin of the androgen. In this study, we investigated the sensitivity of the steroidal module and the IRMS analysis, in subjects administered with three doses of testosterone enanthate (500, 250, and 125 mg), in relation to the UGT2B17 polymorphism. All subjects carrying the UGT2B17 enzyme reached the traditionally used threshold, a T/E ratio of 4, after all three administered doses, whereas none of the subjects devoid of this enzyme reached a T/E of 4. On the other hand, using the athlete biological passport and IRMS analysis, all three doses could be detected to a high degree of sensitivity. The concentrations of all steroids included in the steroidal module were dose dependently increased, except for epitestosterone which decreased independent of dose. The decrease in epitestosterone was significantly associated with circulatory levels of testosterone post dose (rs =0.60 and p=0.007). In conclusion, these results demonstrate that administration of a single dose of 125-500 mg testosterone enanthate could be detected using the athlete biological passport, together with IRMS. Since IRMS is sensitive to testosterone doping independent of UGT2B17 genotype, also very small changes in the steroidal passport should be investigated with IRMS. PMID:26198073

  6. Dose-dependent effects on sphingoid bases and cytokines in chickens fed diets prepared with fusarium verticillioides culture material containing fumonisins.

    PubMed

    Grenier, Bertrand; Schwartz-Zimmermann, Heidi E; Caha, Sylvia; Moll, Wulf Dieter; Schatzmayr, Gerd; Applegate, Todd J

    2015-04-13

    In chickens, the effect of mycotoxins, especially fumonisins (FB), in the gastrointestinal tract (GIT) is not well documented. Thus, this study in broiler chicks determined the effects of consuming diets prepared with Fusarium verticillioides culture material containing FB on intestinal gene expression and on the sphinganine (Sa)/sphingosine (So) ratio (Sa/So; a biomarker of FB effect due to disruption of sphingolipid metabolism). Male broilers were assigned to 6 diets (6 cages/diet; 6 birds/cage) from hatch to 20 days containing 0.4, 5.6, 11.3, 17.5, 47.8, or 104.8 mg FB/kg diet. Exposure to FB altered the Sa/So ratio in all tissues analyzed, albeit to varying extents. Linear dose-responses were observed in the kidney, jejunum and cecum. The liver and the ileum were very sensitive and data fit a cubic and quadratic polynomial model, respectively. Gene expression in the small intestine revealed low but significant upregulations of cytokines involved in the pro-inflammatory, Th1/Th17 and Treg responses, especially at 10 days of age. Interestingly, the cecal tonsils exhibited a biphasic response. Unlike the sphingolipid analysis, the effects seen on gene expression were not dose dependent, even showing more effects when birds were exposed to 11.3 mg FB/kg. In conclusion, this is the first report on the disruption of the sphingolipid metabolism by FB in the GIT of poultry. Further studies are needed to reach conclusions on the biological meaning of the immunomodulation observed in the GIT, but the susceptibility of chickens to intestinal pathogens when exposed to FB, at doses lower than those that would cause overt clinical symptoms, should be addressed.

  7. DIMETHYLARSINIC ACID ALTERS EXPRESSION OF OXIDATIVE STRESS AND DNA REPAIR GENES IN A DOSE DEPENDENT MANNER IN THE TRANSITIONAL EPITHELIUM OF THE URINARY BLADDER FROM FEMALE F344 RATS.

    EPA Science Inventory

    Dose-dependent alteration of oxidative stress and DNA repair gene expression by Dimethylarsinic acid [DMA(V)] in transitional epithelium of urinary bladder from female F344 rats.
    Arsenic (As) is a major concern as millions of people are at risk from drinking arsenic contaminat...

  8. Grazing incidence beam expander

    SciTech Connect

    Akkapeddi, P.R.; Glenn, P.; Fuschetto, A.; Appert, Q.; Viswanathan, V.K.

    1985-01-01

    A Grazing Incidence Beam Expander (GIBE) telescope is being designed and fabricated to be used as an equivalent end mirror in a long laser resonator cavity. The design requirements for this GIBE flow down from a generic Free Electron Laser (FEL) resonator. The nature of the FEL gain volume (a thin, pencil-like, on-axis region) dictates that the output beam be very small. Such a thin beam with the high power levels characteristic of FELs would have to travel perhaps hundreds of meters or more before expanding enough to allow reflection from cooled mirrors. A GIBE, on the other hand, would allow placing these optics closer to the gain region and thus reduces the cavity lengths substantially. Results are presented relating to optical and mechanical design, alignment sensitivity analysis, radius of curvature analysis, laser cavity stability analysis of a linear stable concentric laser cavity with a GIBE. Fabrication details of the GIBE are also given.

  9. Dose-dependent misrejoining of radiation-induced DNA double-strand breaks in human fibroblasts: Experimental and theoretical study for high and low LET radiation

    SciTech Connect

    Rydberg, Bjorn; Cooper, Brian; Cooper, Priscilla K.; Holley, William; Chatterjee, Aloke

    2004-11-18

    Misrejoining of DNA double-strand breaks (DSBs) was measured in human primary fibroblasts after exposure to X-rays and high LET particles (He, N and Fe) in the dose range 10-80 Gy. To measure joining of wrong DNA ends, the integrity of a 3.2 Mbp restriction fragment was analyzed directly after exposure and after 16 hr of repair incubation. It was found that the misrejoining frequency for X-rays was non-linearly related to dose, with less probability of misrejoining at low doses than at high doses. The dose dependence for the high LET particles, on the other hand, was closer to being linear, with misrejoining frequencies higher than for X-rays particularly at the lower doses. These experimental results were simulated with a Monte-Carlo approach that includes a cell nucleus model with all 46 chromosomes present, combined with realistic track structure simulations to calculate the geometrical positions of all DSBs induced for each dose. The model assumes that the main determinant for misrejoining probability is the distance between two simultaneously present DSBs. With a Gaussian interaction probability function with distance, it was found that both the low and high LET data could be fitted with an interaction distance (sigma of the Gaussian curve) of 0.25 {micro}m. This is half the distance previously found to best fit chromosomal aberration data in human lymphocytes using the same methods (Holley et al. Radiat. Res . 158, 568-580 (2002)). The discrepancy may indicate inadequacies in the chromosome model, for example insufficient chromosomal overlap, but may also partly be due to differences between fibroblasts and lymphocytes. Although the experimental data was obtained at high doses, the Monte Carlo calculations could be extended to lower doses. It was found that a linear component of misrejoining versus dose dominated for doses below 1 Gy for all radiations, including X-rays. The calculated relative biological efficiency (RBE) for misrejoining at this low dose

  10. Long-term, low-level adolescent nicotine exposure produces dose-dependent changes in cocaine sensitivity and reward in adult mice.

    PubMed

    Kelley, Brian M; Rowan, James D

    2004-01-01

    Cigarette smoking by adolescents is a strong predictor of future drug use, abuse, and dependence. While this "gateway drug effect" is assumed to be related to psychosocial factors, data from our laboratory suggests that adolescent nicotine use may permanently disrupt reward systems through changes in dopamine receptor function. Behavioral pharmacological methods known to be indirectly (motor activity) and directly (conditioned-place-preference) related to drug reinforcement were used to examine changes in cocaine sensitivity. Testing was performed on adult mice that were exposed to nicotine (0.3, 1.0, and 3.0 mg/kg, SC, M-F, b.i.d.) or saline during adolescence (postnatal days 25-57). Prior to testing, subjects had a 28 day drug-free, time-off period. After acclimation to the testing apparatus, the locomotor effects (30 min, 30 cm traveled) of cocaine (5, 10, and 20 mg/kg, IP) were measured daily; cocaine tests were preceded and followed by saline control tests. Following the acute dose-response curve, mice received saline followed by 5 days of 20.0 mg/kg cocaine. Thereafter, mice underwent condition-place-preference testing. A pre-test was performed to determine compartment preference (i.e., no injection, 20 min test). Cocaine (10 mg/kg, IP) was paired with the subjects non-preferred side and saline with the other. Conditioning sessions were conducted for 8 days with the order of drug/saline injections counter-balanced across subjects. A drug-free, post-test occurred on the day following the final conditioning session. A dose-dependent relationship between adolescent nicotine exposure and cocaine reward was noted in the adult mice across both test conditions. Subjects exposed to nicotine showed an increased response to cocaine's motor activating effects and a decreased response to cocaine's rewarding effects. A follow-up study was undertaken to evaluate dopamine D1, D2, and D3 receptor function in adult mice exposed to the highest dose of nicotine from the first

  11. Incidents of Security Concern

    SciTech Connect

    Atencio, Julian J.

    2014-05-01

    This presentation addresses incidents of security concern and an incident program for addressing them. It addresses the phases of an inquiry, and it divides incidents into categories based on severity and interest types based on whether security, management, or procedural interests are involved. A few scenarios are then analyzed according to these breakdowns.

  12. Cyber Incidents Involving Control Systems

    SciTech Connect

    Robert J. Turk

    2005-10-01

    The Analysis Function of the US-CERT Control Systems Security Center (CSSC) at the Idaho National Laboratory (INL) has prepared this report to document cyber security incidents for use by the CSSC. The description and analysis of incidents reported herein support three CSSC tasks: establishing a business case; increasing security awareness and private and corporate participation related to enhanced cyber security of control systems; and providing informational material to support model development and prioritize activities for CSSC. The stated mission of CSSC is to reduce vulnerability of critical infrastructure to cyber attack on control systems. As stated in the Incident Management Tool Requirements (August 2005) ''Vulnerability reduction is promoted by risk analysis that tracks actual risk, emphasizes high risk, determines risk reduction as a function of countermeasures, tracks increase of risk due to external influence, and measures success of the vulnerability reduction program''. Process control and Supervisory Control and Data Acquisition (SCADA) systems, with their reliance on proprietary networks and hardware, have long been considered immune to the network attacks that have wreaked so much havoc on corporate information systems. New research indicates this confidence is misplaced--the move to open standards such as Ethernet, Transmission Control Protocol/Internet Protocol, and Web technologies is allowing hackers to take advantage of the control industry's unawareness. Much of the available information about cyber incidents represents a characterization as opposed to an analysis of events. The lack of good analyses reflects an overall weakness in reporting requirements as well as the fact that to date there have been very few serious cyber attacks on control systems. Most companies prefer not to share cyber attack incident data because of potential financial repercussions. Uniform reporting requirements will do much to make this information available to

  13. Neonatal ethanol exposure results in dose-dependent impairments in the acquisition and timing of the conditioned eyeblink response and altered cerebellar interpositus nucleus and hippocampal CA1 unit activity in adult rats.

    PubMed

    Lindquist, Derick H; Sokoloff, Greta; Milner, Eric; Steinmetz, Joseph E

    2013-09-01

    Exposure to ethanol in neonatal rats results in reduced neuronal numbers in the cerebellar cortex and deep nuclei of juvenile and adult animals. This reduction in cell numbers is correlated with impaired delay eyeblink conditioning (EBC), a simple motor learning task in which a neutral conditioned stimulus (CS; tone) is repeatedly paired with a co-terminating unconditioned stimulus (US; periorbital shock). Across training, cell populations in the interpositus (IP) nucleus model the temporal form of the eyeblink-conditioned response (CR). The hippocampus, though not required for delay EBC, also shows learning-dependent increases in CA1 and CA3 unit activity. In the present study, rat pups were exposed to 0, 3, 4, or 5 mg/kg/day of ethanol during postnatal days (PD) 4-9. As adults, CR acquisition and timing were assessed during 6 training sessions of delay EBC with a short (280 ms) interstimulus interval (ISI; time from CS onset to US onset) followed by another 6 sessions with a long (880 ms) ISI. Neuronal activity was recorded in the IP and area CA1 during all 12 sessions. The high-dose rats learned the most slowly and, with the moderate-dose rats, produced the longest CR peak latencies over training to the short ISI. The low dose of alcohol impaired CR performance to the long ISI only. The 3E (3 mg/kg/day of ethanol) and 5E (5 mg/kg/day of ethanol) rats also showed slower-than-normal increases in learning-dependent excitatory unit activity in the IP and CA1. The 4E (4 mg/kg/day of ethanol) rats showed a higher rate of CR production to the long ISI and enhanced IP and CA1 activation when compared to the 3E and 5E rats. The results indicate that binge-like ethanol exposure in neonatal rats induces long-lasting, dose-dependent deficits in CR acquisition and timing and diminishes conditioning-related neuronal excitation in both the cerebellum and hippocampus.

  14. Doxycycline Prophylaxis to Reduce Incident Syphilis among HIV-Infected Men who have Sex with Men who Continue to Engage in High Risk Sex: A Randomized, Controlled Pilot Study

    PubMed Central

    Bolan, Robert K.; Beymer, Matthew R.; Weiss, Robert E.; Flynn, Risa P.; Leibowitz, Arleen A.; Klausner, Jeffrey D.

    2014-01-01

    Background Incident syphilis infections continue to be especially prevalent among a core group of HIV-infected men who have sex with men (MSM). Because of synergy between syphilis and HIV infections, innovative means for controlling incident syphilis infections are needed. Methods Thirty MSM who had syphilis twice or more since their HIV diagnosis were randomized to receive either daily doxycycline prophylaxis or contingency management (CM) with incentive payments for remaining free of sexually transmitted diseases (STDs). Subjects were tested for the bacterial STDs gonorrhea (NG), chlamydia (CT) and syphilis at Weeks 12, 24, 36 and 48 and completed a behavioral risk questionnaire during each visit to assess number of partners, condom use and drug use since the last visit. Generalized linear mixed models were used to analyze differences between arms in STD incidence and risk behaviors at follow-up. Results Doxycycline arm subjects were significantly less likely to test positive for any selected bacterial STD during 48 weeks of follow-up (OR: 0.27; CI: 0.09-0.83) compared to CM arm subjects (p = 0.02).There were no significant self-reported risk behavior differences between the Doxycycline and CM arms at follow-up. Conclusions Daily doxycycline taken prophylactically was associated with a decreased incidence of NG, CT, or syphilis incident infections among a core group of HIV-infected MSM at high risk for these infections. Safe and effective biomedical tools should be included in the efforts to control transmission of syphilis, especially in this population. A randomized clinical trial should be conducted to confirm and extend these findings. PMID:25585069

  15. Probiotics reduce symptoms of antibiotic use in a hospital setting: a randomized dose response study.

    PubMed

    Ouwehand, Arthur C; DongLian, Cai; Weijian, Xu; Stewart, Morgan; Ni, Jiayi; Stewart, Tad; Miller, Larry E

    2014-01-16

    Probiotics are known to reduce antibiotic associated diarrhea (AAD) and Clostridium difficile associated diarrhea (CDAD) risk in a strain-specific manner. The aim of this study was to determine the dose-response effect of a four strain probiotic combination (HOWARU(®) Restore) on the incidence of AAD and CDAD and severity of gastrointestinal symptoms in adult in-patients requiring antibiotic therapy. Patients (n=503) were randomized among three study groups: HOWARU(®) Restore probiotic 1.70×10(10) CFU (high-dose, n=168), HOWARU(®) Restore probiotic 4.17×10(9) CFU (low-dose, n=168), or placebo (n=167). Subjects were stratified by gender, age, and duration of antibiotic treatment. Study products were administered daily up to 7 days after the final antibiotic dose. The primary endpoint of the study was the incidence of AAD. Secondary endpoints included incidence of CDAD, diarrhea duration, stools per day, bloody stools, fever, abdominal cramping, and bloating. A significant dose-response effect on AAD was observed with incidences of 12.5, 19.6, and 24.6% with high-dose, low-dose, and placebo, respectively (p=0.02). CDAD was the same in both probiotic groups (1.8%) but different from the placebo group (4.8%; p=0.04). Incidences of fever, abdominal pain, and bloating were lower with increasing probiotic dose. The number of daily liquid stools and average duration of diarrhea decreased with higher probiotic dosage. The tested four strain probiotic combination appears to lower the risk of AAD, CDAD, and gastrointestinal symptoms in a dose-dependent manner in adult in-patients.

  16. Estimating magnitude and duration of incident delays

    SciTech Connect

    Garib, A.; Radwan, A.E.; Al-Deek, H.

    1997-11-01

    Traffic congestion is a major operational problem on urban freeways. In the case of recurring congestion, travelers can plan their trips according to the expected occurrence and severity of recurring congestion. However, nonrecurring congestion cannot be managed without real-time prediction. Evaluating the efficiency of intelligent transportation systems (ITS) technologies in reducing incident effects requires developing models that can accurately predict incident duration along with the magnitude of nonrecurring congestion. This paper provides two statistical models for estimating incident delay and a model for predicting incident duration. The incident delay models showed that up to 85% of variation in incident delay can be explained by incident duration, number of lanes affected, number of vehicles involved, and traffic demand before the incident. The incident duration prediction model showed that 81% of variation in incident duration can be predicted by number of lanes affected, number of vehicles involved, truck involvement, time of day, police response time, and weather condition. These findings have implications for on-line applications within the context of advanced traveler information systems (ATIS).

  17. Diffraction of H from LiF(001): From slow normal incidence to fast grazing incidence

    NASA Astrophysics Data System (ADS)

    Muzas, A. S.; Gatti, F.; Martín, F.; Díaz, C.

    2016-09-01

    Describing diffraction of atomic and molecular projectiles at fast grazing incidence presents a real challenge for quantum theoretical simulations due to the high incidence energy (100 eV-1 keV) used in experiments. This is one of the main reasons why most theoretical simulations performed to date are based on reduced dimensional models. Here we analyze two alternatives to reduce the computational effort, while preserving the real dimensionality of the system. First, we show that grazing incidence conditions are already fulfilled for incidence angles ⩽ 5 ° , i.e., incidence angles higher than those typically used in experiments. Thus, accurate comparisons with experiment can be performed considering diffraction at grazing incidence, but with smaller total incidence energies, whilst keeping the same experimental normal energy in the calculations. Second, we show that diffraction probabilities obtained at fast grazing incidence are fairly well reproduced by simulations performed at slow normal incidence. This latter approach would allow one to simulate several experimental spectra, measured at the same normal incidence energy for several incidence crystallographic directions, with only one calculation. This approach requires to keep the full dimensionality of the system.

  18. Hazard based models for freeway traffic incident duration.

    PubMed

    Tavassoli Hojati, Ahmad; Ferreira, Luis; Washington, Simon; Charles, Phil

    2013-03-01

    Assessing and prioritising cost-effective strategies to mitigate the impacts of traffic incidents and accidents on non-recurrent congestion on major roads represents a significant challenge for road network managers. This research examines the influence of numerous factors associated with incidents of various types on their duration. It presents a comprehensive traffic incident data mining and analysis by developing an incident duration model based on twelve months of incident data obtained from the Australian freeway network. Parametric accelerated failure time (AFT) survival models of incident duration were developed, including log-logistic, lognormal, and Weibul-considering both fixed and random parameters, as well as a Weibull model with gamma heterogeneity. The Weibull AFT models with random parameters were appropriate for modelling incident duration arising from crashes and hazards. A Weibull model with gamma heterogeneity was most suitable for modelling incident duration of stationary vehicles. Significant variables affecting incident duration include characteristics of the incidents (severity, type, towing requirements, etc.), and location, time of day, and traffic characteristics of the incident. Moreover, the findings reveal no significant effects of infrastructure and weather on incident duration. A significant and unique contribution of this paper is that the durations of each type of incident are uniquely different and respond to different factors. The results of this study are useful for traffic incident management agencies to implement strategies to reduce incident duration, leading to reduced congestion, secondary incidents, and the associated human and economic losses.

  19. Hazard based models for freeway traffic incident duration.

    PubMed

    Tavassoli Hojati, Ahmad; Ferreira, Luis; Washington, Simon; Charles, Phil

    2013-03-01

    Assessing and prioritising cost-effective strategies to mitigate the impacts of traffic incidents and accidents on non-recurrent congestion on major roads represents a significant challenge for road network managers. This research examines the influence of numerous factors associated with incidents of various types on their duration. It presents a comprehensive traffic incident data mining and analysis by developing an incident duration model based on twelve months of incident data obtained from the Australian freeway network. Parametric accelerated failure time (AFT) survival models of incident duration were developed, including log-logistic, lognormal, and Weibul-considering both fixed and random parameters, as well as a Weibull model with gamma heterogeneity. The Weibull AFT models with random parameters were appropriate for modelling incident duration arising from crashes and hazards. A Weibull model with gamma heterogeneity was most suitable for modelling incident duration of stationary vehicles. Significant variables affecting incident duration include characteristics of the incidents (severity, type, towing requirements, etc.), and location, time of day, and traffic characteristics of the incident. Moreover, the findings reveal no significant effects of infrastructure and weather on incident duration. A significant and unique contribution of this paper is that the durations of each type of incident are uniquely different and respond to different factors. The results of this study are useful for traffic incident management agencies to implement strategies to reduce incident duration, leading to reduced congestion, secondary incidents, and the associated human and economic losses. PMID:23333698

  20. Incident analysis report

    SciTech Connect

    Gregg, D.W.; Buerer, A.; Leeds, S.

    1996-02-20

    This document presents information about a fire that occurred in January 1996 at Lawrence Livermore National Laboratory. This fire was caused by the spontaneous combustion of 100% fuming nitric acid. Topics discussed include: Summary of the incident; technical background; procedural background; supervision; previous incidents with 100% fuming nitric acid; and judgment of potential hazards.

  1. A mega-analysis of fixed-dose trials reveals dose-dependency and a rapid onset of action for the antidepressant effect of three selective serotonin reuptake inhibitors

    PubMed Central

    Hieronymus, F; Nilsson, S; Eriksson, E

    2016-01-01

    The possible dose-dependency for the antidepressant effect of selective serotonin reuptake inhibitors (SSRIs) remains controversial. We believe we have conducted the first comprehensive patient-level mega-analysis exploring this issue, one incentive being to address the possibility that inclusion of low-dose arms in previous meta-analyses may have caused an underestimation of the efficacy of these drugs. All company-sponsored, acute-phase, placebo-controlled, fixed-dose trials using the Hamilton Depression Rating Scale (HDRS) and conducted to evaluate the effect of citalopram, paroxetine or sertraline in adult major depression were included (11 trials, n=2859 patients). The single-item depressed mood, which has proven a more sensitive measure to detect an antidepressant signal than the sum score of all HDRS items, was designated the primary effect parameter. Doses below or at the lower end of the usually recommended dose range (citalopram: 10–20 mg, paroxetine: 10 mg; sertraline: 50 mg) were superior to placebo but inferior to higher doses, hence confirming a dose-dependency to be at hand. In contrast, among doses above these, there was no indication of a dose–response relationship. The effect size (ES) after exclusion of suboptimal doses was of a more respectable magnitude (0.5) than that usually attributed to the antidepressant effect of the SSRIs. In conclusion, the observation that low doses are less effective than higher ones challenges the oft-cited view that the effect of the SSRIs is not dose-dependent and hence not caused by a specific, pharmacological antidepressant action. Moreover, we suggest that inclusion of suboptimal doses in previous meta-analyses has led to an underestimation of the efficacy of these drugs. PMID:27271860

  2. A mega-analysis of fixed-dose trials reveals dose-dependency and a rapid onset of action for the antidepressant effect of three selective serotonin reuptake inhibitors.

    PubMed

    Hieronymus, F; Nilsson, S; Eriksson, E

    2016-01-01

    The possible dose-dependency for the antidepressant effect of selective serotonin reuptake inhibitors (SSRIs) remains controversial. We believe we have conducted the first comprehensive patient-level mega-analysis exploring this issue, one incentive being to address the possibility that inclusion of low-dose arms in previous meta-analyses may have caused an underestimation of the efficacy of these drugs. All company-sponsored, acute-phase, placebo-controlled, fixed-dose trials using the Hamilton Depression Rating Scale (HDRS) and conducted to evaluate the effect of citalopram, paroxetine or sertraline in adult major depression were included (11 trials, n=2859 patients). The single-item depressed mood, which has proven a more sensitive measure to detect an antidepressant signal than the sum score of all HDRS items, was designated the primary effect parameter. Doses below or at the lower end of the usually recommended dose range (citalopram: 10-20 mg, paroxetine: 10 mg; sertraline: 50 mg) were superior to placebo but inferior to higher doses, hence confirming a dose-dependency to be at hand. In contrast, among doses above these, there was no indication of a dose-response relationship. The effect size (ES) after exclusion of suboptimal doses was of a more respectable magnitude (0.5) than that usually attributed to the antidepressant effect of the SSRIs. In conclusion, the observation that low doses are less effective than higher ones challenges the oft-cited view that the effect of the SSRIs is not dose-dependent and hence not caused by a specific, pharmacological antidepressant action. Moreover, we suggest that inclusion of suboptimal doses in previous meta-analyses has led to an underestimation of the efficacy of these drugs. PMID:27271860

  3. Parathyroid hormone linked to a collagen binding domain (PTH-CBD) promotes hair growth in a mouse model of chemotherapy-induced alopecia in a dose-dependent manner

    PubMed Central

    Katikaneni, Ranjitha; Ponnapakkam, Tulasi; Seymour, Andrew; Sakon, Joshua; Gensure, Robert

    2014-01-01

    Chemotherapy-induced alopecia is a major source of psychological stress in patients undergoing cancer chemotherapy, and can influence treatment decisions. While there is currently no therapy, PTH-CBD, a fusion protein of parathyroid hormone and collagen binding domain, has shown promise in animal models. Objective To determine if there are dose-dependent effects of PTH-CBD on chemotherapy-induced alopecia in a mouse model. Methods C57BL/6J mice were waxed to synchronize hair follicles; treated on day 7 with vehicle or PTH-CBD (100, 320 and 1000 mcg/kg subcutaneous injection); treated on day 9 with vehicle or cyclophosphamide (150 mg/kg i.p.). Mice were photographed every 3–4 days and sacrificed on day 63 for histological analysis. Photographs were quantified by grey scale analysis to assess hair content. Results Mice not receiving chemotherapy showed regrowth of hair 2 weeks following waxing, and normal histology after 2 months. Mice receiving chemotherapy alone showed marked hair loss after chemotherapy, which was sustained for 10 days and was followed by rapid regrowth of a normal coat. Histology revealed rapid cycling dystrophic anagen/catagen follicles. Animals receiving chemotherapy and PTH-CBD showed decreased hair loss and more rapid regrowth of hair than that seen with chemotherapy alone (increased hair growth by grey scale analysis, p<0.05), and the effects were dose dependent. Histologically, hair follicles in animals receiving the highest dose of PTH-CBD were in a quiescent phase, similar to mice which did not receive chemotherapy. Conclusions Single dose subcutaneous administration of PTH-CBD showed dose-dependent effects in minimizing hair loss and speeding recovery from chemotherapy-induced alopecia. PMID:24710191

  4. The dose dependent in vitro responses of MCF-7 and MDA-MB-231 cell lines to extracts of Vatica diospyroides symington type SS fruit include effects on mode of cell death

    PubMed Central

    Srisawat, Theera; Sukpondma, Yaowapa; Graidist, Potchanapond; Chimplee, Siriphon; Kanokwiroon, Kanyanatt

    2015-01-01

    Background: Vatica diospyroides type LS is a known source of valuable compounds for cancer treatment, however, in contrast little is known about therapeutic efficacy of type SS. Objective: This study focused on in vitro cytotoxicity of these fruit extracts, and the cell death mode they induce in breast cancer cells. Materials and Methods: Acetone extracts of fruit were tested for cytotoxicity against MCF-7 and MDA-MB-231 cell lines. The apoptosis and necrosis of these cells were quantified by fluorescence activated cell sorter (FACS) and western blot analyses. Results: After 72 h of treatment, the 50% growth inhibition concentrations (IC50) levels were 16.21 ± 0.13 µg/mL against MCF-7 and 30.0 ± 4.30 µg/mL against MDA-MB-231, indicating high and moderate cytotoxicity, respectively. From the FACS results, we estimate that the cotyledon extract at half IC50 produced 11.7% dead MCF-7 cells via apoptosis, whereas another concentrations both apoptosis and necrosis modes co-existed in a dose-dependent manner. In MDA-MB-231 cell line, only the apoptosis was induced by the pericarp extract in a dose-dependent manner. With the extracts at half IC50 concentration, in both cells, the expression of p21 decreased while that of Bax increased within 12–48 h of dosing, confirming apoptosis induced by time-dependent responses. Apoptosis dependent on p53 was found in MCF-7, whereas the mutant p53 of MDA-MB-231 cells was expressed. Conclusion: The results indicate that fruit extracts of V. diospyroides have cytotoxic effects against MCF-7 and MDA-MB-231 cells via apoptosis pathway in a dose-dependent manner. This suggests that the extracts could provide active ingredients for the development, targeting breast cancer therapy. PMID:26109760

  5. Dose dependent inhibitory effect of dietary caraway on 1,2-dimethylhydrazine induced colonic aberrant crypt foci and bacterial enzyme activity in rats.

    PubMed

    Deeptha, Kumaraswami; Kamaleeswari, Muthaiyan; Sengottuvelan, Murugan; Nalini, Namasivayam

    2006-11-01

    Colon cancer has become one of the major causes of cancer mortality. We determined the effect of caraway (Carum carvi L.) on the development of aberrant crypt foci (ACF) and modulation of fecal bacterial enzyme activities in 1,2-dimethylhydrazine (DMH)-induced experimental rat colon carcinogenesis. Male Wistar albino rats were divided into six groups and all the animals were fed 15.8% peanut oil making a total of 20% fat in the diet. Group 1 served as control and group 2 animals received 90 mg/kg body weight caraway p.o. daily for 15 weeks. To induce ACF, DMH (20 mg/kg body weight) was injected subcutaneously once a week for the first four weeks (groups 3-6). In addition caraway was administered at the dose of 30, 60 and 90 mg/kg body weight everyday orally for the entire period of 15 weeks (groups 4-6). First, we analyzed ACF number (incidence), multiplicity and its distribution along the colon in all experimental groups at the end of 15 weeks. Subsequently, we also assayed the fecal bacterial enzyme activities. ACF formation and the fecal bacterial enzyme activities were found to be significantly high in DMH-alone treated group as compared to control group. Caraway supplementation at three different doses significantly suppressed ACF development, bacterial enzyme activities and modulated oxidative stress significantly as compared to the unsupplemented DMH-treated group. Results of our present study indicate that dietary caraway markedly inhibited DMH-induced colon carcinogenesis and the optimal dose of 60 mg/kg body weight was more effective than the other two doses.

  6. Opposite effects of leptin on bone metabolism: a dose-dependent balance related to energy intake and insulin-like growth factor-I pathway.

    PubMed

    Martin, Aline; David, Valentin; Malaval, Luc; Lafage-Proust, Marie-Hélène; Vico, Laurence; Thomas, Thierry

    2007-07-01

    Published data describing leptin effects on bone are at variance with both positive and negative consequences reported. These findings are consistent with a bimodal threshold response to serum leptin levels. To test this theory, two groups of female rats (tail-suspended and unsuspended) were treated with ip leptin at two different doses or vehicle for 14 d. In tail-suspended rats, low-dose leptin compensated the decrease in serum leptin levels observed with suspension and was able to prevent the induced bone loss at both the trabecular and cortical level (assessed by three-dimensional microtomography). In contrast, high-dose leptin inhibited femoral bone growth and reduced bone mass by decreasing bone formation rate and increasing bone resorption in both tail-suspended and unsuspended groups. High- and low-dose leptin administration resulted in a reduced medullar adipocytic volume in all groups. High-dose leptin (but not low) induced a decrease in body-weight abdominal fat mass and serum IGF-I levels. Thus, the observed bone changes at high-dose leptin are at least partly mediated by a leptin-induced energy imbalance. In conclusion, a balance between negative and positive leptin effects on bone is dependent on a bimodal threshold that is triggered by leptin serum concentration. Also, the negative effects of high leptin levels are likely induced by reduced energy intake and related hormonal changes. The respective part of each pathway will be unraveled by additional studies.

  7. An injectable elastin-based gene delivery platform for dose-dependent modulation of angiogenesis and inflammation for critical limb ischemia.

    PubMed

    Dash, Biraja C; Thomas, Dilip; Monaghan, Michael; Carroll, Oliver; Chen, Xizhe; Woodhouse, Kimberly; O'Brien, Timothy; Pandit, Abhay

    2015-10-01

    Critical limb ischemia is a major clinical problem. Despite rigorous treatment regimes, there has been only modest success in reducing the rate of amputations in affected patients. Reduced level of blood flow and enhanced inflammation are the two major pathophysiological changes that occur in the ischemic tissue. The objective of this study was to develop a controlled dual gene delivery system capable of delivering therapeutic plasmid eNOS and IL-10 in a temporal manner. In order to deliver multiple therapeutic genes, an elastin-like polypeptide (ELP) based injectable system was designed. The injectable system was comprised of hollow spheres and an in situ-forming gel scaffold of elastin-like polypeptide capable of carrying gene complexes, with an extended manner release profile. In addition, the ELP based injectable system was used to deliver human eNOS and IL-10 therapeutic genes in vivo. A subcutaneous dose response study showed enhanced blood vessel density in the treatment groups of eNOS (20 μg) and IL-10 (10 μg)/eNOS (20 μg) and reduced inflammation with IL-10 (10 μg) alone. Next, we carried out a hind-limb ischemia model comparing the efficacy of the following interventions; Saline; IL-10, eNOS and IL-10/eNOS. The selected dose of eNOS, exhibited enhanced angiogenesis. IL-10 treatment groups showed reduction in the level of inflammatory cells. Furthermore, we demonstrated that eNOS up-regulated major proangiogenic growth factors such as vascular endothelial growth factors, platelet derived growth factor B, and fibroblast growth factor 1, which may explain the mechanism of this approach. These factors help in formation of a stable vascular network. Thus, ELP injectable system mediating non-viral delivery of human IL10-eNOS is a promising therapy towards treating limb ischemia.

  8. Efficient selenium transfer from mother to offspring in selenoprotein-P-deficient mice enables dose-dependent rescue of phenotypes associated with selenium deficiency.

    PubMed Central

    Schweizer, Ulrich; Michaelis, Marten; Köhrle, Josef; Schomburg, Lutz

    2004-01-01

    Mice deficient in selenoprotein P exhibit a disturbed selenium distribution and reduced activities of other selenoenzymes and display defects in growth and motor co-ordination. We have normalized selenoenzyme activities and rescued the phenotype of mutant mice by supplementing their nursing mothers with sodium selenite. Our results indicate that selenium from inorganic sources can be transferred efficiently via mother's milk to the developing offspring in a form that is both highly bioavailable by target tissues and yet sufficiently safe to prevent overdosages. PMID:14664694

  9. Implications of dose-dependent target tissue absorption for linear and non-linear/threshold approaches in development of a cancer-based oral toxicity factor for hexavalent chromium.

    PubMed

    Haney, J

    2015-07-01

    Dose-dependent changes in target tissue absorption have important implications for determining the most defensible approach for developing a cancer-based oral toxicity factor for hexavalent chromium (CrVI). For example, mouse target tissue absorption per unit dose is an estimated 10-fold lower at the CrVI dose corresponding to the federal maximum contaminant level (MCL) than at the USEPA draft oral slope factor (SFo) point of departure dose. This decreasing target tissue absorption as doses decrease to lower, more environmentally-relevant doses is inconsistent with linear low-dose extrapolation. The shape of the dose-response curve accounting for this toxicokinetic phenomenon would clearly be non-linear. Furthermore, these dose-dependent differences in absorption indicate that the magnitude of risk overestimation by a linear low-dose extrapolation approach (e.g., SFo) increases and is likely to span one or perhaps more orders of magnitude as it is used to predict risk at progressively lower, more environmentally-relevant doses. An additional apparent implication is that no single SFo can reliably predict risk across potential environmental doses (e.g., doses corresponding to water concentrations⩽the federal MCL). A non-linear approach, consistent with available mode of action data, is most scientifically defensible for derivation of an oral toxicity factor for CrVI-induced carcinogenesis.

  10. Methylphenidate has dose-dependent negative effects on rat spermatogenesis: decreased round spermatids and testicular weight and increased p53 expression and apoptosis.

    PubMed

    Cansu, Ali; Ekinci, Ozgür; Ekinci, Ozalp; Serdaroglu, Ayse; Erdogan, Deniz; Coskun, Zafer Kutay; Gürgen, Seren Gulsen

    2011-10-01

    In the present study, we aimed to evaluate the possible effects of methylphenidate on rat testes. Forty-two Wistar rats were randomly distributed into three experimental groups of 14 rats each. For 90 days, each group via gavage received the following: group 1 = tap water (control group), group 2 = 5 mg/kg/day of ritalin (methylphenidate, MPH), and group 3 = 10 mg/kg/day of ritalin. After sacrificing the animals, the body weights as well as the absolute and relative testicular weights were measured. Testes were sampled, fixed, and processed and, by histopathological examination, quantitative morphometric analysis of Sertoli cells, spermatocytes, and spermatids was performed in stages II, V, and XII. Immunohistochemistry was performed for transforming growth factor (TGF)-β1 and p53, and the apoptotic index was assessed through the TUNEL method. Group 2 had a reduction of round spermatids in stage II. Group 3 had reduction in both stage II and stage V spermatids, as well as lower testicular weight. The p53 expression was increased in group 3. In groups 2 and 3, the TGF-β1 expression was reduced and the apoptotic index by TUNEL was increased. Body weights remained stable on either group. Our results showed that methylphenidate might negatively affect spermatogenesis not only by reducing testicular weight and amount of round spermatids but also by increasing apoptotic death and p53 activation. The findings of the study, however, must be cautiously interpreted.

  11. Altitude Modulates Concussion Incidence

    PubMed Central

    Smith, David W.; Myer, Gregory D.; Currie, Dustin W.; Comstock, R. Dawn; Clark, Joseph F.; Bailes, Julian E.

    2013-01-01

    Background: Recent research indicates that the volume and/or pressure of intracranial fluid, a physiology affected by one’s altitude (ie, elevation above sea level), may be associated with the likelihood and/or severity of a concussion. The objective was to employ an epidemiological field investigation to evaluate the relationship between altitude and concussion rate in high school sports. Hypothesis: Because of the physiologies that occur during acclimatization, including a decline in intracranial compliance (a “tighter fit”), increased altitude may be related to a reduction in concussion rates in high school athletes. Study Design: Cohort study; Level of evidence, 3. Methods: Data on concussions and athlete exposures (AEs) between 2005-2006 and 2011-2012 were obtained from a large national sample of high schools (National High School Sports-Related Injury Surveillance System [High School RIO]) and were used to calculate total, competition, and practice concussion rates for aggregated sports and for football only. Results: Altitude of participating schools ranged from 7 to 6903 ft (median, 600 ft), and a total of 5936 concussions occurred in 20,618,915 exposures (2.88 per 10,000 AEs). When concussion rates were dichotomized by altitude using the median, elevated altitude was associated with a reduction in concussion rates overall (rate ratio [RR], 1.31; P < .001), in competition (RR, 1.31; P < .001), and in practice (RR, 1.29; P < .001). Specifically, high school sports played at higher altitude demonstrated a 31% reduction (95% confidence interval [CI], 25%-38%) in the incidence of total reported concussions. Likewise, concussion rates at increased altitude were reduced 30% for overall exposures, 27% for competition exposures, and 28% for practice exposures in football players (P < .001). Conclusion: The results of this epidemiological investigation indicate increased physiological responses to altitude may be associated with a reduction in sports

  12. Genetically Altered Mutant Mouse Models of Guanylyl Cyclase/Natriuretic Peptide Receptor-A Exhibit the Cardiac Expression of Proinflammatory Mediators in a Gene-Dose-Dependent Manner

    PubMed Central

    Vellaichamy, Elangovan; Das, Subhankar; Subramanian, Umadevi; Maeda, Nobuyo

    2014-01-01

    The objective of this study was to examine whether genetically determined differences in the guanylyl cyclase/natriuretic peptide receptor-A gene (Npr1) affect cardiac expression of proinflammatory cytokines, hypertrophic markers, nuclear factor-κB (NF-κB), and activating protein-1 (AP-1) in am Npr1 gene-dose–dependent manner. In the present studies, adult male Npr1 gene-disrupted (Npr1−/−), wild-type (Npr1+/+), and gene-duplicated (Npr1++/++) mice were used. The Npr1−/− mice showed 41 mm Hg higher systolic blood pressure and 60% greater heart weight to body weight (HW/BW) ratio; however, Npr1++/++ mice exhibited 15 mm Hg lower systolic blood pressure and 12% reduced HW/BW ratio compared with Npr1+/+ mice. Significant upregulation of gene expression of proinflammatory cytokines and hypertrophic markers along with enhanced NF-κB/AP-1 binding activities were observed in the Npr1−/− mouse hearts. Conversely, hypertrophic markers and proinflammatory cytokines gene expression as well as NF-κB/AP-1 binding activities were markedly decreased in Npr1++/++ mouse hearts compared with wild-type mice. The ventricular guanylyl cyclase activity and cGMP levels were reduced by 96% and 87%, respectively, in Npr1−/− mice; however, these parameters were amplified by 2.8-fold and 3.8-fold, respectively, in Npr1++/++ mice. Echocardiographic analysis revealed significantly increased fractional shortening in Npr1++/++ mice (P < .05) but greatly decreased in Npr1−/− mice (P < .01) hearts compared with Npr1+/+ mice. The present findings suggest that Npr1 represses the expression of cardiac proinflammatory mediators, hypertrophic markers, and NF-κB/AP-1–mediated mechanisms, which seem to be associated in an Npr1 gene-dose–dependent manner. PMID:24424043

  13. Peroxidised dietary lipids impair intestinal function and morphology of the small intestine villi of nursery pigs in a dose-dependent manner.

    PubMed

    Rosero, David S; Odle, Jack; Moeser, Adam J; Boyd, R Dean; van Heugten, Eric

    2015-12-28

    The objective of this study was to investigate the effect of increasing degrees of lipid peroxidation on structure and function of the small intestine of nursery pigs. A total of 216 pigs (mean body weight was 6·5 kg) were randomly allotted within weight blocks and sex and fed one of five experimental diets for 35 d (eleven pens per treatment with three to four pigs per pen). Treatments included a control diet without added lipid, and diets supplemented with 6 % soyabean oil that was exposed to heat (80°C) and constant oxygen flow (1 litre/min) for 0, 6, 9 and 12 d. Increasing lipid peroxidation linearly reduced feed intake (P<0·001) and weight gain (P=0·024). Apparent faecal digestibility of gross energy (P=0·001) and fat (P<0·001) decreased linearly as the degree of peroxidation increased. Absorption of mannitol (linear, P=0·097) and d-xylose (linear, P=0·089), measured in serum 2 h post gavage with a solution containing 0·2 g/ml of d-xylose and 0·3 g/ml of mannitol, tended to decrease progressively as the peroxidation level increased. Increasing peroxidation also resulted in increased villi height (linear, P<0·001) and crypt depth (quadratic, P=0·005) in the jejunum. Increasing peroxidation increased malondialdehyde concentrations (quadratic, P=0·035) and reduced the total antioxidant capacity (linear, P=0·044) in the jejunal mucosa. In conclusion, lipid peroxidation progressively diminished animal performance and modified the function and morphology of the small intestine of nursery pigs. Detrimental effects were related with the disruption of redox environment of the intestinal mucosa.

  14. Critical incident monitoring in anaesthesia.

    PubMed

    Choy, Y C

    2006-12-01

    Critical incident monitoring in anaesthesia is an important tool for quality improvement and maintenance of high safety standards in anaesthetic services. It is now widely accepted as a useful quality improvement technique for reducing morbidity and mortality in anaesthesia and has become part of the many quality assurance programmes of many general hospitals under the Ministry of Health. Despite wide-spread reservations about its value, critical incident monitoring is a classical qualitative research technique which is particularly useful where problems are complex, contextual and influenced by the interaction of physical, psychological and social factors. Thus, it is well suited to be used in probing the complex factors behind human error and system failure. Human error has significant contributions to morbidities and mortalities in anaesthesia. Understanding the relationships between, errors, incidents and accidents is important for prevention and risk management to reduce harm to patients. Cardiac arrests in the operating theatre (OT) and prolonged stay in recovery, constituted the bulk of reported incidents. Cardiac arrests in OT resulted in significant mortality and involved mostly de-compensated patients and those with unstable cardiovascular functions, presenting for emergency operations. Prolonged-stay in the recovery extended period of observation for ill patients. Prolonged stay in recovery was justifiable in some cases, as these patients needed a longer period of post-operative observation until they were stable enough to return to the ward. The advantages of the relatively low cost, and the ability to provide a comprehensive body of detailed qualitative information, which can be used to develop strategies to prevent and manage existing problems and to plan further initiatives for patient safety makes critical incident monitoring a valuable tool in ensuring patient safety. The contribution of critical incident reporting to the issue of patient safety is

  15. [Incidence of inguinal hernias].

    PubMed

    Michalský, R

    2001-04-01

    Groin hernia operation is the third most frequent operation in the Czech republic. Early recurrence of the hernia after prime operation is a medical failure. The recurrences can arise after all types of operation. Incidence of recurrences, time factors of its genesis and treatment are discussed there.

  16. Critical Incidents in Negotiation.

    ERIC Educational Resources Information Center

    American Association of School Administrators, Washington, DC.

    This report presents imaginary dialogues between a management team and an employee team and critiques the dialogues to emphasize the significance of situations and episodes that can hasten or hamper a settlement at the negotiation table. Three critical incidents are studied within each developmental phase of the negotiation process: (1) procedural…

  17. RAPID INCIDENT RESPONSE FRAMEWORK

    EPA Science Inventory

    Will discuss WERF Contract (RFP# 03-HHE-5PP), Protocols for the Timely Investigation of Potential Health Incidents Associated with Biosolids Land Application, as a member of the project advisory committee. The contractor, University of North Carolina, started work in early June, ...

  18. Incident meteoroid flux density

    NASA Technical Reports Server (NTRS)

    Badadjanov, P. B.; Bibarsov, R. SH.; Getman, V. S.; Kolmakov, V. M.

    1987-01-01

    Complex photographic and radar meteor observations were carried out. Using the available observational data, the density of incident flux of meteoroids was estimated over a wide mass range of 0.001 to 100 g. To avoid the influence of apparatus selectivity a special technique was applied. The main characteristics of this technique are given and discussed.

  19. Dose dependent effects of exercise training and detraining ontotal and regional adiposity in 4,663 men and 1,743

    SciTech Connect

    Williams, Paul T.; Thompson, Paul D.

    2006-01-06

    Objective: To determine if exercise reduces body weight andto examine the dose-response relationships between changes in exerciseand changes in total and regional adiposity. Methods and Results:Questionnaires on weekly running distance and adiposity from a largeprospective study of 3,973 men and 1,444 women who quit running(detraining), 270 men and 146 women who started running (training) and420 men and 153 women who remained sedentary during 7.4 years offollow-up. There were significant inverse relationships between change inthe amount of vigorous exercise (km/wk run) and changes in weight and BMIin men (slope+-SE:-0.039+-0.005 kg and -0.012+-0.002 kg/m2 per km/wk,respectively) and older women (-0.060+-0.018 kg and -0.022+-0.007 kg/m2per km/wk) who quit running, and in initially sedentary men(-0.098+-0.017 kg and -0.032+-0.005 kg/m2 per km/wk) and women(-0.062+-0.023 kg and -0.021+-0.008 kg/m2 per km/wk) who started running.Changes in waist circumference were also inversely related to changes inrunning distance in men who quit (-0.026+-0.005 cm per km/wk) or startedrunning (-0.078+-0.017 cm per km/wk). Conclusions. The initiation andcessation of vigorous exercise decrease and increase body weight andintra-abdominal fat, respectively, and these changes are proportional tothe change in exercise dose.

  20. Quercetin Induces Dose-Dependent Differential Morphological and Proliferative Changes in Rat Uteri in the Presence and in the Absence of Estrogen.

    PubMed

    Shahzad, Huma; Giribabu, Nelli; Sekaran, Muniandy; Salleh, Naguib

    2015-12-01

    Quercetin could have profound effects on uterine morphology and proliferation, which are known to be influenced by estrogen. This study investigated the effect of quercetin on these uterine parameters in the presence and in the absence of estrogen. Ovariectomized adult female rats received peanut oil, quercetin (10, 50, and 100 mg/kg/day), estrogen, or estrogen+quercetin (10, 50, or 100 mg/kg/day) treatment for 7 consecutive days. At the end of the treatment, uteri were harvested for histological and molecular biological analyses. Distribution of proliferative cell nuclear antigen (PCNA) protein in the uterus was observed by immunohistochemistry. Levels of expression of PCNA protein and mRNA in uterine tissue homogenates were determined by Western blotting and real-time polymerase chain reaction, respectively. Our findings indicated that administration of 10 mg/kg/day of quercetin either alone or with estrogen resulted in decreased uterine expression of PCNA protein and mRNA with the percentage of PCNA-positive cells in uterine luminal and glandular epithelia markedly reduced compared with estrogen-only treatment. Changes in uterine morphology were the opposite of changes observed following estrogen treatment. Treatment with 100 mg/kg/day of quercetin either alone or with estrogen resulted in elevated PCNA protein and mRNA expression. In addition, the percentages of PCNA-positive cells in the epithelia, which line the lumen and glands, were increased with morphological features mimicking changes that occur following estrogen treatment. Following 50 mg/kg/day quercetin treatment, the changes observed were in between those changes that occur following 10 and 100 mg/kg/day quercetin treatment. In conclusion, changes in uterine morphology and proliferation following 10 mg/kg/day quercetin treatment could be attributed to quercetin's antiestrogenic properties, while changes that occur following 100 mg/kg/day quercetin treatment could be attributed to

  1. Sertraline behavioral response associates closer and dose-dependently with cortical rather than hippocampal serotonergic activity in the rat forced swim stress.

    PubMed

    Mikail, Hudu G; Dalla, Christina; Kokras, Nikolaos; Kafetzopoulos, Vasilios; Papadopoulou-Daifoti, Z

    2012-09-10

    The rat Forced Swim Test (FST) is widely used to investigate the response to antidepressant treatment. Selective serotonin reuptake inhibitors (SSRIs) elongate swimming duration during the FST, while climbing duration is unaffected. In the present study, we aimed to correlate behavioral effects of the SSRI sertraline in the FST with respective changes in the serotonergic activity of the hippocampus and the prefrontal cortex. Male rats were subjected to the standard FST (two swim sessions in two consecutive days) and between the two sessions they received three i.p. injections of sertraline (10 mg/kg or 40 mg/kg) or vehicle. All rats were killed immediately after the second FST session. Unstressed animals received the same administration schemes and were killed in equivalent time-points. Serotonin and its metabolite 5-HIAA were assayed in the hippocampus and the prefrontal cortex with the use of high-performance liquid chromatography (HPLC-ED) and their ratio 5-HIAA/5-HT was calculated. Sertraline enhanced swimming and decreased immobility duration at both doses. Serotonergic activity was not altered by the 2-day swim stress in either brain region, while subchronic sertraline treatment enhanced 5-HT levels and decreased 5-HIAA/5-HT in the hippocampus and the prefrontal cortex. The serotonin turnover rate (5-HIAA/5-HT ratio) decrease is probably indicative of reduced 5-HT metabolism, as a result of 5-HT reuptake inhibition. This effect was significant in the prefrontal cortex of unstressed rats only after a higher dose of sertraline. In the prefrontal cortex, but not in the hippocampus, immobility duration was negatively correlated with 5-HT tissue levels, whereas swimming duration was positively correlated with 5-HT. These results indicate that after antidepressant treatment, behavior during the FST can be predictive of respective serotonergic changes, especially in the prefrontal cortex.

  2. Reducing risk of Anthracycline-related heart failure after childhood cancer | Division of Cancer Prevention

    Cancer.gov

    DESCRIPTION (provided by applicant): Childhood cancer survivors are at a 15-fold risk of developing heart failure (HF) compared to age-matched controls. There is a strong dose-dependent association between anthracyclines and risk of HF;the incidence approaches 20% at cumulative doses between 300-600 mg/m2, and exceeds 30% for doses >600 mg/m2. Outcome following HF is poor;5-year survival rate is |

  3. Incident duration modeling using flexible parametric hazard-based models.

    PubMed

    Li, Ruimin; Shang, Pan

    2014-01-01

    Assessing and prioritizing the duration time and effects of traffic incidents on major roads present significant challenges for road network managers. This study examines the effect of numerous factors associated with various types of incidents on their duration and proposes an incident duration prediction model. Several parametric accelerated failure time hazard-based models were examined, including Weibull, log-logistic, log-normal, and generalized gamma, as well as all models with gamma heterogeneity and flexible parametric hazard-based models with freedom ranging from one to ten, by analyzing a traffic incident dataset obtained from the Incident Reporting and Dispatching System in Beijing in 2008. Results show that different factors significantly affect different incident time phases, whose best distributions were diverse. Given the best hazard-based models of each incident time phase, the prediction result can be reasonable for most incidents. The results of this study can aid traffic incident management agencies not only in implementing strategies that would reduce incident duration, and thus reduce congestion, secondary incidents, and the associated human and economic losses, but also in effectively predicting incident duration time.

  4. Incident duration modeling using flexible parametric hazard-based models.

    PubMed

    Li, Ruimin; Shang, Pan

    2014-01-01

    Assessing and prioritizing the duration time and effects of traffic incidents on major roads present significant challenges for road network managers. This study examines the effect of numerous factors associated with various types of incidents on their duration and proposes an incident duration prediction model. Several parametric accelerated failure time hazard-based models were examined, including Weibull, log-logistic, log-normal, and generalized gamma, as well as all models with gamma heterogeneity and flexible parametric hazard-based models with freedom ranging from one to ten, by analyzing a traffic incident dataset obtained from the Incident Reporting and Dispatching System in Beijing in 2008. Results show that different factors significantly affect different incident time phases, whose best distributions were diverse. Given the best hazard-based models of each incident time phase, the prediction result can be reasonable for most incidents. The results of this study can aid traffic incident management agencies not only in implementing strategies that would reduce incident duration, and thus reduce congestion, secondary incidents, and the associated human and economic losses, but also in effectively predicting incident duration time. PMID:25530753

  5. Germinated brown rice (GBR) reduces the incidence of aberrant crypt foci with the involvement of β-catenin and COX-2 in azoxymethane-induced colon cancer in rats

    PubMed Central

    2010-01-01

    Chemoprevention has become an important area in cancer research due to the failure of current therapeutic modalities. Epidemiological and preclinical studies have demonstrated that nutrition plays a vital role in the etiology of cancer. This study was conducted to determine the chemopreventive effects of germinated brown rice (GBR) in rats induced with colon cancer. GBR is brown rice that has been claimed to be richer in nutrients compared to the common white rice. The male Sprague Dawley rats (6 weeks of age) were randomly divided into 5 groups: (G1) positive control (with colon cancer, unfed with GBR), (G2) fed with 2.5 g/kg of GBR (GBR (g)/weight of rat (kg)), (G3) fed with 5 g/kg of GBR, (G4) fed with 10 g/kg of GBR and (G5) negative control (without colon cancer, unfed with GBR). GBR was administered orally once daily via gavage after injection of 15 mg/kg of body weight of azoxymethane (AOM) once a week for two weeks, intraperitonially. After 8 weeks of treatment, animals were sacrificed and colons were removed. Colonic aberrant crypt foci (ACF) were evaluated histopathologically. Total number of ACF and AC, and multicrypt of ACF, and the expression of β-catenin and COX-2 reduced significantly (p < 0.05) in all the groups treated with GBR (G2, G3 and G4) compared to the control group (G1). Spearman rank correlation test showed significant positive linear relationship between total β-catenin and COX-2 score (Spearman's rho = 0.616, p = 0.0001). It is demonstrated that GBR inhibits the development of total number of ACF and AC, and multicrypt of ACF, reduces the expression of β-catenin and COX-2, and thus can be a promising dietary supplement in prevention of colon cancer. PMID:20346115

  6. Incidence of dilated cardiomyopathy

    PubMed Central

    Abelmann, Walter H.

    1985-01-01

    Full reliable data on the incidence and prevalence of dilated cardiomyopathy are not available. In the United States, at least 0.7% of cardiac deaths are attributable to cardiomyopathy. Dilated cardiomyopathy probably contributes the great majority of these cases. The mortality rate for cardiomyopathy in males is twice that of females, and for blacks it is 2.4 times that of whites. Cardiomyopathy was diagnosed in 0.67% of patients discharged from hospitals in 1979 with diagnoses of disease of the circulatory system. Cardiomyopathy accounted for 1% of general cardiologists' and for 7% of academic cardiologists' patient encounters. In Scandinavia, population surveys suggested an annual incidence of dilated cardiomyopathy ranging from 0.73 to 7.5 cases per 100,000 population; for Tokyo this figure is 2.6. The prevalence of cardiomyopathy in underdeveloped and in tropical countries is considerably higher than in developed countries.

  7. Regionally selective and dose-dependent effects of the ampakines Org 26576 and Org 24448 on local cerebral glucose utilisation in the mouse as assessed by 14C-2-deoxyglucose autoradiography.

    PubMed

    Jordan, Graeme R; McCulloch, James; Shahid, Mohammed; Hill, David R; Henry, Brian; Horsburgh, Karen

    2005-08-01

    AMPA receptor potentiating drugs (e.g. ampakines) enhance glutamatergic neurotransmission, and may have potential therapeutic consequences in CNS disorders. The neuroanatomical basis of action for these compounds is at present unclear. This study aimed to identify the effects of two novel ampakines, Org 26576 and Org 24448, on local cerebral glucose use (LCGU) in the mouse. C57BL/6J mice received Org 26576 (0.1, 1, 10 mg/kg i.p.) or Org 24448 (3, 10, 30 mg/kg i.p.) or vehicle and LCGU was assessed using 14C-2-deoxyglucose autoradiography. Both compounds produced dose-dependent increases in LCGU with specific regional activation at low doses. Org 26576 (1 mg/kg) produced significant increases in 9 of the 43 areas examined, including the anteroventral and laterodorsal thalamus, cingulate cortex, dentate gyrus and CA3 subfield of the hippocampus. Org 24448 (3 mg/kg) produced significant increases in LCGU in 4 of the 43 regions examined, including the dorsal raphe nucleus, medial lateral habenula, CA1 subfield of the hippocampus and median forebrain bundle. Furthermore, the increases in LCGU observed with both Org 26576 (10 mg/kg) and Org 24448 (10 mg/kg) were blocked by pre-treatment with the AMPA receptor antagonist NBQX (10 mg/kg). These data demonstrate that both Org 26576 and Org 24448 produce dose-dependent AMPA receptor mediated increases in LCGU and provide an anatomical basis suggestive that these drugs may be of use in the treatment of conditions such as depression or schizophrenia.

  8. Life-stage-, sex-, and dose-dependent dietary toxicokinetics and relationship to toxicity of 2,4-dichlorophenoxyacetic acid (2,4-D) in rats: implications for toxicity test dose selection, design, and interpretation.

    PubMed

    Saghir, Shakil A; Marty, Mary S; Zablotny, Carol L; Passage, Julie K; Perala, Adam W; Neal, Barbara H; Hammond, Larry; Bus, James S

    2013-12-01

    Life-stage-dependent toxicity and dose-dependent toxicokinetics (TK) were evaluated in Sprague Dawley rats following dietary exposure to 2,4-dichlorophenoxyacetic acid (2,4-D). 2,4-D renal clearance is impacted by dose-dependent saturation of the renal organic anion transporter; thus, this study focused on identifying inflection points of onset of dietary nonlinear TK to inform dose selection decisions for toxicity studies. Male and female rats were fed 2,4-D-fortified diets at doses to 1600 ppm for 4-weeks premating, <2 weeks during mating, and to test day (TD) 71 to parental (P1) males and to P1 females through gestation/lactation to TD 96. F1 offspring were exposed via milk with continuing diet exposure until postnatal day (PND) 35. As assessed by plasma area under the curve for the time-course plasma concentration, nonlinear TK was observed ≥ 1200 ppm (63 mg/kg/day) for P1 males and between 200 and 400 ppm (14-27 mg/kg/day) for P1 females. Dam milk and pup plasma levels were higher on lactation day (LD) 14 than LD 4. Relative to P1 adults, 2,4-D levels were higher in dams during late gestation/lactation and postweaning pups (PND 21-35) and coincided with elevated intake of diet/kg body weight. Using conventional maximum tolerated dose (MTD) criteria based on body weight changes for dose selection would have resulted in excessive top doses approximately 2-fold higher than those identified incorporating critical TK data. These data indicate that demonstration of nonlinear TK, if present at dose levels substantially above real-world human exposures, is a key dose selection consideration for improving the human relevance of toxicity studies compared with studies employing conventional MTD dose selection strategies.

  9. Education and Training for Major Incidents Through Medical Response to Major Incidents-MRMI course.

    PubMed

    Samardzic, Josip; Hreckovski, Boris; Hasukic, Ismar

    2015-06-01

    Incidence of major incidents nowadays is in constant growth, especially in last decade. Main goal of all health systems is to minimize and prevent tragic outcomes of major incidents, thus reducing morbidity and mortality and psychological and physical suffering. Lessons learned from Major Incidents throughout the World point out that tragical outcomes could be avoided through adequate preparation and planning. Necessity to plan and to educate to response to Major incident is greater than ever. Finally it is legal obligation that every hospital has plan in case of Major Incident. Effective planning must incorporate: identification of risks, methods of prevention, identification of all recourses, anticipation of errors and detailed protocol of response for each participant. Knowledge and skills needed for Major incident situations must be adopted through interactive training and practical exercise ("learning by doing"). That can be achieved by field exercises and by simulation model. Simulation model has many advantages and enables simultaneous education and training of all participants; scene, transport, hospitals, communication and command which than can be evaluated through objective outcomes. The goal is to train medical staff in real time, on position they are assigned to, with available resources in conditions of Major incident.

  10. Recording pressure ulcer risk assessment and incidence.

    PubMed

    Plaskitt, Anne; Heywood, Nicola; Arrowsmith, Michaela

    2015-07-15

    This article reports on the introduction of an innovative computer-based system developed to record and report pressure ulcer risk and incidence at an acute NHS trust. The system was introduced to ensure that all patients have an early pressure ulcer risk assessment, which prompts staff to initiate appropriate management if a pressure ulcer is detected, thereby preventing further patient harm. Initial findings suggest that this electronic process has helped to improve the timeliness and accuracy of data on pressure ulcer risk and incidence. In addition, it has resulted in a reduced number of reported hospital-acquired pressure ulcers.

  11. The Provision of Critical Incident Stress Debriefing Services by EAPs: A Case Study.

    ERIC Educational Resources Information Center

    McWhirter, Ellen Hawley; Linzer, Marc

    1994-01-01

    Provides a description of critical incident stress debriefing (CISD) strategies used after a bank robbery-hostage incident. Intervention intended to reduce the effects of the incident on the employees' morale, health, and productivity. Knowledge of CISD procedures will enable counselors to respond effectively to traumatic incidents in the…

  12. Incident Management: Process into Practice

    ERIC Educational Resources Information Center

    Isaac, Gayle; Moore, Brian

    2011-01-01

    Tornados, shootings, fires--these are emergencies that require fast action by school district personnel, but they are not the only incidents that require risk management. The authors have introduced the National Incident Management System (NIMS) and the Incident Command System (ICS) and assured that these systems can help educators plan for and…

  13. Racist Incident-Based Trauma

    ERIC Educational Resources Information Center

    Bryant-Davis, Thema; Ocampo, Carlota

    2005-01-01

    Racist incidents are potentially traumatizing forms of victimization that may lead to increased psychiatric and psychophysiological symptoms in targets. The magnitude of the problem of racist incidents in the United States is difficult to estimate; however, data from several sources permit the inference that the prevalence of racist incidents,…

  14. When less is more: reducing the incidence of antipsychotic polypharmacy.

    PubMed

    Tucker, William M

    2007-05-01

    In 2003, the New York State Office of Mental Health initiated a program aimed at supporting patient recovery by simplifying antipsychotic regimens. A key component of the program, which has been essential in supporting physician autonomy, was the introduction of a software program, Psychiatric Clinical Knowledge Enhancement System, termed "PSYCKES." This software program enables physicians to visualize at a glance the medication history of each of their patients as well as of their colleagues' patients, as a way of making better-informed decisions. The fiscal impact, in the direction of a significant reduction in antipsychotic polypharmacy, was not lost on policy-makers, who have included $1.3 million in the current state budget for the dissemination of this program. PMID:17522566

  15. Combination chemoprophylaxis and immunoprophylaxis in reducing the incidence of leprosy

    PubMed Central

    Duthie, Malcolm S; Balagon, Marivic F

    2016-01-01

    Leprosy is a complex infectious disease caused by Mycobacterium leprae that is a leading cause of nontraumatic peripheral neuropathy. Current control strategies, with a goal of early diagnosis and treatment in the form of multidrug therapy, have maintained new case reports at ~225,000 per year. Diagnostic capabilities are limited and even with revisions to multidrug therapy regimen, treatment can still require up to a year of daily drug intake. Although alternate chemotherapies or adjunct immune therapies that could provide shorter or simpler treatment regimen appear possible, only a limited number of trials have been conducted. More proactive strategies appear necessary in the drive to elimination. As a prevention strategy, most chemoprophylaxis campaigns to date have provided about a 2-year protective window. Vaccination, in the form of a single bacillus Calmette–Guérin (BCG) immunization, generally provides ~50% reduction in leprosy cases. Adapting control strategies to provide both chemoprophylaxis and immunoprophylaxis has distinct appeal, with chemoprophylaxis theoretically buttressed by vaccination to generate immediate protection that can be sustained in the long term. We also discuss simple assays measuring biomarkers as surrogates for disease development or replacements for invasive, but not particularly sensitive, direct measures of M. leprae infection. Such assays could facilitate the clinical trials required to develop these new chemoprophylaxis, immunoprophylaxis strategies, and transition into wider use. PMID:27175099

  16. Automated Classification of Clinical Incident Types.

    PubMed

    Gupta, Jaiprakash; Koprinska, Irena; Patrick, Jon

    2015-01-01

    We consider the task of automatic classification of clinical incident reports using machine learning methods. Our data consists of 5448 clinical incident reports collected from the Incident Information Management System used by 7 hospitals in the state of New South Wales in Australia. We evaluate the performance of four classification algorithms: decision tree, naïve Bayes, multinomial naïve Bayes and support vector machine. We initially consider 13 classes (incident types) that were then reduced to 12, and show that it is possible to build accurate classifiers. The most accurate classifier was the multinomial naïve Bayes achieving accuracy of 80.44% and AUC of 0.91. We also investigate the effect of class labelling by an ordinary clinician and an expert, and show that when the data is labelled by an expert the classification performance of all classifiers improves. We found that again the best classifier was multinomial naïve Bayes achieving accuracy of 81.32% and AUC of 0.97. Our results show that some classes in the Incident Information Management System such as Primary Care are not distinct and their removal can improve performance; some other classes such as Aggression Victim are easier to classify than others such as Behavior and Human Performance. In summary, we show that the classification performance can be improved by expert class labelling of the training data, removing classes that are not well defined and selecting appropriate machine learning classifiers. PMID:26210423

  17. Influenza A Virus and Influenza B Virus Can Induce Apoptosis via Intrinsic or Extrinsic Pathways and Also via NF-κB in a Time and Dose Dependent Manner

    PubMed Central

    El-Sayed, Ibrahim; Nokaly, Aziz; Abdelghani, Ahmed S.

    2016-01-01

    Influenza viruses are able to cause annual epidemics and pandemics due to their mutation rates and reassortment capabilities leading to antigenic shifts and drifts. To identify host response to influenza A and B viruses on A549 and MDCK II cells at low and high MOIs, expressions of MxA and caspases 3, 8, and 9 and BAD, TNFα, and IκBα genes were measured in the cells supernatants. H1N1 and H3N2 prefer to initially enhance the intrinsic pathway, determined by higher caspase 9 activity in MDCK II cells compared to caspase 8 activity and vice versa in A549 cells at different MOIs, while INF B prefers extrinsic pathway in A549 cells according to significant low or undetectable caspase 9 activity and high activity of caspase 8 but also can induce intrinsic pathway in MDCK II cells as determined by significant low or undetectable activity of caspase 8 and high caspase 9 activity at different MOIs; the considerable MxA expression was found in influenza A and B viruses infected A549 and MDCK II cells at low MOIs. In conclusion, influenza A and B viruses induced extrinsic and intrinsic apoptosis in parallel, and the induction was associated with viral infection in a dose dependent manner. PMID:27042352

  18. Oscillating cascade aerodynamics at large mean incidence

    NASA Technical Reports Server (NTRS)

    Buffum, Daniel H.; King, Aaron J.; El-Aini, Yehia M.; Capece, Vincent R.

    1996-01-01

    The aerodynamics of a cascade of airfoils oscillating in torsion about the midchord is investigated experimentally at a large mean incidence angle and, for reference, at a low mean incidence angle. The airfoil section is representative of a modern, low aspect ratio, fan blade tip section. Time-dependent airfoil surface pressure measurements were made for reduced frequencies of up to 1.2 for out-of-phase oscillations at a Mach number of 0.5 and chordal incidence angles of 0 deg and 10 deg; the Reynolds number was 0.9 x l0(exp 6). For the 10 deg chordal incidence angle, a separation bubble formed at the leading edge of the suction surface. The separated flow field was found to have a dramatic effect on the chordwise distribution of the unsteady pressure. In this region, substantial deviations from the attached flow data were found with the deviations becoming less apparent in the aft region of the airfoil for all reduced frequencies. In particular, near the leading edge the separated flow had a strong destabilizing influence while the attached flow had a strong stabilizing influence.

  19. Delay Adjusted Incidence Infographic

    Cancer.gov

    This Infographic shows the National Cancer Institute SEER Incidence Trends. The graphs show the Average Annual Percent Change (AAPC) 2002-2011. For Men, Thyroid: 5.3*,Liver & IBD: 3.6*, Melanoma: 2.3*, Kidney: 2.0*, Myeloma: 1.9*, Pancreas: 1.2*, Leukemia: 0.9*, Oral Cavity: 0.5, Non-Hodgkin Lymphoma: 0.3*, Esophagus: -0.1, Brain & ONS: -0.2*, Bladder: -0.6*, All Sites: -1.1*, Stomach: -1.7*, Larynx: -1.9*, Prostate: -2.1*, Lung & Bronchus: -2.4*, and Colon & Rectum: -3/0*. For Women, Thyroid: 5.8*, Liver & IBD: 2.9*, Myeloma: 1.8*, Kidney: 1.6*, Melanoma: 1.5, Corpus & Uterus: 1.3*, Pancreas: 1.1*, Leukemia: 0.6*, Brain & ONS: 0, Non-Hodgkin Lymphoma: -0.1, All Sites: -0.1, Breast: -0.3, Stomach: -0.7*, Oral Cavity: -0.7*, Bladder: -0.9*, Ovary: -0.9*, Lung & Bronchus: -1.0*, Cervix: -2.4*, and Colon & Rectum: -2.7*. * AAPC is significantly different from zero (p<.05). Rates were adjusted for reporting delay in the registry. www.cancer.gov Source: Special section of the Annual Report to the Nation on the Status of Cancer, 1975-2011.

  20. Red Blood Cell Docosapentaenoic Acid (DPA n-3) is Inversely Associated with Triglycerides and C-reactive Protein (CRP) in Healthy Adults and Dose-Dependently Increases Following n-3 Fatty Acid Supplementation

    PubMed Central

    Skulas-Ray, Ann C.; Flock, Michael R.; Richter, Chesney K.; Harris, William S.; West, Sheila G.; Kris-Etherton, Penny M.

    2015-01-01

    The role of the long-chain omega-3 (n-3) fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in lipid metabolism and inflammation has been extensively studied; however, little is known about the relationship between docosapentaenoic acid (DPA, 22:5 n-3) and inflammation and triglycerides (TG). We evaluated whether n-3 DPA content of red blood cells (RBC) was associated with markers of inflammation (interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), and C-reactive protein (CRP) and fasting TG prior to n-3 supplementation in two studies (Study 1: n = 115, aged 20–44 years, body mass index (BMI) 20–30 kg/m2, TG = 34–176 mg/dL; Study 2: n = 28, aged 22–65 years, BMI 24–37 kg/m2, TG = 141–339 mg/dL). We also characterized the dose-response effects of n-3 fatty acid supplementation on RBC n-3 DPA after five months of supplementation with fish oil (Study 1: 0, 300, 600, 900, and 1800 mg/day EPA + DHA) and eight weeks of prescription n-3 ethyl esters (Study 2: 0, 850, and 3400 mg/day EPA + DHA). In Study 1, RBC n-3 DPA was inversely correlated with CRP (R2 = 36%, p < 0.001) and with fasting TG (r = −0.30, p = 0.001). The latter finding was replicated in Study 2 (r = −0.33, p = 0.04). In both studies, n-3 supplementation significantly increased RBC n-3 DPA dose-dependently. Relative increases were greater for Study 1, with increases of 29%–61% vs. 14%–26% for Study 2. The associations between RBC n-3 DPA, CRP, and fasting TG may have important implications for the prevention of atherosclerosis and chronic inflammatory diseases and warrant further study. PMID:26247967

  1. Incidence and therapy of midazolam induced hiccups in paediatric anaesthesia.

    PubMed

    Marhofer, P; Glaser, C; Krenn, C G; Grabner, C M; Semsroth, M

    1999-01-01

    A prospective, randomized and double blind study was undertaken to determine the incidence and a possible dose- or age-dependence of hiccups in children premedicated with rectal midazolam and to investigate the treatment of hiccups by intranasal ethyl chloride spray application. Two hundred ASA physical status 1 and 2 children, weighing 3.0 to 15.0 kg, scheduled for minor surgery, were randomly assigned to be given either 0.5 mg.kg-1 midazolam(n=100) or 1.0 mg. kg-1 midazolam (n=100) administered rectally. If hiccups were observed during a period of 20 min after premedication with midazolam, these children were treated after 3 min of hiccups with two short intranasal applications of ethyl chloride spray. Hiccups occurred in 22% of children in the 0.5 mg.kg-1 group and 26% in the 1.0 mg.kg-1 group (n.s.). The intranasal application with ethyl chloride was successful in 100% in both groups. The mean age levels between children with or without hiccups were 5+/-9 months vs 21+/-19 months (P<0.01) in the 0.5 mg.kg-1 group and 6+/-7 months vs 20+/-14 months (P<0.01) in the 1.0 mg.kg-1 group. Intranasal application of ethyl chloride spray seems to be an effective therapy for midazolam induced hiccups in paediatric anaesthesia. The incidence of these hiccups is highly age significant, but not dose dependent.

  2. Harnessing Critical Incidents for Learning

    ERIC Educational Resources Information Center

    Patahuddin, Sitti Maesuri; Lowrie, Tom

    2015-01-01

    A critical incident is a situation or event that holds significance for learning, both for the students and teachers. This paper presents four examples of critical incidents from a Year 7 teacher's lesson excerpts in Indonesia involving teaching of fractions, to show how they shaped classroom situation, brought forward elements of conflict, and…

  3. Radiation-epidemiological analysis of incidence of non-cancer diseases among the Chernobyl liquidators.

    PubMed

    Ivanov, V K; Maksioutov, M A; Chekin SYu; Kruglova, Z G; Petrov, A V; Tsyb, A F

    2000-05-01

    The work is concerned with assessment of radiation risks for non-cancer disease among the Chernobyl liquidators from 1986 to 1996. As of 1 January 1999, the Russian National Medical and Dosimetric Registry contains medical and dosimetric data for 174,000 liquidators. The cohort of 68,309 liquidators for whom best verified medical data are available is discussed. The dose dependency of incidence of non-cancer diseases was estimated by the cohort method and using the software package Epicure. For some classes of non-cancer diseases among liquidators, statistically significant estimates of radiation risk were derived for the first time. The highest excess relative risk per 1 Gy was found for cerebrovascular diseases; ERR Gy(-1)=1.17 at the 95% confidence interval (0.45; 1.88). PMID:10772021

  4. SU-E-P-07: Retrospective Analysis of Incident Reports at a Radiology Department: Feedback From Incident Reporting System

    SciTech Connect

    Kakinohana, Y; Toita, T; Heianna, J; Murayama, S

    2015-06-15

    department, therefore, the primary action to prevent/reduce similar incidents should be ‘communication improvement’.

  5. The dual-acting H3 receptor antagonist and AChE inhibitor UW-MD-71 dose-dependently enhances memory retrieval and reverses dizocilpine-induced memory impairment in rats.

    PubMed

    Khan, Nadia; Saad, Ali; Nurulain, Syed M; Darras, Fouad H; Decker, Michael; Sadek, Bassem

    2016-01-15

    Both the histamine H3 receptor (H3R) and acetylcholine esterase (AChE) are involved in the regulation of release and metabolism of acetylcholine and several other central neurotransmitters. Therefore, dual-active H3R antagonists and AChE inhibitors (AChEIs) have shown in several studies to hold promise to treat cognitive disorders like Alzheimer's disease (AD). The novel dual-acting H3R antagonist and AChEI 7-(3-(piperidin-1-yl)propoxy)-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline (UW-MD-71) with excellent selectivity profiles over both the three other HRs as well as the AChE's isoenzyme butyrylcholinesterase (BChE) shows high and balanced in vitro affinities at both H3R and AChE with IC50 of 33.9nM and hH3R antagonism with Ki of 76.2nM, respectively. In the present study, the effects of UW-MD-71 (1.25-5mg/kg, i.p.) on acquisition, consolidation, and retrieval in a one-trial inhibitory avoidance task in male rats were investigated applying donepezil (DOZ) and pitolisant (PIT) as reference drugs. Furthermore, the effects of UW-MD-71 on memory deficits induced by the non-competitive N-methyl-d-aspartate (NMDA) antagonist dizocilpine (DIZ) were tested. Our results indicate that administration of UW-MD-71 before the test session dose-dependently increased performance and enhanced procognitive effect on retrieval. However neither pre- nor post-training acute systemic administration of UW-MD-71 facilitated acquisition or consolidation. More importantly, UW-MD-71 (2.5mg/kg, i.p.) ameliorated the DIZ-induced amnesic effects. Furthermore, the procognitive activity of UW-MD-71 in retrieval was completely reversed and partly abrogated in DIZ-induced amnesia when rats were pretreated with the centrally-acting H2R antagonist zolantidine (ZOL), but not with the CNS penetrant H1R antagonist pyrilamine (PYR). These results demonstrate the procognitive effects of UW-MD-71 in two in vivo memory models, and are to our knowledge the first demonstration in vivo that a potent dual

  6. Intranasally Administered Adjunctive Dexmedetomidine Reduces Perioperative Anesthetic Requirements in General Anesthesia

    PubMed Central

    Wu, Xiang; Hang, Li-Hua; Wang, Hong; Shao, Dong-Hua; Xu, Yi-Guo; Cui, Wei

    2016-01-01

    Purpose Intranasal dexmedetomidine is an effective sedative for premedication and is regularly used to reduce preoperative tension and anxiety in children. This study aimed to assess the effect of intranasally adjunctive dexmedetomidine on perioperative sedative and analgesic requirements in adults. Materials and Methods Patients were randomly divided into four groups to receive preoperative administration of saline, intranasal dexmedetomidine 1 µg/kg and 2 µg/kg, and intravenous dexmedetomidine 1 µg/kg, respectively. Propofol and remifentanil were target-controlled infused to maintain intraoperative bispectral index at 45–55 and blood pressure at baseline value±20%. Sufentanil was administered to maintain postoperative visual analogue scale ≤3. Perioperative anesthetics requirements were compared using nonparametric tests. Results Intranasal dexmedetomidine significantly attenuated propofol requirements for anesthesia induction and maintenance in a dose-dependent manner. Patients given intranasal dexmedetomidine 2 µg/kg required less remifentanil for anesthesia maintenance. The first postoperative request for sufentanil analgesia was delayed in patients given intranasal dexmedetomidine 2 µg/kg. The anesthetics-sparing effect of intranasal dexmedetomidine was significantly weaker than intravenous dexmedetomidine at the same dose of 1 µg/kg. The incidences of adverse events, including hemodynamic instability and delayed recovery, were comparable with and without intranasal dexmedetomidine. Conclusion Intranasal administration of dexmedetomidine can reduce perioperative anesthetic requirements, and a dose of dexmedetomidine 2 µg/kg produces a better effect in adults. The anesthetics-sparing effect of intranasal dexmedetomidine 1 µg/kg is less than that with the same intravenous dose of dexmedetomidine. PMID:27189297

  7. Pulmonary Predictors of Incident Diabetes in Smokers

    PubMed Central

    Kinney, Gregory L.; Baker, Emma H.; Klein, Oana L.; Black-Shinn, Jennifer L.; Wan, Emily S.; Make, Barry; Regan, Elizabeth; Bowler, Russell P.; Lutz, Sharon M.; Young, Kendra A.; Duca, Lindsey M.; Washko, George R.; Silverman, Edwin K.; Crapo, James D.; Hokanson, John E.

    2016-01-01

    Background Diabetes mellitus and its complications are a large and increasing burden for health care worldwide. Reduced pulmonary function has been observed in diabetes (both type 1 and type 2), and this reduction is thought to occur prior to diagnosis. Other measures of pulmonary health are associated with diabetes, including lower exercise tolerance, greater dyspnea, lower quality of life (as measured by the St. George’s Respiratory Questionaire [SGRQ]) and susceptibility to lung infection and these measures may also predate diabetes diagnosis. Methods We examined 7080 participants in the COPD Genetic Epidemiology (COPDGene) study who did not report diabetes at their baseline visit and who provided health status updates during 4.2 years of longitudinal follow-up (LFU). We used Cox proportional hazards modeling, censoring participants at final LFU contact, reported mortality or report of incident diabetes to model predictors of diabetes. These models were constructed using known risk factors as well as proposed markers related to pulmonary health, forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC, respiratory exacerbations (RE), 6-minute walk distance (6MWD), pulmonary associated quality of life (as measured by the SGRQ), corticosteroid use, chronic bronchitis and dyspnea. Results Over 21,519 person years of follow-up, 392 of 7080 participants reported incident diabetes which was associated with expected predictors; increased body mass index (BMI), high blood pressure, high cholesterol and current smoking status. Age, gender and accumulated smoking exposure were not associated with incident diabetes. Additionally, preserved ratio with impaired spirometry (PRISm) pattern pulmonary function, reduced 6MWD and any report of serious pulmonary events were associated with incident diabetes. Conclusions This cluster of pulmonary indicators may aid clinicians in identifying and treating patients with pre- or undiagnosed diabetes. PMID

  8. Idiot Savants: Rate of Incidence

    ERIC Educational Resources Information Center

    Hill, A. Lewis

    1977-01-01

    A survey of 300 public residential facilities for the mentally retarded revealed a .06 percent incidence rate for idiot savants, persons of low intelligence who possess an unusually high skill in some special task. (CL)

  9. Incidence of Narcolepsy in Germany

    PubMed Central

    Oberle, Doris; Drechsel-Bäuerle, Ursula; Schmidtmann, Irene; Mayer, Geert; Keller-Stanislawski, Brigitte

    2015-01-01

    Study Objectives: Following the 2009 pandemic, reports of an association between an AS03 adjuvanted H1N1 pandemic influenza vaccine and narcolepsy were published. Besides determining background incidence rates for narcolepsy in Germany this study aimed at investigating whether there was a change in incidence rates of narcolepsy between the pre-pandemic, pandemic, and the post-pandemic period on the population level. Design: Retrospective epidemiological study on the incidence of narcolepsy with additional capture-recapture analysis. Setting: German sleep centers. Patients or Participants: Eligible were patients with an initial diagnosis of narcolepsy (ICD10 Code G47.4) within the period from January 1, 2007 to December 31, 2011. Interventions: None; observational study. Measurements and Results: A total of 342 sleep centers were invited to participate in the study. Adequate and suitable data were provided by 233 sleep centers (68.1%). A total of 1,198 patients with an initial diagnosis of narcolepsy within the observed period were included, of whom 106 (8.8%) were children and adolescents under the age of 18 years and 1,092 (91.2%) were adults. In children and adolescents, the age-standardized adjusted incidence rate significantly increased from 0.14/100,000 person-years in the pre-pandemic period to 0.50/100,000 person-years in the post-pandemic period (incidence density ratio, IDR 3.57; 95% CI 1.94–7.00). In adults, no significant change was detectable. This increase started in spring 2009. Conclusions: For the years 2007–2011, valid estimates for the incidence of narcolepsy in Germany were provided. In individuals under 18, the incidence rates continuously increased from spring 2009. Citation: Oberle D, Drechsel-Bäuerle U, Schmidtmann I, Mayer G, Keller-Stanislawski B. Incidence of narcolepsy in Germany. SLEEP 2015;38(10):1619–1628. PMID:25902804

  10. Racial differences in melanoma incidence.

    PubMed Central

    Crombie, I. K.

    1979-01-01

    The incidences of malignant melanoma recorded by 59 population-based cancer registries were investigated to determine the effects of racial and skin-colour differences. White populations exhibited a wide range of melanoma incidences and females commonly, though not invariably, had a higher incidence than males. Non-white populations experienced in general a much lower incidence of melanoma although there was some overlap of white and non-white rates. No predominant sex difference emerged among non-whites. Populations of African descent were found to have a higher incidence than those of Asiatic origin, but it was concluded that this was due largely to the high frequency of tumours among Africans on the sole of the foot. A clear negative correlation between degree of skin pigmentation and melanoma incidence emerged for the exposed body sites. These data provide strong support for the hypotheses that UV radiation is a major cause of malignant melanoma and that melanin pigmentation protects against it. Further research is required to elucidate the aetiology of melanoma of the sole of the foot. PMID:475965

  11. Impact of metabolic syndrome components on incident stroke subtypes: a Chinese cohort study.

    PubMed

    Chen, Y-C; Sun, C-A; Yang, T; Chu, C-H; Bai, C-H; You, S-L; Hwang, L-C; Chen, C-H; Wei, C-Y; Chou, Y-C

    2014-11-01

    Limited evidence is available on the risk differences in the development of stroke subtypes in relation to particular clustering patterns of the metabolic syndrome (MetS) components. A follow-up study of a Chinese cohort involving 10,292 individuals was performed to assess the roles of cluster patterns of the MetS components in the prediction of incident stroke subtypes. During follow-up, there were 161 incident cases of ischemic strokes and 41 incident cases of hemorrhagic strokes. Among MetS components, only the hypertensive trait was associated with significantly elevated risks of both ischemic and hemorrhagic strokes. Furthermore, MetS with hypertension as components was associated with increased risk of ischemic and hemorrhagic strokes (adjusted hazards ratio (95% confidence interval) was 2.96 (1.94-4.50) and 2.93 (1.25-6.90), respectively) as compared with those who had neither hypertension nor MetS. Notably, as the number of the MetS components increased, the risk of ischemic stroke significantly and dose-dependently increased. This implies a cumulative effect of MetS components in elevating the risk of ischemic stroke. These findings suggest that MetS comprises heterogenous clusters with respect to the risk of developing the subtype of stroke.

  12. Spatial Distribution of Black Bear Incident Reports in Michigan

    PubMed Central

    McFadden-Hiller, Jamie E.; Beyer, Dean E.; Belant, Jerrold L.

    2016-01-01

    Interactions between humans and carnivores have existed for centuries due to competition for food and space. American black bears are increasing in abundance and populations are expanding geographically in many portions of its range, including areas that are also increasing in human density, often resulting in associated increases in human-bear conflict (hereafter, bear incidents). We used public reports of bear incidents in Michigan, USA, from 2003–2011 to assess the relative contributions of ecological and anthropogenic variables in explaining the spatial distribution of bear incidents and estimated the potential risk of bear incidents. We used weighted Normalized Difference Vegetation Index mean as an index of primary productivity, region (i.e., Upper Peninsula or Lower Peninsula), primary and secondary road densities, and percentage land cover type within 6.5-km2 circular buffers around bear incidents and random points. We developed 22 a priori models and used generalized linear models and Akaike’s Information Criterion (AIC) to rank models. The global model was the best compromise between model complexity and model fit (w = 0.99), with a ΔAIC 8.99 units from the second best performing model. We found that as deciduous forest cover increased, the probability of bear incident occurrence increased. Among the measured anthropogenic variables, cultivated crops and primary roads were the most important in our AIC-best model and were both positively related to the probability of bear incident occurrence. The spatial distribution of relative bear incident risk varied markedly throughout Michigan. Forest cover fragmented with agriculture and other anthropogenic activities presents an environment that likely facilitates bear incidents. Our map can help wildlife managers identify areas of bear incident occurrence, which in turn can be used to help develop strategies aimed at reducing incidents. Researchers and wildlife managers can use similar mapping techniques to

  13. Spatial Distribution of Black Bear Incident Reports in Michigan.

    PubMed

    McFadden-Hiller, Jamie E; Beyer, Dean E; Belant, Jerrold L

    2016-01-01

    Interactions between humans and carnivores have existed for centuries due to competition for food and space. American black bears are increasing in abundance and populations are expanding geographically in many portions of its range, including areas that are also increasing in human density, often resulting in associated increases in human-bear conflict (hereafter, bear incidents). We used public reports of bear incidents in Michigan, USA, from 2003-2011 to assess the relative contributions of ecological and anthropogenic variables in explaining the spatial distribution of bear incidents and estimated the potential risk of bear incidents. We used weighted Normalized Difference Vegetation Index mean as an index of primary productivity, region (i.e., Upper Peninsula or Lower Peninsula), primary and secondary road densities, and percentage land cover type within 6.5-km2 circular buffers around bear incidents and random points. We developed 22 a priori models and used generalized linear models and Akaike's Information Criterion (AIC) to rank models. The global model was the best compromise between model complexity and model fit (w = 0.99), with a ΔAIC 8.99 units from the second best performing model. We found that as deciduous forest cover increased, the probability of bear incident occurrence increased. Among the measured anthropogenic variables, cultivated crops and primary roads were the most important in our AIC-best model and were both positively related to the probability of bear incident occurrence. The spatial distribution of relative bear incident risk varied markedly throughout Michigan. Forest cover fragmented with agriculture and other anthropogenic activities presents an environment that likely facilitates bear incidents. Our map can help wildlife managers identify areas of bear incident occurrence, which in turn can be used to help develop strategies aimed at reducing incidents. Researchers and wildlife managers can use similar mapping techniques to

  14. Spatial Distribution of Black Bear Incident Reports in Michigan.

    PubMed

    McFadden-Hiller, Jamie E; Beyer, Dean E; Belant, Jerrold L

    2016-01-01

    Interactions between humans and carnivores have existed for centuries due to competitio