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Sample records for dose-dependently reduce incidence

  1. Dose-Dependent Incidence of Hepatic Tumors in Adult Mice following Perinatal Exposure to Bisphenol A

    PubMed Central

    Weinhouse, Caren; Anderson, Olivia S.; Bergin, Ingrid L.; Vandenbergh, David J.; Gyekis, Joseph P.; Dingman, Marc A.; Yang, Jingyun

    2014-01-01

    Background: Bisphenol A (BPA) is a high production volume chemical with hormone-like properties that has been implicated as a potential carcinogen. Early-life exposure has been linked to increased risk for precancerous lesions in mammary and prostate glands and the uterus, but no prior study has shown a significant association between BPA exposure and cancer development. Objective: We explored the effects of BPA exposure during gestation and lactation on adult incidence of hepatic tumors in mice. Methods: Isogenic mice were perinatally exposed to BPA through maternal diets containing one of four environmentally relevant doses of BPA (0, 50 ng, 50 μg, or 50 mg per kilogram of diet), and we followed approximately one male and one female per litter until they were 10 months of age. Animals were tested for known risk factors for hepatocellular carcinoma, including bacterial and viral infections. Results: We found dose-dependent incidence of hepatic tumors in 10-month-old BPA-exposed mice. Of the offspring examined, 23% presented with hepatic tumors or preneoplastic lesions. We observed a statistically significant dose–response relationship, with an odds ratio for neoplastic and preneoplastic lesions of 7.23 (95% CI: 3.23, 16.17) for mice exposed to 50 mg BPA/kg diet compared with unexposed controls. Observed early disease onset, absence of bacterial or viral infection, and lack of characteristic sexual dimorphism in tumor incidence support a nonclassical etiology. Conclusions: To our knowledge, this is the first report of a statistically significant association between BPA exposure and frank tumors in any organ. Our results link early-life exposure to BPA with the development of hepatic tumors in rodents, and have potential implications for human health and disease. Citation: Weinhouse C, Anderson OS, Bergin IL, Vandenbergh DJ, Gyekis JP, Dingman MA, Yang J, Dolinoy DC. 2014. Dose-dependent incidence of hepatic tumors in adult mice following perinatal exposure to

  2. 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

  3. Hypocretin Receptor 2 Antagonism Dose-Dependently Reduces Escalated Heroin Self-Administration in Rats

    PubMed Central

    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

    2015-01-01

    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. PMID:25367502

  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. Flaxseed reduces the pro-carcinogenic micro-environment in the ovaries of normal hens by altering the PG and oestrogen pathways in a dose-dependent manner.

    PubMed

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

    2015-05-14

    The objective of the present study was to find the optimum dose of flaxseed that would decrease PG and alter oestrogen pathway endpoints implicated in ovarian cancer. In the study, four groups of fifty 1.5-year-old chickens were fed different amounts of flaxseed (0, 5, 10 or 15% of their total diet) for 4 months and were then killed to collect blood and tissues. Levels of flaxseed lignan metabolites, Enterolactone (EL) and Enterodiol (ED) were measured in the serum, liver and ovaries by liquid chromatography-MS/MS, and n-3 and n-6 fatty acid (FA) levels were measured by GC. The effects of the varied flaxseed doses were assessed by measuring levels of PGE2 and oestrogen metabolites (16-hydroxyestrone (16-OHE1) and 2-hydroxyestrone (2-OHE1)) as well as by analysing the expression of the oestradiol metabolising enzymes CYP3A4 (cytochrome p450, family 3, subfamily A, polypeptide 4), CYP1B1 (cytochrome p450, family 1, subfamily B, polypeptide 1) and CYP1A1 (cytochrome p450, family 1, subfamily A, polypeptide 1) and that of oestrogen receptor α (ERα) in the ovaries. The ratio of n-3:n-FA increased with an increase in flaxseed supplementation and corresponded to a dose-dependent decrease in cyclo-oxygenase-2 protein and PGE2 levels. EL and ED increased in the serum, liver and ovaries with increased concentrations of flaxseed. Flaxseed decreased the expression of ERα in the ovaries. The ratio of 2-OHE1:16-OHE1 in the serum increased significantly in the 15% flaxseed diet, and there was a corresponding increase in CYP1A1 in the liver and decrease in CYP3A4 in the ovaries. CYP1B1 mRNA also decreased with flaxseed diet in the ovaries. The 15% flaxseed-supplemented diet significantly decreased inflammatory PGE2, ERα, CYP3A4, CYP1B1 and 16-OHE1, but it increased CYP1A1 and 2-OHE1, which thus reduced the inflammatory and pro-carcinogenic micro-environment of the ovaries. PMID:25850566

  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. 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

  8. Reduced Risk of Incident Kidney Cancer from Walking and Running

    PubMed Central

    Williams, Paul T.

    2013-01-01

    Purpose Test whether incident kidney cancer risk is associated with exercise energy expenditure (i.e., metabolic equivalents, 1 MET) when calculated from distance walked or run. Methods Hazard ratios (HR) and 95% confidence intervals (95%CI) from Cox proportional hazard analyses of self-reported physician-diagnosed incident kidney cancer vs. MET-hours/wk in 91,820 subjects recruited between 1991 and 1993 (7.7 yr follow-up of 42,833 subjects) and between 1998 and 1999 (6.4 yr follow-up of 33,053 subjects) as part of the National Runners' Health Study and between 1998 and 1999 as part of the National Walkers' Health Study (5.7 yr follow-up of 15,934 subjects). Results Fifty-two incident cancers were reported. Age- and sex-adjusted risk declined 1.9% per MET-hour/wk run or walked (HR: 0.981; 95%CI: 0.964 to 0.997, P=0.02). Compared to walking or running below guidelines levels (<7.5 MET-hours/wk), the risk for incident kidney cancer was 61% lower for meeting the guidelines (HR: 0.39, 95%CI: 0.11 to 1.08, P=0.07 for 7.5 to 12.5 MET-hours/wk), 67% lower for exercising one to two-times the recommended level (HR: 0.33; 95%CI: 0.15 to 0.72, P=0.005 for 12.6 to 25.1 MET-hours/wk), and 76.3% lower for exercising ≥2-times the recommended level (HR: 0.24; 95%CI: 0.11 to 0.52, P=0.0005 for ≥25.2 MET-hours/wk). Incident kidney cancer risk also increased in association with baseline BMI (P=0.002), smoking (P=0.02), and hypertensive (P=0.007) and diabetes medication use (P=0.01), however, exercise-associated reductions in kidney cancer risk persisted for 12.6 to 25.1 MET-hours/wk (HR: 0.35, P=0.01), and ≥ 25.2 MET-hours/wk (HR: 0.29, P=0.004) vis-à-vis <7.5 MET-hours/wk when also adjusted for BMI, hypertension, diabetes, and pack-years smoked. Conclusion Running and walking may reduce incident kidney cancer risk independent of its other known risk factors. PMID:23863620

  9. Would decreased aluminum ingestion reduce the incidence of Alzheimer's disease?

    PubMed Central

    McLachlan, D R; Kruck, T P; Lukiw, W J; Krishnan, S S

    1991-01-01

    Although the cause of Alzheimer's disease (AD) remains unknown there is mounting evidence that implicates aluminum as a toxic environmental factor of considerable importance. Four independent lines of evidence--laboratory studies of the effects of intracerebral aluminum on the cognitive and memory performance of animals, biochemical studies, epidemiologic studies and the slowing of the progress of the disease with the use of an agent that removes aluminum from the body--now support the concept that aluminum is one of the pathogenic factors in AD. The evidence warrants serious consideration of reducing human exposure to aluminum. We hypothesize that a public health effort to restrict human ingestion of aluminum would reduce the incidence of this common chronic illness in the elderly. PMID:1822096

  10. Mechanical Ventilation as a Therapeutic Tool to Reduce ARDS Incidence.

    PubMed

    Nieman, Gary F; Gatto, Louis A; Bates, Jason H T; Habashi, Nader M

    2015-12-01

    Trauma, hemorrhagic shock, or sepsis can incite systemic inflammatory response syndrome, which can result in early acute lung injury (EALI). As EALI advances, improperly set mechanical ventilation (MV) can amplify early injury into a secondary ventilator-induced lung injury that invariably develops into overt ARDS. Once established, ARDS is refractory to most therapeutic strategies, which have not been able to lower ARDS mortality below the current unacceptably high 40%. Low tidal volume ventilation is one of the few treatments shown to have a moderate positive impact on ARDS survival, presumably by reducing ventilator-induced lung injury. Thus, there is a compelling case to be made that the focus of ARDS management should switch from treatment once this syndrome has become established to the application of preventative measures while patients are still in the EALI stage. Indeed, studies have shown that ARDS incidence is markedly reduced when conventional MV is applied preemptively using a combination of low tidal volume and positive end-expiratory pressure in both patients in the ICU and in surgical patients at high risk for developing ARDS. Furthermore, there is evidence from animal models and high-risk trauma patients that superior prevention of ARDS can be achieved using preemptive airway pressure release ventilation with a very brief duration of pressure release. Preventing rather than treating ARDS may be the way forward in dealing with this recalcitrant condition and would represent a paradigm shift in the way that MV is currently practiced. PMID:26135199

  11. Temporal, latitude and altitude absorbed dose dependences

    NASA Astrophysics Data System (ADS)

    Stozhkov, Y.; Svirzhevsky, N.; Bazilevskaya, G.

    The regular balloon measurements in the Earth's atmosphere are carried on at the Lebedev Physical Institute since 1957. The regular balloon flights have been made at the high latitude stations (near Murmansk - northern hemisphere and Mi ny -r Antarctica) and at the middle latitude (Moscow). Based on these long-term measurements as well as on the latitude data obtained in the several Soviet Antarctic expeditions the calculations of absorbed doses were fulfilled for altitudes of 10, 15, 20 and 30 km. The absorbed dose dependences on the geomagnetic cutoff rigidities and the phase of the 11-year solar cycle were found. The evaluation of the solar proton events and energetic electron precipitation contributions to the absorbed dose enhancements was made.

  12. [Dose dependent effects of dichloroacetate on lactic acidosis in dogs].

    PubMed

    Fujita, Y; Fukui, A; Yoshida, H; Ohsumi, A; Sakai, T; Takaori, M

    1989-08-01

    Dose dependent effects of DCA (dichloroacetate) on lactic acidosis were studied in 30 mongrel dogs under pentobarbital anesthesia. Lactic acidosis was induced by infusion of either lactate (n = 15) or pyruvate (n = 15) for 20 min. In each dog, saline or DCA (100 mg.kg-1 or 300 mg.kg-1) was given for ten min iv. at ten min after the beginning of lactate or pyruvate infusions. Reduction in serum pyruvate levels was more prominent than that in lactate levels in both the lactate and pyruvate infusion groups. DCA in a dose of 100 mg.kg-1 was more effective to reduce serum pyruvate levels and arterial pH than 300 mg.kg-1 of DCA. There were no differences between saline and DCA (100 mg.kg-1 or 300 mg.kg-1) administrations in mean arterial pressure and cardiac index. This study confirmed the hypothesis that DCA reduces serum lactate levels via acceleration of pyruvate metabolism. It was concluded that the ability of DCA to reduce serum lactate levels is dose-dependent and a large dose of DCA (300 mg.kg-1) would not be necessary for lactic acidosis. PMID:2810694

  13. CRIMINAL ABORTION—A Consideration of Ways to Reduce Incidence

    PubMed Central

    Kummer, Jerome M.; Leavy, Zad

    1961-01-01

    The problem of criminal abortion in the United States is of enormous magnitude, both in terms of incidence and of resultant morbidity and mortality. Several studies suggest that one of every five pregnancies terminates in criminal abortion, or a total of more than one million abortions for 1960, with a possibility of more than 5,000 deaths resulting therefrom. The inadequate laws regarding therapeutic abortion in most jurisdictions contribute much to the problem. Tracing the origins of these laws provides additional clues concerning the development of this enigma. Suggested answers to the problem include: (1) Broadening and clarifying therapeutic abortion laws to reflect current medical practice, yet provide stringent controls; (2) prevention of unwanted pregnancy through consultation centers for women, encouragement of contraceptive research and education of the public. PMID:13755105

  14. 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

  15. 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)

  16. Reducing the Incidence of Plagiarism in an Undergraduate Course: The Role of Education

    ERIC Educational Resources Information Center

    Breen, Lauren; Maassen, Margaret

    2005-01-01

    Plagiarism by students is an increasing problem at higher education institutions. However, the development of academic misconduct policies has done little to reduce the incidence of plagiarism as many incidents result from ignorance and poor skill development rather than intentional misconduct. Our purpose in embarking on this research project was…

  17. 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

  18. 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…

  19. Positive changes in ideal CVH metrics reduce the incidence of stroke

    PubMed Central

    Yang, Xiaomeng; Wang, Anxin; Liu, Xiaoxue; An, Shasha; Chen, Shuohua; Wang, Yilong; Wang, Yongjun; Wu, Shouling

    2016-01-01

    The American Heart Association defined 7 ideal cardiovascular health (CVH) metrics and the benefits of them in reducing the incidence of stroke are well established, but it is unclear whether changes in them alter stroke risk. We calculated the changes of 7 ideal CVH metrics from 2006 to 2008 among 64,373 participants in the Kailuan study. We tested whether changes in the numbers and total scores for the CVH metrics were associated with the incidence of stroke in the 4.89 person-years follow-up. Cox regression modeling was used to estimate the risk of stroke. By year 2008, CVH metrics number of 32.54% participants improved (change ≥+1); 31.90% deteriorated (≤−1); 35.56% stayed the same; In the follow-up,we identified1,182 incident stroke events. Each increase in CVH metrics and every 1-point increase in total CVH score from 2006 to 2008 were associated with reduced odds of total stroke (hazard ratio = 0.87; 95% confidence interval; 0.83–0.92 and 0.89[0.86–0.92] respectively), after adjusting for age, gender, educational level, income and scores for the metrics of ideal CVH at baseline. Positive changes in ideal CVH metrics reduce the incidence of stroke. Our results support the concept that achieving ideal CVH helps to prevent stroke. PMID:26790535

  20. Reducing the Probability of Incidents Through Behavior-Based Safety -- An Anomaly or Not?

    SciTech Connect

    Turek, John A

    2002-07-23

    Reducing the probability of incidents through Behavior-Based Safety-an anomaly or not? Can a Behavior-Based Safety (BBS) process reduce the probability of an employee sustaining a work-related injury or illness? This presentation describes the actions taken to implement a sustainable BBS process and evaluates its effectiveness. The BBS process at the Stanford Linear Accelerator Center used a pilot population of national laboratory employees to: Achieve employee and management support; Reduce the probability of employees' sustaining work-related injuries and illnesses; and Provide support for additional funding to expand within the laboratory.

  1. Reducing the Probability of Incidents Through Behavior-Based Safety -- An Anomaly or Not?

    SciTech Connect

    Turek, John A

    2002-07-23

    Reducing the probability of incidents through Behavior-Based Safety--an anomaly or not? Can a Behavior-Based Safety (BBS) process reduce the probability of an employee sustaining a work-related injury or illness? This presentation describes the actions taken to implement a sustainable BBS process and evaluates its effectiveness. The BBS process at the Stanford Linear Accelerator Center used a pilot population of national laboratory employees to: Achieve employee and management support; Reduce the probability of employees' sustaining work-related injuries and illnesses; and Provide support for additional funding to expand within the laboratory.

  2. Underreporting of patient safety incidents reduces health care's ability to quantify and accurately measure harm reduction.

    PubMed

    Noble, Douglas J; Pronovost, Peter J

    2010-12-01

    Underreporting of patient safety incidents creates a reservoir of information that is plagued with epidemiological bias. These include systematic biases such as the practice of reporting minor incidents at the expense of more serious ones. This leads to inaccurate rates of errors and an inability to generalize results to whole patient populations. It leaves reporting incidents, in epidemiological terms, comparable to nonrandom samples from an unknown universe of events. These epidemiological problems lead to a situation where priorities are skewed toward what "we know we know." As "we know what we do not know," for example, gaps in knowledge about serious incidents due to low reporting rates, due caution must be applied in making policy based on biased underreporting. Barriers to reporting contribute to low participation rates and further bias information. Lack of feedback and fear of personal consequences are common barriers. Evaluation of reporting systems indicates reports can be used as tools for learning, but it is not yet possible to monitor improvement in patient safety or measurably prove reduction in harm. Mandatory reporting makes sense from an epidemiological point of view, but there are legitimate fears that it could further reduce reporting rates due to fear of reprisal. Underreporting and the associated biases are a significant problem in realizing the epidemiological potential of incident reporting in health care. PMID:21500613

  3. Reduced incidence and mortality from colorectal cancer with flexible-sigmoidoscopy screening: A meta-analysis

    PubMed Central

    Shroff, Jennifer; Thosani, Nirav; Batra, Sachin; Singh, Harminder; Guha, Sushovan

    2014-01-01

    AIM: To conduct a systematic review and meta-analysis of published population-based randomized controlled trials (RCTs). METHODS: RCTs evaluating the difference in mortality and incidence of colorectal cancer (CRC) between a screening flexible sigmoidoscopy (FS) group and control group (not assigned to screening FS) with a minimum 5 years median follow-up were identified by a search of MEDLINE and EMBASE databases and the Cochrane Central Register for Controlled Trials through August 2013. Random effects model was used for meta-analysis. RESULTS: Four RCTs with a total of 165659 patients in the FS group and 249707 patients in the control group were included in meta-analysis. Intention-to-treat analysis showed that there was a 22% risk reduction in total incidence of CRC (RR = 0.78, 95%CI: 0.74-0.83), 31% in distal CRC incidence (RR = 0.69, 95%CI: 0.63-0.75), and 9% in proximal CRC incidence (RR = 0.91, 95%CI: 0.83-0.99). Those who underwent screening FS were 18% less likely to be diagnosed with advanced CRC (OR = 0.82, 95%CI: 0.71-0.94). There was a 28% risk reduction in overall CRC mortality (RR = 0.72, 95%CI: 0.65-0.80) and 43% in distal CRC mortality (RR = 0.57, 95%CI: 0.45-0.72). CONCLUSION: This meta-analysis suggests that screening FS can reduce the incidence of proximal and distal CRC and mortality from distal CRC along with reduction in diagnosis of advanced CRC. PMID:25561818

  4. 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

  5. Stimulation of incretin secretion by dietary lipid: is it dose dependent?

    PubMed

    Yoder, Stephanie M; Yang, Qing; Kindel, Tammy L; Tso, Patrick

    2009-08-01

    After the ingestion of nutrients, secretion of the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) by the enteroendocrine cells increases rapidly. Previous studies have shown that oral ingestion of fat stimulates secretion of both incretins; however, it is unclear whether there is a dose-dependent relationship between the amount of lipid ingested and the secretion of the hormones in vivo. Recently, we found a higher concentration of the incretin hormones in intestinal lymph than in peripheral or portal plasma. We therefore used the lymph fistula rat model to test for a dose-dependent relationship between the secretion of GIP and GLP-1 and dietary lipid. Under isoflurane anesthesia, the major mesenteric lymphatic duct of male Sprague-Dawley rats was cannulated. Each animal received a single, intraduodenal bolus of saline or varying amounts of the fat emulsion Liposyn II (0.275, 0.55, 1.1, 2.2, and 4.4 kcal). Lymph was continuously collected for 3 h and analyzed for triglyceride, GIP, and GLP-1 content. In response to increasing lipid calories, secretion of triglyceride, GIP, and GLP-1 into lymph increased dose dependently. Interestingly, the response to changes in intraluminal lipid content was greater in GLP-1- than in GIP-secreting cells. The different sensitivities of the two cell types to changes in intestinal lipid support the concept that separate mechanisms may underlie lipid-induced GIP and GLP-1 secretion. Furthermore, we speculate that the increased sensitivity of GLP-1 to intestinal lipid content reflects the hormone's role in the ileal brake reflex. As lipid reaches the distal portion of the gut, GLP-1 is secreted in a dose-dependent manner to reduce intestinal motility and enhance proximal fat absorption. PMID:19520739

  6. 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

  7. 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

  8. [Is it possible to reduce the incidence of aminoglycoside-induced nephrotoxicity?].

    PubMed

    Fillastre, J P

    1999-01-01

    The incidence of nephrotoxicity due to aminoglycosides should be sharply reduced. The indications for prescribing these antibiotics should be limited to infectious disorders induced by aerobic Gram-negative bacteria and by some Gram-positive bacteria requiring treatment in specialized hospital units using an association of aminoglycosides and another antibiotic. Daily doses should not exceed those indicated by the manufacturer, and the length of treatment should be as short as possible, with a relay to other antibiotics that are not or are less nephrotoxic. The possibilities for reducing the incidence of nephrotoxicity are few. It is not possible to prevent the antibiotic from entering the renal tubular cell or from producing deleterious effects therein. However, by using short-term intravenous infusion as the administration route, prolonged contact between the antibiotic and its receptors on the brush borders of the proximal tubular cells can be avoided, particularly since the process of cellular absorption is saturable. Essentially, doses should be adapted according to the age and the glomerular filtration of the patient, since renal function usually decreases with age. Volemic and hydroelectrolytic disorders favour nephrotoxicity and should be corrected. Associations with other nephrotoxic drugs should either be avoided or used with increased caution. The same is true in special situations such as endotoxaemia, severe renal parenchymatous infections and cholestasis. In any case, given the well-known insidious onset of nephropathy, aminoglycoside treatment always requires laboratory follow-up consisting of repeated testing of creatinemia during the two weeks of treatment. PMID:10465001

  9. 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

  10. 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.

  11. Incident Diabetes and Mobility Limitations: Reducing Bias Through Risk-set Matching

    PubMed Central

    2015-01-01

    Background. Increased prevalence of diabetes in the U.S. population could contribute substantially to increases in disability at older ages. Previous studies have examined the association between prevalent diabetes and various impairments and disabilities. Methods considering incident, rather than prevalent, diabetes as the exposure of interest can reduce bias in estimates of these associations. Methods. Risk-set matching, a type of propensity score matching meant to handle time-varying exposures, was used to estimate the relationship between incident diabetes and mobility limitations among adults in the Health and Retirement Study. This approach ensures that covariates precede diabetes onset rather than follow it. Results. Individuals who were diagnosed with diabetes during the study period accumulated more subsequent mobility limitations than were accumulated by matched controls. Among observationally similar pairs of individuals, those who developed diabetes reported an average of 24.9% more mobility limitations at study exit than those who did not. Conclusions. The magnitude of the relationship between diabetes and limitations estimated in this article is smaller than that presented in previous studies, but the method presented here is likely to provide a less-biased estimate of the association between diabetes and accumulation of mobility limitations. PMID:25414516

  12. 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

  13. 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

  14. Reducing the incidence of infection after caesarean section: implications of prophylaxis with antibiotics for hospital resources.

    PubMed Central

    Mugford, M.; Kingston, J.; Chalmers, I.

    1989-01-01

    OBJECTIVES--To estimate the cost effectiveness of giving prophylactic antibiotics routinely to reduce the incidence of wound infection after caesarean section. DESIGN--Estimation of cost effectiveness was based, firstly, on a retrospective overview of 58 controlled trials and, secondly, on evidence about costs derived from data and observations of practice. SETTING--Trials included in the overview were from obstetric units in several different countries, including the United Kingdom. The costing study was based on data referring to the John Radcliffe Maternity Hospital, Oxford. SUBJECTS--A total of 7777 women were included in the 58 controlled trials comparing the effects of giving routine prophylactic antibiotics at caesarean section with either treatment with a placebo or no treatment. Cost estimates were based on data on 486 women who had caesarean sections between January and September 1987. MAIN OUTCOME MEASURE--Cost effectiveness of prophylaxis with antibiotics. RESULTS--The odds of wound infection are likely to be reduced by between about 50 and 70% by giving antibiotics routinely at caesarean section. Forty one (8.4%) women who had caesarean section were coded by the Oxford obstetric data system as having developed wound infection. The additional average cost of hospital postnatal care for women with wound infection (compared with women who had had caesarean section and no wound infection) was estimated to be 716 pounds; introducing routine prophylaxis with antibiotics would reduce average costs of postnatal care by between 1300 pounds and 3900/100 pounds caesarean sections (at 1988 prices), depending on the cost of the antibiotic used and its effectiveness. CONCLUSIONS--The results suggest that giving antibiotics routinely at caesarean section will not only reduce rates of infection after caesarean section but also reduce costs. PMID:2511938

  15. 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

  16. Butyrylated starch affects colorectal cancer markers beneficially and dose-dependently in genotoxin-treated rats

    PubMed Central

    Toden, Shusuke; Lockett, Trevor J; Topping, David L; Scherer, Benjamin L; Watson, Emma-Jane L; Southwood, Jessica G; Clarke, Julie M

    2014-01-01

    Population studies suggest that greater dietary fiber intake may lower colorectal cancer (CRC) risk, possibly through the colonic bacterial fermentative production of butyrate. Butyrylated starch delivers butyrate to the colon of humans with potential to reduce CRC risk but high doses may exacerbate risk through promoting epithelial proliferation. Here we report the effects of increasing dietary butyrylated high amylose maize starch (HAMSB) on azoxymethane (AOM) induced distal colonic DNA damage, cell proliferation, mucus layer thickness and apoptosis in rats. Five groups of 15 rats were fed AIN-93G based diets containing 0–40% HAMSB for 4 weeks then injected with (AOM) and killed 6 hours later. Large bowel total SCFA, acetate and butyrate pools and hepatic portal venous plasma total SCFA, acetate and butyrate concentrations were higher with greater HAMSB intake. Distal colonic epithelial apoptotic index and colonic mucus thickness increased, while DNA single strand breaks decreased dose-dependently with greater HAMSB intake. Colonocyte proliferation rates were unaffected by diet. These data suggest that increasing large bowel butyrate may reduce the risk of CRC in a dose dependent manner by enhancing apoptotic surveillance in the colonic epithelium for damaged cells without promoting the risk of tumorigenesis through increased cell proliferation. PMID:25482948

  17. Butyrylated starch affects colorectal cancer markers beneficially and dose-dependently in genotoxin-treated rats.

    PubMed

    Toden, Shusuke; Lockett, Trevor J; Topping, David L; Scherer, Benjamin L; Watson, Emma-Jane L; Southwood, Jessica G; Clarke, Julie M

    2014-01-01

    Population studies suggest that greater dietary fiber intake may lower colorectal cancer (CRC) risk, possibly through the colonic bacterial fermentative production of butyrate. Butyrylated starch delivers butyrate to the colon of humans with potential to reduce CRC risk but high doses may exacerbate risk through promoting epithelial proliferation. Here we report the effects of increasing dietary butyrylated high amylose maize starch (HAMSB) on azoxymethane (AOM) induced distal colonic DNA damage, cell proliferation, mucus layer thickness and apoptosis in rats. Five groups of 15 rats were fed AIN-93G based diets containing 0-40% HAMSB for 4 weeks then injected with (AOM) and killed 6 hours later. Large bowel total SCFA, acetate and butyrate pools and hepatic portal venous plasma total SCFA, acetate and butyrate concentrations were higher with greater HAMSB intake. Distal colonic epithelial apoptotic index and colonic mucus thickness increased, while DNA single strand breaks decreased dose-dependently with greater HAMSB intake. Colonocyte proliferation rates were unaffected by diet. These data suggest that increasing large bowel butyrate may reduce the risk of CRC in a dose dependent manner by enhancing apoptotic surveillance in the colonic epithelium for damaged cells without promoting the risk of tumorigenesis through increased cell proliferation. PMID:25482948

  18. 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

  19. Subcutaneous Bortezomib in Multiple Myeloma Patients Induces Similar Therapeutic Response Rates as Intravenous Application But It Does Not Reduce the Incidence of Peripheral Neuropathy

    PubMed Central

    Minarik, Jiri; Pavlicek, Petr; Pour, Ludek; Pika, Tomas; Maisnar, Vladimir; Spicka, Ivan; Jarkovsky, Jiri; Krejci, Marta; Bacovsky, Jaroslav; Radocha, Jakub; Straub, Jan; Kessler, Petr; Wrobel, Marek; Walterova, Lenka; Sykora, Michal; Obernauerova, Jarmila; Brozova, Lucie; Gregora, Evzen; Adamova, Dagmar; Gumulec, Jaromir; Adam, Zdenek; Scudla, Vlastimil; Hajek, Roman

    2015-01-01

    Objective Subcutaneous (SC) application of bortezomib has been recently introduced as a new application route in multiple myeloma (MM) patients. We performed an analysis to compare the outcomes of bortezomib-based therapy in multiple myeloma (MM) patients treated using either intravenous (IV) or subcutaneous (SC) route of administration. Patients and methods During January 2012 through December 2013, we performed a retrospective analysis of 446 patients with MM treated with bortezomib-based regimens (either once weekly – 63% or twice weekly – 27%) in both, the first line setting, and in relapse, with separate analysis of patients undergoing autologous stem cell transplantation. We assessed the response rates and toxicity profiles in both, IV and SC route of bortezomib administration. Results The response rates in both IV and SC arm were similar with overall response rate 71.7% vs 70.7%, complete remissions in 13.9% vs 8.6%, very good partial remissions in 30.8% vs 34.5% and partial remissions in 27% vs 27.6%. The most frequent grade ≥3 toxicities were anemia, thrombocytopenia and neutropenia, with no significant differences between IV and SC group. There were no significant differences in the rate of peripheral neuropathy (PN). PN of any grade was present in 48% in the IV arm and in 41% in the SC arm. PN grade ≥2 was present in 20% vs 18% and PN grade ≥3 was present in 6% vs 4%. Conclusions We conclude that subcutaneous application of bortezomib has similar therapeutic outcomes and toxicity profile as intravenous route of application. In our cohort there was no difference in the incidence of PN, suggesting that PN is dose dependent and might be reduced by lower intensity schemes rather than by the route of administration. PMID:25875484

  20. 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

  1. Reducing the Incidence of Postoperative Nausea and Vomiting Begins With Risk Screening: An Evaluation of the Evidence.

    PubMed

    Smith, Christopher A; Ruth-Sahd, Lisa

    2016-04-01

    Postoperative nausea and vomiting (PONV) is a daily concern for patients and perianesthesia nurses. PONV is experienced by approximately one third of all surgical patients. Identification of patients at risk for PONV through preoperative risk assessment is an effective means in reducing the incidence of PONV. Perianesthesia nurses are positioned to implement such risk assessments by using simplified risk scores to identify moderate to high-risk patients. Risk assessment allows for facilitation of targeted prophylaxis which positively impacts the patients' surgical outcome and experience. Targeted prophylaxis is efficacious in reducing the institutional incidence of PONV which decreases resource utilization and cost. The perianesthesia nurse is the crucial component in minimizing the PONV in the post-surgical patient. This evaluation of the evidence reveals that preoperative PONV risk screening leads to decreased incidence of PONV for the surgical patient, improves patient satisfaction and reduces postoperative complications. PMID:27037170

  2. 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. PMID:23756077

  3. 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

  4. 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

  5. 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

  6. Ceruletide increases dose dependently both jejunal motor activity and threshold and tolerance to experimentally induced pain in healthy man.

    PubMed Central

    Stacher, G; Steinringer, H; Schmierer, G; Schneider, C; Winklehner, S; Mittelbach, G; De Paolis, C; Praga, C

    1984-01-01

    The effects of ceruletide on jejunal motility and experimentally induced pain were studied in 16 healthy men, who participated each in four experiments and received in random double blind fashion 5, 10, or 20 micrograms ceruletide intramuscularly or placebo. Jejunal pressures were recorded by three perfused catheters with orifices between 10 and 20 cm aboral of the ligament of Treitz. Ceruletide dose dependently diminished phase I and increased phase II type activity and tended to reduce the number, but not the duration, of activity fronts. The number and amplitude of contractions as well as the area under the curve increased significantly and dose dependently as did threshold and tolerance to electrically and threshold to thermally induced pain. Only mild sedative and other side effects occurred. PMID:6714795

  7. 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. PMID:26683907

  8. 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

  9. 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

  10. 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

  11. 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.

  12. Dietary arachidonic acid dose-dependently increases the arachidonic acid concentration in human milk.

    PubMed

    Weseler, Antje R; Dirix, Chantal E H; Bruins, Maaike J; Hornstra, Gerard

    2008-11-01

    Lactation hampers normalization of the maternal arachidonic acid (AA) status, which is reduced after pregnancy and can further decline by the presently recommended increased consumption of (n-3) long-chain PUFA [(n-3) LCPUFA]. This may be unfavorable for breast-fed infants, because they also require an optimum supply of (n-6) LCPUFA. We therefore investigated the LCPUFA responses in nursing mothers upon increased consumption of AA and (n-3) LCPUFA. In a parallel, double-blind, controlled trial, lactating women received for 8 wk no extra LCPUFA (control group, n = 8), 200 (low AA group, n = 9), or 400 (high AA group, n = 8) mg/d AA in combination with (n-3) LCPUFA [320 mg/d docosahexaenoic acid (DHA), 80 mg/d eicosapentaenoic acid, and 80 mg/d other (n-3) fatty acids], or this dose of (n-3) LCPUFA alone [DHA + eicosapentaenoic acid group, n = 8]. Relative concentrations of AA, DHA, and sums of (n-6) and (n-3) LCPUFA were measured in milk total lipids (TL) and erythrocyte phospholipids (PL) after 2 and 8 wk and changes were compared by ANCOVA. The combined consumption of AA and (n-3) LCPUFA caused dose-dependent elevations of AA and total (n-6) LCPUFA concentrations in milk TL and did not significantly affect the DHA and total (n-3) LCPUFA increases caused by (n-3) LCPUFA supplementation only. This latter treatment did not significantly affect breast milk AA and total (n-6) LCPUFA concentrations. AA and DHA concentrations in milk TL and their changes were strongly and positively correlated with their corresponding values in erythrocyte PL (r(2) = 0.27-0.50; P dose dependently increased the AA concentration of their milk TL. PMID:18936218

  13. 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…

  14. 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

  15. Reducing surgical site infection incidence through a network: results from the French ISO-RAISIN surveillance system.

    PubMed

    Astagneau, P; L'Hériteau, F; Daniel, F; Parneix, P; Venier, A-G; Malavaud, S; Jarno, P; Lejeune, B; Savey, A; Metzger, M-H; Bernet, C; Fabry, J; Rabaud, C; Tronel, H; Thiolet, J-M; Coignard, B

    2009-06-01

    Surgical-site infections (SSIs) are a key target for nosocomial infection control programmes. We evaluated the impact of an eight-year national SSI surveillance system named ISO-RAISIN (infection du site opératoire - Réseau Alerte Investigation Surveillance des Infections). Consecutive patients undergoing surgery were enrolled during a three-month period each year and surveyed for 30 days following surgery. A standardised form was completed for each patient including SSI diagnosis according to standard criteria, and several risk factors such as wound class, American Society of Anesthesiologists (ASA) score, operation duration, elective/emergency surgery, and type of surgery. From 1999 to 2006, 14,845 SSIs were identified in 964,128 patients (overall crude incidence: 1.54%) operated on in 838 participating hospitals. The crude overall SSI incidence decreased from 2.04% to 1.26% (P<0.001; relative reduction: -38%) and the National Nosocomial Infections Surveillance system (NNIS)-0 adjusted SSI incidence from 1.10% to 0.74% (P<0.001; relative reduction: -33%). The most significant SSI incidence reduction was observed for hernia repair and caesarean section, and to a lesser extent, cholecystectomy, hip prosthesis arthroplasty, and mastectomy. Active surveillance striving for a benchmark throughout a network is an effective strategy to reduce SSI incidence. PMID:19380181

  16. A multifactorial injury prevention intervention reduces injury incidence in Physical Education Teacher Education students.

    PubMed

    Goossens, L; Cardon, G; Witvrouw, E; Steyaert, A; De Clercq, D

    2016-01-01

    Physical Education Teacher Education (PETE) students are at considerable risk for non-contact sports injuries of the lower extremities. Multifactorial injury prevention interventions including exercises have been successful in sports populations, but no such study has ever been performed in PETE students. This study investigated the efficacy of a multifactorial injury prevention intervention on injury incidence reduction in PETE students. PETE students in the intervention group (n = 154) and in the control group (n = 189) registered sports injuries prospectively. The intervention lasted one academic year and consisted of an injury awareness programme and preventive strategies, implemented by the PETE sports lecturers. Differences in injury incidence between the intervention and control group were tested by Poisson regression Wald tests. There was a trend towards significantly lower incidence rate (2.18 vs. 2.73; p = 0.061) in the intervention group compared with the control group. Students in the intervention group had significantly less acute, first-time and extracurricular injuries. The largest reduction was observed for injuries during unsupervised practice sessions. A multifactorial injury prevention intervention embedded into a regular PETE programme is a promising and feasible strategy to prevent injuries in PETE students. Further research is needed to investigate whether the results may be generalised to other PETE programmes. PMID:25768808

  17. 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

  18. 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

  19. 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. PMID:26142452

  20. Cryoradiolytic reduction of heme proteins: Maximizing dose dependent yield

    PubMed Central

    Denisov, Ilia G.; Victoria, Doreen C.; Sligar, Stephen. G.

    2007-01-01

    Radiolytic reduction in frozen solutions and crystals is a useful method for generation of trapped intermediates in protein based radical reactions. In this communication we define the conditions which provide the maximum yield of one electron reduced myoglobin at 77 K using 60Co γ-irradiation in aqueous glycerol glass. The yield reached 50% after 20 kGy, was almost complete at ∼160 kGy total dose, and does not depend on the protein concentration in the range 0.01 – 5 mM. PMID:18379640

  1. 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

  2. Co-Trimoxazole Prophylaxis Is Associated with Reduced Risk of Incident Tuberculosis in Participants in the Swiss HIV Cohort Study

    PubMed Central

    Walker, A. Sarah; Fehr, Jan; Furrer, Hansjakob; Hoffmann, Matthias; Battegay, Manuel; Calmy, Alexandra; Fellay, Jacques; Di Benedetto, Caroline; Weber, Rainer; Ledergerber, Bruno

    2014-01-01

    Co-trimoxazole reduces mortality in HIV-infected adults with tuberculosis (TB), and in vitro data suggest potential antimycobacterial activity of co-trimoxazole. We aimed to evaluate whether prophylaxis with co-trimoxazole is associated with a decreased risk of incident TB in Swiss HIV Cohort Study (SHCS) participants. We determined the incidence of TB per 1,000 person-years from January 1992 to December 2012. Rates were analyzed separately in participants with current or no previous antiretroviral treatment (ART) using Poisson regression adjusted for CD4 cell count, sex, region of origin, injection drug use, and age. A total of 13,431 cohort participants contributed 107,549 person-years of follow-up: 182 patients had incident TB—132 (73%) before and 50 (27%) after ART initiation. The multivariable incidence rate ratios for cumulative co-trimoxazole exposure per year for persons with no previous ART and current ART were 0.70 (95% confidence interval [CI], 0.55 to 0.89) and 0.87 (95% CI, 0.74 to 1.0), respectively. Co-trimoxazole may prevent the development of TB among HIV-positive persons, especially among those with no previous ART. PMID:24514096

  3. Dose-dependent onset and cessation of action of inhaled budesonide on exhaled nitric oxide and symptoms in mild asthma

    PubMed Central

    Kharitonov, S; Donnelly, L; Montuschi, P; Corradi, M; Collins, J; Barnes, P

    2002-01-01

    Background: Dose dependent anti-inflammatory effects of inhaled corticosteroids in asthma are difficult to demonstrate in clinical practice. The anti-inflammatory effect of low dose inhaled budesonide on non-invasive exhaled markers of inflammation and oxidative stress were assessed in patients with mild asthma. Methods: 28 patients entered a double blind, placebo controlled, parallel group study and were randomly given either 100 or 400 µg budesonide or placebo once daily, inhaled from a dry powder inhaler (Turbohaler), for 3 weeks followed by 1 week without treatment. Exhaled nitric oxide (NO), exhaled carbon monoxide (CO), nitrite/nitrate, S-nitrosothiols, and 8-isoprostanes in exhaled breath condensate were measured four times during weeks 1 and 4, and once a week during weeks 2 and 3. Results: A dose-dependent speed of onset and cessation of action of budesonide was seen on exhaled NO and asthma symptoms. Treatment with 400 µg/day reduced exhaled NO faster (–2.06 (0.37) ppb/day) than 100 µg/day (–0.51 (0.35) ppb/day; p<0.01). The mean difference between the effect of 100 and 400 µg budesonide was –1.55 ppb/day (95% CI –2.50 to –0.60). Pretreatment NO levels were positively related to the subsequent speed of reduction during the first 3–5 days of treatment. Faster recovery of exhaled NO was seen after stopping treatment with budesonide 400 µg/day (1.89 (1.43) ppb/day) than 100 µg/day (0.49 (0.34) ppb/day, p<0.01). The mean difference between the effect of 100 and 400 µg budesonide was 1.40 ppb/day (95% CI –0.49 to 2.31). Symptom improvement was dose-dependent, although symptoms returned faster in patients treated with 400 µg/day. A significant reduction in exhaled nitrite/nitrate and S-nitrosothiols after budesonide treatment was not dose-dependent. There were no significant changes in exhaled CO or 8-isoprostanes in breath condensate. Conclusion: Measurement of exhaled NO levels can indicate a dose-dependent onset and cessation of anti

  4. Polyunsaturated fatty acid supplementation alters proinflammatory gene expression and reduces the incidence of necrotizing enterocolitis in a neonatal rat model.

    PubMed

    Lu, Jing; Jilling, Tamas; Li, Dan; Caplan, Michael S

    2007-04-01

    Although supplementation of preterm formula with polyunsaturated fatty acids (PUFA) has been shown to reduce the incidence of necrotizing enterocolitis (NEC) in animal models and clinical trials, the mechanisms remain elusive. We hypothesized that the protective effect of PUFA on NEC may be due to the ability of PUFA to suppress Toll-like receptor (TLR) 4 and platelet-activating factor receptor (PAFR) gene expression (molecules that are important in the pathogenesis of NEC) in epithelial cells. To investigate the efficacy of different PUFA preparations on NEC in a neonatal rat model, we compared the incidence of NEC among the four PUFA supplemented groups--A: arachidonic acid and docosahexaenoic acid (AA+DHA), B: egg phospholipids (EP), C: DHA, and D: control without PUFA. PUFA supplementation reduced the incidence of NEC and inhibited intestinal PAFR and TLR4 gene expression compared with the controls. To validate the in vivo observations, IEC-6 cells were exposed to PAF after pretreatment with AA or DHA. Both AA and DHA supplementation blocked PAF-induced TLR4 and PAFR mRNA expression in these enterocytes. These results suggest that PUFA modulates gene expression of key factors involved in experimental NEC pathogenesis. These effects might in part explain the protective effect of PUFA on neonatal NEC. PMID:17515866

  5. A practical guide to the implementation of an effective incident reporting scheme to reduce medication error on the hospital ward.

    PubMed

    Webster, Craig S; Anderson, David J

    2002-08-01

    This paper discusses an anonymous incident reporting scheme to reduce drug administration error on the hospital ward, as part of an effective, non-punitive, systems-focused approach to safety. Drug error is costly in terms of increased hospital stay, resources consumed, patient harm, lives lost and careers ruined. Safety initiatives that focus, not on blaming individuals, but on improving the wider system in which personnel work have been adopted in a number of branches of health care. However, in nursing, blame remains the predominant approach for dealing with error, and the ward has seen little application of the systems approach to safety. Safety interventions founded on an effective incident scheme typically pay for themselves in terms of dollar savings arising from averted harm. Recent calls for greater health-care safety require finding new ways to make drug administration safer throughout the hospital, and the scope for such safety gains on the hospital ward remains considerable. PMID:12100674

  6. 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

  7. 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

  8. Efficacy of Aerial Spraying of Mosquito Adulticide in Reducing Incidence of West Nile Virus, California, 2005

    PubMed Central

    Husted, Stan; Jean, Cynthia; Glaser, Carol; Kramer, Vicki

    2008-01-01

    Epidemic transmission of West Nile virus (WNV) in Sacramento County, California, in 2005 prompted aerial application of pyrethrin, a mosquito adulticide, over a large urban area. Statistical analyses of geographic information system datasets indicated that adulticiding reduced the number of human WNV cases within 2 treated areas compared with the untreated area of the county. When we adjusted for maximum incubation period of the virus from infection to onset of symptoms, no new cases were reported in either of the treated areas after adulticiding; 18 new cases were reported in the untreated area of Sacramento County during this time. Results indicated that the odds of infection after spraying were ≈6× higher in the untreated area than in treated areas, and that the treatments successfully disrupted the WNV transmission cycle. Our results provide direct evidence that aerial mosquito adulticiding is effective in reducing human illness and potential death from WNV infection. PMID:18439356

  9. 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

  10. 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

  11. Reduced incidence of postoperative endometritis by the use of Laminaria tents in connection with first trimester abortion.

    PubMed

    Bryman, I; Granberg, S; Norström, A

    1988-01-01

    A Laminaria tent was inserted in the cervical canal of 115 primigravidae prior to vacuum aspiration in the first trimester. A mean dilatation of 9.7 mm was thereby achieved. Only 2 of these patients were treated by antibiotics due to 'mild' endometritis, as compared with 10 of 130 control patients due to endometritis and 7 patients due to 'mild' endometritis. Three non-treated control patients had to undergo laparoscopy due to perforation of the uterus during dilatation of the cervical canal. It is concluded that pre-treatment with the Laminaria tent prior to vacuum aspiration reduces the incidence of per- and post-operative complications. PMID:3176954

  12. 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

  13. Platelet-rich plasma inside the sternotomy wound reduces the incidence of sternal wound infections.

    PubMed

    Serraino, Giuseppe F; Dominijanni, Andrea; Jiritano, Federica; Rossi, Michele; Cuda, Aldo; Caroleo, Santo; Brescia, Adalgisa; Renzulli, Attilio

    2015-06-01

    Despite the large choice of wide-spectrum antibiotic therapy, deep sternal wound infection (DSWI) following cardiac surgery is a life-threatening complication worldwide. This study evaluated that the use of platelet-rich plasma (PRP) applied inside the sternotomy wound would reduce the effect of sternal wound infections, both superficial and deep. Between January 2007 and January 2012, 1093 consecutive patients underwent cardiac surgery through median sternotomy. Patients were divided into two groups. Group B, the study group, included those who received the PRP applied inside the sternotomy wound before closure. Group A, the control group, included patients who received a median sternotomy but without the application of PRP. Antibiotic prophylaxis remained unchanged across the study and between the two groups. Occurrence of DSWI was significantly higher in group A than in group B [10 of 671 (1·5%) versus 1 of 422 (0·20%), P = 0·043]. Also, superficial sternal wound infections (SSWIs) were significantly higher in group A than in group B [19 of 671 (2·8%) versus 2 of 422 (0·5%), P = 0·006]. The use of PRP can significantly reduce the occurrence of DSWI and SSWI in cardiac surgery. PMID:23692143

  14. Atraumatic needle reduces the incidence of post-lumbar puncture syndrome.

    PubMed

    Müller, B; Adelt, K; Reichmann, H; Toyka, K

    1994-05-01

    We investigated the occurrence of the post-lumbar syndrome (PPS) in relation to the puncture technique used, in a prospective randomised double-blind study comprising 100 patients. A new atraumatic 22-gauge cannula was compared with a 20-gauge cannula with a Quincke bevel. The atraumatic cannula is a needle with a tip shaped like a closed circular cone with a lateral opening, usually used with an outer cannula (introducer). The study showed that both the frequency of PPS and of acute complaints during lumbar puncture can be dramatically reduced with the atraumatic puncture technique. A marked PPS occurred after lumbar puncture with the 20-gauge cannula in 31% of patients, whereas only 5% of patients reported marked post-puncture symptoms after lumbar puncture with the atraumatic cannula. PMID:7931432

  15. Radiation safety education reduces the incidence of adult fingers on neonatal chest radiographs.

    PubMed

    Sahota, N; Burbridge, B E; Duncan, M D

    2014-06-01

    A previous audit revealed a high frequency of adult fingers visualised on neonatal intensive care unit (NICU) chest radiographs-representing an example of inappropriate occupational radiation exposure. Radiation safety education was provided to staff and we hypothesised that the education would reduce the frequency of adult fingers visualised on NICU chest radiographs. Two cross-sectional samples taken before and after the administration of the education were compared. We examined fingers visualised directly in the beam, fingers in the direct beam but eliminated by technologists editing the image, and fingers under the cones of the portable x-ray machine. There was a 46.2% reduction in fingers directly in the beam, 50.0% reduction in fingers directly in the beam but cropped out, and 68.4% reduction in fingers in the coned area. There was a 57.1% overall reduction in adult fingers visualised, which was statistically significant (Z value - 7.48, P < 0.0001). This study supports radiation safety education in minimising inappropriate occupational radiation exposure. PMID:24705198

  16. 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

  17. ABCA2 transporter deficiency reduces incidence of TRAMP prostate tumor metastasis and cellular chemotactic migration

    PubMed Central

    Mack, Jody T.; Helke, Kristi L.; Normand, Gabrielle; Green, CoDanielle; Townsend, Danyelle M.; Tew, Kenneth D.

    2010-01-01

    In order to study the effects of ATP-binding cassette transporter 2 (ABCA2) deficiency on the progression of prostate cancer, congenic Abca2 knockout (KO) mice were crossed to the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. ABCA2 expression was elevated in wild-type/TRAMP (WT/Tg) dorsal prostate, a region comprising the most aggressive tumors in this model, compared to non-transgenic WT mice. Primary prostate tumor progression was similar in KO/Tg and WT/Tg mice with respect to pathological score, prostate tumor growth, as calculated using MRI volumetry, and proliferative index, as determined by PCNA immunostaining. Vimentin, a marker of the epithelial-mesenchymal transition, was expressed at similar levels in prostate, but elevated in histologically normal seminal vesicles (SV) in KO/Tg mice (P < 0.02), concomitant with an increased SV volume (P < 0.01). These changes in the SV did not exacerbate the metastatic phenotype of this disease model; rather, KO/Tg mice aged 20-25 weeks had no detectable metastases while 38% of WT/Tg developed metastases to lung and/or lymph nodes. The absence of a metastatic phenotype in KO/Tg mice was reprised in stable ABCA2 knockdown (KD) cells where chemotactic, but not random, migration was impaired (P = 0.0004). Expression levels of sphingolipid biosynthetic enzymes were examined due to the established link of the transporter with sphingolipid homeostasis. Galactosylceramide synthase (GalCerS) mRNA levels were over 8-fold higher in KD cells (P = 0.001), while lactosylceramide synthase (LacCerS) and CTP:choline cytidylyltransferase (CCT) were significantly reduced (P < 0.0001 and 0.03, respectively). Overall, we demonstrate that ABCA2 deficiency inhibits prostate tumor metastasis in vivo and decreases chemotactic potential of cells, conceivably due to altered sphingolipid metabolism. PMID:21041019

  18. 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

  19. 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

  20. [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

  1. Branched Chain Fatty Acids Reduce the Incidence of Necrotizing Enterocolitis and Alter Gastrointestinal Microbial Ecology in a Neonatal Rat Model

    PubMed Central

    Ran-Ressler, Rinat R.; Khailova, Ludmila; Arganbright, Kelly M.; Adkins-Rieck, Camille K.; Jouni, Zeina E.; Koren, Omry; Ley, Ruth E.; Brenna, J. Thomas; Dvorak, Bohuslav

    2011-01-01

    Introduction Branched chain fatty acids (BCFA) are found in the normal term human newborn's gut, deposited as major components of vernix caseosa ingested during late fetal life. We tested the hypothesis that premature infants' lack of exposure to gastrointestinal (GI) BCFA is associated with their microbiota and risk for necrotizing enterocolitis (NEC) using a neonatal rat model. Methods Pups were collected one day before scheduled birth. The pups were exposed to asphyxia and cold stress to induce NEC. Pups were assigned to one of three experimental treatments. DF (dam-fed) ; Control, hand-fed rat milk substitute ; BCFA, hand-fed rat milk substitute with 20%w/w BCFA. Total fat was equivalent (11%wt) for both the Control and BCFA groups. Cecal microbiota were characterized by 16S rRNA gene pyrosequencing, and intestinal injury, ileal cytokine and mucin gene expression, interleukin-10 (IL-10) peptide immunohistochemistry, and BCFA uptake in ileum phospholipids, serum and liver were assessed. Results NEC incidence was reduced by over 50% in the BCFA group compared to the Control group as assessed in ileal tissue; microbiota differed among all groups. BCFA-fed pups harbored greater levels of BCFA-associated Bacillus subtilis and Pseudomonas aeruginosa compared to Controls. Bacillus subtilis levels were five-fold greater in healthy pups compared to pups with NEC. BCFA were selectively incorporated into ileal phospholipids, serum and liver tissue. IL-10 expression increased three-fold in the BCFA group versus Controls and no other inflammatory or mucosal mRNA markers changed. Conclusion At constant dietary fat level, BCFA reduce NEC incidence and alter microbiota composition. BCFA are also incorporated into pup ileum where they are associated with enhanced IL-10 and may exert other specific effects. PMID:22194981

  2. 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...

  3. Use of the Tego needlefree connector is associated with reduced incidence of catheter-related bloodstream infections in hemodialysis patients

    PubMed Central

    Brunelli, Steven M; Njord, Levi; Hunt, Abigail E; Sibbel, Scott P

    2014-01-01

    Background and objectives Catheter-related bloodstream infections (CRBSIs) are common in hemodialysis patients using central venous catheters, and catheter occlusion also occurs frequently. The Tego needlefree connector was developed to reduce the incidence of these complications; however, existing studies of its effectiveness and safety are limited. Materials and methods This retrospective analysis compared outcomes among patients of a large dialysis organization receiving in-center hemodialysis using a central venous catheter with either the Tego connector or standard catheter caps between October 1 and June 30, 2013. Incidence rates for intravenous (IV) antibiotic starts, receipt of an IV antibiotic course, positive blood cultures, mortality, and missed dialysis treatments were calculated, and incidence-rate ratios (IRRs) were estimated using Poisson regression models. Utilization of erythropoiesis-stimulating agents (ESAs) and thrombolytics was described for each patient-month and compared using mixed linear models. Models were run without adjustment, adjusted for covariates that were imbalanced between cohorts, or fully adjusted for all potential confounders. Results The analysis comprised 10,652 Tego patients and 6,493 controls. Tego use was independently associated with decreased risk of CRBSI, defined by initiation of IV antibiotics (adjusted IRR 0.92, 95% confidence interval [CI] 0.87–0.97) or initiation of IV antibiotic course (adjusted IRR 0.89, 95% CI 0.84–0.95). Tego use was independently associated with decreased rate of missed dialysis treatments (adjusted IRR 0.98, 95% CI 0.97–1.00); no significant difference between Tego and control cohorts was observed with respect to mortality. Tego use was associated with decreased likelihood of thrombolytic use (adjusted per-month probability of 5.6% versus 6.2% for controls) and lower utilization of ESAs in study months 7–9. Conclusion Use of the Tego connector may reduce the risk of CRBSI and result

  4. 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.

  5. 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.

  6. 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.

  7. Fermented milk containing Lactobacillus casei strain Shirota reduces incidence of hard or lumpy stools in healthy population.

    PubMed

    Sakai, Takafumi; Makino, Hiroshi; Ishikawa, Eiji; Oishi, Kenji; Kushiro, Akira

    2011-06-01

    The objective of the present study was to investigate the efficacy of fermented milk containing Lactobacillus casei strain Shirota (LcS) in a healthy population. Healthy subjects with Bristol Stool Form Scale (BS) score < 3.0 were randomized to fermented milk treatment for 3 weeks or non-intervention control. The primary endpoint was the proportion of subjects that produced hard or lumpy stools (HLS) ≥ 25% of bowel movements (H-HLS). Secondary endpoints included changes in BS score, constipation-related symptom scores and stool parameters. Efficacy was analyzed in 39 subjects. After 3 weeks of treatment the proportion of H-HLS subjects had significantly decreased from 73.7% to 36.8%, whereas in the control group the proportion had increased from 75.0% to 85.0% during the same period (P = 0.002). The BS score was significantly improved after the treatment compared with the control (P < 0.001). In conclusion, daily consumption of fermented milk containing LcS reduced the incidence of HLS. PMID:21322768

  8. 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

  9. Mammary gland-specific ablation of focal adhesion kinase reduces the incidence of p53-mediated mammary tumour formation

    PubMed Central

    van Miltenburg, M H A M; van Nimwegen, M J; Tijdens, I; Lalai, R; Kuiper, R; Klarenbeek, S; Schouten, P C; de Vries, A; Jonkers, J; van de Water, B

    2014-01-01

    Background: Elevated expression of focal adhesion kinase (FAK) occurs in numerous human cancers including colon-, cervix- and breast cancer. Although several studies have implicated FAK in mammary tumour formation induced by ectopic oncogene expression, evidence supporting a role for FAK in spontaneous mammary tumour development caused by loss of tumour suppressor genes such as p53 is lacking. Alterations in the tumour suppressor gene p53 have been implicated in over 50% of human breast cancers. Given that elevated FAK expression highly correlates with p53 mutation status in human breast cancer, we set out to investigate the importance of FAK in p53-mediated spontaneous mammary tumour development. Methods: To directly assess the role of FAK, we generated mice with conditional inactivation of FAK and p53. We generated female p53lox/lox/FAK+/+/WapCre, p53lox/lox/FAKflox/+/WapCre and p53lox/lox/FAKflox/−/WapCre mice, and mice with WapCre-mediated conditional expression of p53R270H, the mouse equivalent of human p53R273H hot spot mutation, together with conditional deletion of FAK, P53R270H/+/FAKlox/+/WapCre and p53R270H/+/FAKflox/−/WapCre mice. All mice were subjected to one pregnancy to induce WapCre-mediated deletion of p53 or expression of p53 R270H, and Fak genes flanked by two loxP sites, and subsequently followed the development of mammary tumours. Results: Using this approach, we show that FAK is important for p53-induced mammary tumour development. In addition, mice with the mammary gland-specific conditional expression of p53 point mutation R270H, the mouse equivalent to human R273H, in combination with conditional deletion of Fak showed reduced incidence of p53R270H-induced mammary tumours. In both models these effects of FAK were related to reduced proliferation in preneoplastic lesions in the mammary gland ductal structures. Conclusions: Mammary gland-specific ablation of FAK hampers p53-regulated spontaneous mammary tumour formation. Focal adhesion

  10. 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

  11. 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

  12. Empagliflozin (BI 10773), a Potent and Selective SGLT2 Inhibitor, Induces Dose-Dependent Glucosuria in Healthy Subjects.

    PubMed

    Seman, Leo; Macha, Sreeraj; Nehmiz, Gerhard; Simons, Gudrun; Ren, Bailuo; Pinnetti, Sabine; Woerle, Hans J; Dugi, Klaus

    2013-04-01

    Empagliflozin is an orally available, selective inhibitor of sodium glucose cotransporter 2. In this study, single oral doses of empagliflozin from 0.5 to 800 mg were not associated with any clinically significant safety concerns in healthy male volunteers. The incidence of adverse events (AEs) was similar in subjects receiving placebo (22.2%) or empagliflozin (25.0%) in the single rising dose part of the study and after 50 mg empagliflozin under fed (28.6%) or fasted (28.6%) conditions. The most frequent AE was headache. No clinically relevant changes in laboratory or electrocardiogram (ECG) measurements were observed. Single oral doses of empagliflozin were rapidly absorbed, reaching peak levels after 1.0-2.1 hours. Increases in empagliflozin exposure were roughly dose-proportional and a dose-dependent increase in urinary glucose excretion was observed for empagliflozin doses up to 100 mg. After ingestion of 50 mg empagliflozin in conjunction with a high-fat, high-calorie meal, no clinically relevant changes in exposure were found, indicating that empagliflozin can be administered independent of food. Empagliflozin up to 800 mg did not generate clinically significant safety concerns in healthy male subjects. The pharmacokinetic properties of empagliflozin support once daily administration independent of food. PMID:27121669

  13. Lenograstim reduces the incidence of febrile episodes, when compared with filgrastim, in multiple myeloma patients undergoing stem cell mobilization.

    PubMed

    Orciuolo, Enrico; Buda, Gabriele; Marturano, Emerenziana; Mauro, Elisa; Milone, Giuseppe; Cangialosi, Clotilde; Di Renzo, Nicola; Pastore, Domenico; Specchia, Giorgina; De Paolis, Maria Rosaria; Mazza, Patrizio; Pietrantuono, Giuseppe; Petrini, Mario

    2011-07-01

    The aim of this study was to show a lower incidence of febrile episodes in multiple myeloma patients receiving lenograstim vs. filgrastim after high-dose cyclophosphamide for stem cell mobilization. Patients treated with cyclophosphamide were randomly assigned to receive filgrastim or lenograstim. Primary endpoint was the incidence of febrile episodes. 5.1% patients developed a febrile episode, 9.1% with filgrastim and 1.1% with lenograstim. Lenograstim group presented a significantly higher absolute CD34+ cell number compared with the filgrastim group but no differences were detected for collection efficacy. The study demonstrated a lower incidence of febrile episodes with lenograstim compared to filgrastim. PMID:21134693

  14. 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

  15. 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

    2016-01-01

    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

  16. Dose-dependent effects of isoflurane on regional activity and neural network function: A resting-state fMRI study of 14 rhesus monkeys: An observational study.

    PubMed

    Lv, Peilin; Xiao, Yuan; Liu, Bin; Wang, Yuqing; Zhang, Xiang; Sun, Huaiqiang; Li, Fei; Yao, Li; Zhang, Wenjing; Liu, Lu; Gao, Xin; Wu, Min; Tang, Yingying; Chen, Qin; Gong, Qiyong; Lui, Su

    2016-01-12

    The dose-dependent effect of isoflurane on cerebral regional activity and functional connectivity (FC) in 14 rhesus monkeys was investigated using resting-state functional MRI. Amplitude of low-frequency fluctuations (ALFF) decreased in the cerebellum, visual cortex, and cortico-subcortical network when the isoflurane dose changed from 1.0 to 1.3 MAC. ALFF decreased in the arousal system, cerebellum, sensory, visual areas, cortico-subcortical network and default mode network and increased in the bilateral dorsal prefrontal cortices, frontal eye fields and motor-related areas from 1.0 to 1.6 MAC. FC of the default mode network, frontal-parietal, cortico-subcortical, motor, sensory, auditory and visual areas was reduced when isoflurane increased from 1.0 to 1.3 MAC. FC decreased in more widespread areas, especially in regions of cortico-subcortical networks and limbic systems, when isoflurane further increased from 1.0 to 1.6 MAC. Both dose-dependent decreased and increased ALFF were separately observed, while FC deteriorated as the anesthesia deepened. These results suggest that changes continue to occur past the loss of consciousness, and the dose-dependent effects of isoflurane are different with regard to regional function and neural network integration. PMID:26633103

  17. 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. PMID

  18. Risperidone-induced Gingival Bleeding in a Pediatric Case: A Dose-dependent Side Effect

    PubMed Central

    Hergüner, Sabri; Özayhan, Hatice Yardım; Erdur, Emire Aybuke

    2016-01-01

    There are several case reports on risperidone-related bleeding; however, to our knowledge, there is no report about gingival bleeding associated with risperidone in the literature. We presented a case who experienced gingival bleeding when risperidone dose was increased to 0.5 mg/day, and subsided after decreasing the dose to 0.25 mg/day, suggesting a dose-dependent side-effect. The bleeding side effect of risperidone might be caused by several mechanisms, including 5-hydroxytryptamine 2A receptor antagonism. Although bleeding associated with risperidone is rarely reported, clinicians should be aware of this side effect. PMID:27121433

  19. Dose-dependency of the ratio between carbamazepine serum level and dosage in patients with epilepsy.

    PubMed

    Kumps, A H

    1981-01-01

    Carbamazepine serum levels have been determined by gas-liquid chromatography in 24 children and 26 adults with epilepsy on chronic carbamazepine treatment. A significant correlation has been found between carbamazepine steady-state levels and doses per kilogram body weight in both children (p less than 0.01) and adults (p less than 0.05). This relationship is characterized by a significant decline in the level/dose ratio with the doses for adults (p less than 0.001) and, to a lesser extent, for children (p less than 0.05). These results are consistent with a dose-dependent bioavailability. PMID:7324091

  20. Risperidone-induced Gingival Bleeding in a Pediatric Case: A Dose-dependent Side Effect.

    PubMed

    Hergüner, Sabri; Özayhan, Hatice Yardım; Erdur, Emire Aybuke

    2016-05-31

    There are several case reports on risperidone-related bleeding; however, to our knowledge, there is no report about gingival bleeding associated with risperidone in the literature. We presented a case who experienced gingival bleeding when risperidone dose was increased to 0.5 mg/day, and subsided after decreasing the dose to 0.25 mg/day, suggesting a dose-dependent side-effect. The bleeding side effect of risperidone might be caused by several mechanisms, including 5-hydroxytryptamine 2A receptor antagonism. Although bleeding associated with risperidone is rarely reported, clinicians should be aware of this side effect. PMID:27121433

  1. 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

  2. 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

  3. 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. PMID:26363171

  4. Analysis of Tensile Deformation and Failure in Austenitic Stainless Steels: Part II- Irradiation Dose Dependence

    SciTech Connect

    Kim, Jin Weon; Byun, Thak Sang

    2010-01-01

    Irradiation effects on stable and unstable deformations and fracture behaviors in irradiated austenitic stainless steels (SSs) have been studied in detail based on the equivalent true stress versus true strain curves. An iterative technique in finite element simulation was used to obtain the equivalent true stress-true strain data from experimental tensile curves. It was shown that the strain hardening rate was retained at a high level on unstable deformation after significant irradiation and was independent of the irradiation dose up to the initiation of a localized necking. The equivalent fracture stress was nearly independent of irradiation dose before the damage (embrittlement) mechanism changed. In low dose range (< ~ 2dpa), the fracture strain and tensile fracture energy decreased rapidly with dose and at higher doses they decreased gradually to saturated levels, which were still high for irradiated materials. It was also found that the fracture properties for EC316LN SS were less sensitive to irradiation dose 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.

  5. Dose-Dependent Z-Scan Measurements on GAFCHROMIC® Dosimetry Films

    NASA Astrophysics Data System (ADS)

    Koulouklidis, A.; Karava, K.; Kalef-Ezra, J.; Cohen, S.

    2010-11-01

    The open- and closed-aperture z-scan techniques are applied for investigating the non-linear optical response of GAFCHROMIC® docimetry films, irradiated by 60Co γ-rays. Upon irradiation the films active diacetylene layers undergo radiation-Dose-dependent polymerization to the so-called blue polydiacetylene form. A cw He/Ne laser is used as the light source. Open-aperture z-scan measurements reveal reverse saturable absorption while Dose-dependent thermal effects become apparent with increasing laser intensity. Those effects are tentatively attributed to the transition from the blue form to the conformer red form of the active layer (thermochromic transition) which, for the highest available power, appears to be irreversible. For minimizing the importance of thermal effects the closed aperture z-scan technique is applied with a chopped laser beam. The z-scan curves recorded under those conditions reveal a sensitivity on absorbed Dose which is comparable to that of the films linear absorbance.

  6. 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.

  7. 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

  8. Dose-dependent responses of avian daily rhythms to artificial light at night.

    PubMed

    de Jong, Maaike; Jeninga, Lizanne; Ouyang, Jenny Q; van Oers, Kees; Spoelstra, Kamiel; Visser, Marcel E

    2016-03-01

    Recent studies have shown that animals are affected by night-time light exposure. Light is a continuous variable, but our knowledge on how individuals react to different light intensities during the night is limited. We therefore determined the relationship between night light intensity and the behaviour and physiology of great tits (Parus major). We measured daily activity patterns and melatonin levels in 35 males exposed to five different light intensities and found strong, dose-dependent effects. Activity onset was increasingly advanced, and activity offset delayed with higher light intensities. Furthermore, night-time activity increased and melatonin levels measured at midnight decreased with higher intensities. In this experimental study, we demonstrate for the first time dose-dependent effects of artificial light at night on birds' daily activity patterns and melatonin levels. Our results imply that these effects are not limited to a certain threshold, but emerge even when nocturnal light levels are slightly increased. However, in a natural area, these effects may be limited as artificial light levels are commonly low; light intensities drop rapidly with distance from a light source and birds can avoid exposure to light at night. Future studies should thus focus on examining the impact of different intensities of light at night in the wild. PMID:26703233

  9. 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

  10. 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.

  11. Dose Dependent Effect of Iso-Octane on HaCaT: A Model Study

    PubMed Central

    Das, Lopamudra; Das, Soumen; Chatterjee, Jyotirmoy

    2015-01-01

    Objective: Improved understanding of cytotoxicity under chemical assaults may be achieved by multimodal analysis of cellular morphology, viability, molecular expressions, and biophysical properties. Materials and Methods: In this study dose-dependent effects of an organic solvent (OS), iso-octane (IO), known to cause skin irritation, has been explored multimodally for understanding its effect on structural and functional profile of normal epithelial cell population in vitro. Results: Under IO exposures, after 5 h there was a sharp decrease in viability of HaCaT with increasing doses which may be due to disruption in cellular association noted via immunocytochemical study and was further supported by the decreased expression of E-cadherin at transcriptomic level. Dislocation of E-cadherin from membrane to the cytoplasm occurred with increasing doses. The dose-dependent changes in varied aspects of bioelectrical properties, having plausible correlation with cellular viability, association, and adherence were noteworthy at 5 h of IO exposure. Evaluation of biomechanical properties by micropipette aspiration showed a distinct change in cellular stiffness in terms of increase in suction force and post-suction alteration in cellular shape. The cells became stiffer and fragile with increasing IO doses. Conclusion: Present study explicated dose–dependent cytotoxicity of IO on HaCaT and explored the usefulness of this approach to develop in vitro model system to evaluate epithelial toxicity with level-free markers. PMID:26862266

  12. Reduced incidence of invasive pneumococcal disease after introduction of the 13-valent conjugate vaccine in Navarre, Spain, 2001-2013.

    PubMed

    Guevara, Marcela; Ezpeleta, Carmen; Gil-Setas, Alberto; Torroba, Luis; Beristain, Xabier; Aguinaga, Aitziber; García-Irure, José Javier; Navascués, Ana; García-Cenoz, Manuel; Castilla, Jesús

    2014-05-01

    Pneumococcal conjugate vaccines (PCVs) were licensed for use in children and became available for private purchase in Spain in 2001 (PCV7), 2009 (PCV10) and 2010 (PCV13). This study evaluates changes in the incidence of invasive pneumococcal disease (IPD) and the pattern of serotypes isolated in Navarre, Spain, between the period of use of PCV7 (2004-2009) and that of PCV13 (2010-2013). The percentage of children <2 years who received at least one dose of PCV in these periods ranged from 25 to 61% and 61 to 78%, respectively. Between the periods 2004-2009 and 2010-2013 IPD incidence declined by 37%, from 14.9 to 9.4 cases/100,000 inhabitants (p<0.001). In children <5 years it fell by 69% (p<0.001), in persons aged 5-64 years, by 34% (p<0.001), and in those ≥ 65, by 23% (p=0.024). The incidence of cases due to PCV13 serotypes declined by 81% (p<0.001) in children <5 years and by 52% (p<0.001) in the whole population. No significant changes were seen in the distribution of clinical presentations or in disease severity. The incidence of IPD has declined and the pattern of serotypes causing IPD has changed notably in children and moderately in adults following the replacement of PCV7 by PCV13. PMID:24674661

  13. 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

  14. [Enalapril reduces the degree of left ventricular remodeling after acute myocardial infarction and reduces the incidence of arrhythmia in ischemic disease].

    PubMed

    Altieri, P I; González, R; de Mello, W; Escobales, N

    1994-12-01

    The present study shows that enalapril prevents the excessive remodeling of the left ventricle after acute myocardial infarction. This randomized and double blind clinical study analysed 50 patients with an inferior myocardial infarction. The effect of enalapril was evaluated through cardiac volumes, ejection fraction, neurohormonal levels and incidence of the left ventricle disfunction after acute myocardial infarction. The patients treated with enalapril showed a significant reduction on the values of nor-epinefrine, angiotensine II, natriuretic hormone and vasopressine, four weeks after initiation of treatment. The ejection fraction and the level of the wall movement was more favourable, four weeks after infarction, in the group treated with enalapril. The incidence of congestive heart failure and arrhythmias was lower in the group treated with enalapril. So, we conclude that enalapril is a drug that prevents the excessive remodelling of the left ventricle after an acute myocardial infarction. PMID:7873221

  15. 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

  16. 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

  17. Monensin causes dose dependent inhibition of Mycobacterium avium subspecies paratuberculosis in radiometric culture

    PubMed Central

    Greenstein, Robert J; Su, Liya; Whitlock, Robert H; Brown, Sheldon T

    2009-01-01

    Background Mycobacterium avium subspecies paratuberculosis (MAP) causes a chronic wasting diarrheal disease in ruminants called Johne's disease, that is evocative of human inflammatory bowel disease (IBD). Agents used to treat IBD, called "anti-inflammatories", immuno-modulators" and "immuno-suppressants" inhibit MAP growth in culture. We concluded that, unknowingly, the medical profession has been treating MAP since sulfasalazine's introduction in 1942. Monensin, called a "Growth Enhancer" in cattle, ameliorates Johne's disease without a documented mechanism of action. We hypothesized that Monensin would inhibit MAP in culture. Methods Using the radiometric 14CO2 Bactec® system, that expresses mycobacterial growth in arbitrary growth index (GI) units, we studied the effect of Monensin on the growth kinetic of MAP isolated from humans with IBD ("Dominic", "Ben" & UCF-4) and cattle with Johne's disease (303 & ATCC 19698.) Results are expressed as percent inhibition of cumulative GI (%–ΔcGI). Results The positive control Clofazimine inhibits every strain tested. The negative controls Cycloheximide & Phthalimide, have no inhibition on any MAP strain. Monensin has dose dependent inhibition on every MAP strain tested. The most susceptible human isolate was UCF-4 (73% – ΔcGI at 1 μg/ml) and bovine isolate was 303 (73% – ΔcGI at 4 μg/ml.) Monensin additionally inhibits M. avium ATCC 25291 (87% – ΔcGI at 64 μg/ml) & BCG (92% – ΔcGI at 16 μg/ml). Discussion We show that in radiometric culture the "Growth Enhancer" Monensin causes dose dependent inhibition of mycobacteria including MAP. We posit that the "Growth Enhancer" effect of Monensin may, at least in part, be due to inhibition of MAP in clinical or sub-clinical Johne's disease. PMID:19338684

  18. Dose-dependent effects of perinatal hypothyroidism on postnatal testicular development in rat offspring.

    PubMed

    Kobayashi, Kenichi; Kubota, Hisayo; Hojo, Rieko; Miyagawa, Muneyuki

    2014-01-01

    The role of thyroid hormones in gonad development remains incompletely understood. We examined the dose-related effects of perinatal hypothyroidism induced by a reversible goitrogen, 6-propyl-2-thiouracil (PTU), on reproductive development in male rat offspring. Timed-pregnant Sprague-Dawley rats were orally administered PTU (0, 0.5, 1.0, or 2.0 mg/kg/day) by gavage from gestational day 15 through postnatal day 20. We observed a significant dose-dependent decrease in body weight in offspring with PTU exposure up to 13 weeks of age, but body weight became comparable among groups by 26 weeks of age. Testicular weight tended to be lower up to 7 weeks but was higher after 13 weeks of age. Epididymis weight was not different among the groups at any age. Plasma concentrations of thyroxine and triiodothyronine in the PTU groups were significantly lower at 3 weeks of age but recovered to normal levels by 26 weeks of age. No dose-related trend in plasma testosterone concentrations was found. Seminiferous tubules were larger at 13 and 26 weeks of age with PTU exposure. The number of Sertoli cells was significantly higher from 3 through 26 weeks of age. The number of Leydig cells was significantly lower up to 7 weeks of age but was comparable among groups from 13 weeks of age onwards. Thus, transient gestational and lactational thyroid hormone suppression induced small testes in early life but led to paradoxical dose-dependent testicular enlargement in adults as indicated partly by larger seminiferous tubules with numerous Sertoli cells in male rat offspring. PMID:25392277

  19. 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

  20. Radiation fosters dose-dependent and chemotherapy-induced immunogenic cell death

    PubMed Central

    Golden, Encouse B; Frances, Derek; Pellicciotta, Ilenia; Demaria, Sandra; Helen Barcellos-Hoff, Mary; Formenti, Silvia C

    2014-01-01

    Established tumors are typified by an immunosuppresive microenvironment. Countering this naturally occurring phenomenon, emerging evidence suggests that radiation promotes a proimmunogenic milieu within the tumor capable of stimulating host cancer-specific immune responses. Three cryptic immunogenic components of cytotoxic-agent induced cell death—namely, calreticulin cell surface exposure, the release of high mobility group box 1 (HMGB1) protein, and the liberation of ATP—have been previously shown to be critical for dendritic cell (DC) activation and effector T-cell priming. Thus, these immune-mobilizing components commonly presage tumor rejection in response to treatment. We initially set out to address the hypothesis that radiation-induced immunogenic cell death (ICD) is dose-dependent. Next, we hypothesized that radiation would enhance chemotherapy-induced ICD when given concomitantly, as suggested by the favorable clinical outcomes observed in response to analogous concurrent chemoradiation regimens. Thus, we designed an in vitro assay to examine the 3 hallmark features of ICD at clinically relevant doses of radiation. We then tested the immunogenic-death inducing effects of radiation combined with carboplatin or paclitaxel, focusing on these combinations to mimic chemoradiation regimens actually used in clinical trials of early stage triple negative [NCT0128953/NYU-10–01969] and locally advanced [NYU-06209] breast cancer patients, respectively. Despite the obvious limitations of an in vitro model, radiotherapy produced both a dose-dependent induction and chemotherapeutic enhancement of ICD. These findings provide preliminary evidence that ICD stimulated by either high-dose radiotherapy alone, or concurrent chemoradiation regimens, may contribute to the establishment of a peritumoral proimmunogenic milieu. PMID:25071979

  1. 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. PMID:26275148

  2. 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

  3. 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

  4. Reduced incidence of acute graft versus host disease (GVHD) of the gut in Chinese carriers of Helicobacter pylori during allogeneic bone marrow transplantation.

    PubMed

    Au, W Y; Wong, R W M; Wong, B C Y; Lie, A K W; Liang, R; Leung, A Y H; Kwong, Y-L

    2004-01-01

    Helicobacter pylori ( H. Pylori) infection is associated with gastritis and peptic ulcer, but its relationship with gut graft versus host disease (GVHD) is unknown. We investigated the association between H. Pylori carriage and incidence and severity of mucosal toxicity and GVHD in 128 consecutive matched sibling stem cell transplantation (SCT) recipients. Using a verified enzyme linked immunosorbant assay (ELISA), 43.5% of patients had H. Pylori exposure before SCT. There was absolute concordance between serological and breath test data in 40 prospective cases. There was no increased risk in WHO grade 3 or 4 mucositis in H. Pylori carriers. Significant (grade II or above) overall GVHD was only predicted by preceding mucositis (p<0.001), while gut GVHD was associated with increased age (p=0.001) and mucositis (p=0.022). Despite increased incidence with age, H. Pylori carriage was associated with significantly reduced risk of gut GVHD (p=0.04) but not overall GVHD. The reduced risk of immune-mediated gut inflammation in H. Pylori carriers after SCT may be related to the known reduced incidence of inflammatory bowel disease in chronic H. Pylori carriers. PMID:14551739

  5. 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

  6. Green tea, phytic acid, and inositol in combination reduced the incidence of azoxymethane-induced colon tumors in Fisher 344 male rats.

    PubMed

    Khatiwada, Janak; Verghese, Martha; Davis, Shurrita; Williams, Leonard L

    2011-11-01

    Experimental as well as epidemiologic studies in human populations provide evidence that consumption of phytochemicals reduces the incidence of degenerative diseases. Green tea (GT) catechins are known for their antioxidative potential. Phytic acid (PA) also acts as a natural antioxidant and may have numerous health benefits. This experiment was designed to investigate the inhibitory effects of combinations of 1% and 2% GT, PA, and inositol (I) in reducing the incidence of azoxymethane-induced colon tumors in Fisher 344 male rats. After an acclimatization period of 1 week, nine groups of rats (15 rats per group) were initially assigned to consume AIN 93 G diet and later AIN 93 M diet after 20 weeks of age. Treatments were given in drinking water. All rats received azoxymethane injections (16 mg/kg of body weight) subcutaneously at 7 and 8 weeks of age. Rats were killed at 45 weeks of age by CO(2) euthanasia. Tumor incidence (93.76%) and the number of tumors per tumor-bearing rat ratio (2.25) were significantly (P<.05) higher in the control group compared with treatment groups. Glutathione S-transferase activity was significantly (P<.05) higher in rats fed combinations of 2% GT+PA+I and GT+PA (33.25 ± 1.23 and 29.83 ± 1.10 μmol/mL, respectively) compared with other groups. These findings suggest that the synergistic effect of the 2% level of GT, PA, and I may reduce the incidence of colon tumors and therefore have potential as a chemopreventive agent. PMID:21501094

  7. 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

  8. 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

  9. Characterization of dose-dependent Young's modulus for a radiation-sensitive polymer gel

    NASA Astrophysics Data System (ADS)

    Crescenti, Remo A.; Bamber, Jeffrey C.; Bush, Nigel L.; Webb, Steve

    2009-02-01

    Radiation-sensitive polymer gels for clinical dosimetry have been intensively investigated with magnetic resonance imaging (MRI) because the transversal magnetic relaxation time is dependent on irradiation dose. MRI is expensive and not easily available in most clinics. For this reason, low-cost, quick and easy-to-use potential alternatives such as optical computed tomography (CT), x-ray CT or ultrasound attenuation CT have also been studied by others. Here, we instead evaluate the dose dependence of the elastic material property, Young's modulus and the dose response of the viscous relaxation of radiation-sensitive gels to discuss their potential for dose imaging. Three batches of a radiation-sensitive polymer gel (MAGIC gel) samples were homogeneously irradiated to doses from 0 Gy to 45.5 Gy. Young's modulus was computed from the measured stress on the sample surface and the strain applied to the sample when compressing it axially, and the viscous relaxation was determined from the stress decay under sustained compression. The viscous relaxation was found not to change significantly with dose. However, Young's modulus was dose dependent; it approximately doubled in the gels between 0 Gy and 20 Gy. By fitting a second-order polynomial to the Young's modulus-versus-dose data, 99.4% of the variance in Young's modulus was shown to be associated with the change in dose. The precision of the gel production, irradiation and Young's modulus measurement combined was found to be 4% at 2 Gy and 3% at 20 Gy. Potential sources of measurement error, such as those associated with the boundary conditions in the compression measurement, inhomogeneous polymerization, temperature (up to 1% error) and the evaporation of water from the sample (up to 1% error), were estimated and discussed. It was concluded that Young's modulus could be used for dose determination. Imaging techniques such as elastography may help to achieve this if they can provide a local measurement of Young

  10. Characterization of dose-dependent Young's modulus for a radiation-sensitive polymer gel.

    PubMed

    Crescenti, Remo A; Bamber, Jeffrey C; Bush, Nigel L; Webb, Steve

    2009-02-21

    Radiation-sensitive polymer gels for clinical dosimetry have been intensively investigated with magnetic resonance imaging (MRI) because the transversal magnetic relaxation time is dependent on irradiation dose. MRI is expensive and not easily available in most clinics. For this reason, low-cost, quick and easy-to-use potential alternatives such as optical computed tomography (CT), x-ray CT or ultrasound attenuation CT have also been studied by others. Here, we instead evaluate the dose dependence of the elastic material property, Young's modulus and the dose response of the viscous relaxation of radiation-sensitive gels to discuss their potential for dose imaging. Three batches of a radiation-sensitive polymer gel (MAGIC gel) samples were homogeneously irradiated to doses from 0 Gy to 45.5 Gy. Young's modulus was computed from the measured stress on the sample surface and the strain applied to the sample when compressing it axially, and the viscous relaxation was determined from the stress decay under sustained compression. The viscous relaxation was found not to change significantly with dose. However, Young's modulus was dose dependent; it approximately doubled in the gels between 0 Gy and 20 Gy. By fitting a second-order polynomial to the Young's modulus-versus-dose data, 99.4% of the variance in Young's modulus was shown to be associated with the change in dose. The precision of the gel production, irradiation and Young's modulus measurement combined was found to be 4% at 2 Gy and 3% at 20 Gy. Potential sources of measurement error, such as those associated with the boundary conditions in the compression measurement, inhomogeneous polymerization, temperature (up to 1% error) and the evaporation of water from the sample (up to 1% error), were estimated and discussed. It was concluded that Young's modulus could be used for dose determination. Imaging techniques such as elastography may help to achieve this if they can provide a local measurement of Young

  11. 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. PMID:22886057

  12. 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

  13. Aprotinin Exerts Differential and Dose Dependent Effects on Myocardial Contractility, Oxidative Stress and Cytokine Release Following Ischemia-Reperfusion

    PubMed Central

    McEvoy, Matthew D.; Taylor, Anna-Greta; Zavadzkas, Juozas A.; Mains, Ira M.; Ford, Rachael A.; Stroud, Robert E.; Jeffords, Laura B.; Beck, Christy U.; Reeves, Scott T.; Spinale, Francis G.

    2009-01-01

    Background Cardiac surgery can result in LV ischemia and reperfusion (I/R), the release of cytokines such as tumor necrosis factor, and oxidative-stress with release of myeloperoxidase. While aprotinin has been used in cardiac surgery, the likely multiple effects of this serine protease inhibitor limits clinical utility. This study tested the hypothesis that different APRO doses cause divergent effects on LV contractility, cytokine release and oxidative stress in the context of I/R. Methods/Results LV I/R (30 min I/60 min R) was induced in mice and LV contractility (maximal end-systolic elastance; Emax) determined. Mice were randomized to 2×104 KIU/kg aprotinin (n=11), 4 × 104 KIU/kg aprotinin (n=10), and Vehicle (saline, n=10). Based upon a fluorogenic assay, aprotinin doses of 2 and 4×104 KIU/kg resulted in plasma concentrations similar to those of the half and full Hammersmith doses, respectively. Following I/R, Emax fell by over 40% from baseline (p<0.05), and this effect was attenuated with 2 ×104 KIU/kg but not 4 ×104 KIU/kg aprotinin. Tumor necrosis factor increased by over 60% from control (p<0.05) with I/R, bit was reduced with 4 ×104 KIU/kg aprotinin. Myeloperoxidase increased with I/R, and was reduced to the greatest degree by 2 ×104 KIU/kg aprotinin. Conclusions Aprotinin influences LV contractility, cytokine release and oxidative stress which are dose dependent. These results provide mechanistic evidence that multiple pathways are differentially affected by aprotinin in a context relevant to cardiac surgery. PMID:18640335

  14. Medium chain triglycerides dose-dependently prevent liver pathology in a rat model of non-alcoholic fatty liver disease.

    PubMed

    Ronis, Martin J J; Baumgardner, January N; Sharma, Neha; Vantrease, Jamie; Ferguson, Matthew; Tong, Yudong; Wu, Xianli; Cleves, Mario A; Badger, Thomas M

    2013-02-01

    Metabolic syndrome is often accompanied by development of hepatic steatosis and less frequently by non-alcoholic fatty liver disease (NAFLD) leading to non-alcoholic steatohepatitis (NASH). Replacement of corn oil with medium chain triacylglycerols (MCT) in the diets of alcohol-fed rats has been shown to protect against steatosis and alcoholic liver injury. The current study was designed to determine if a similar beneficial effect of MCT occurs in a rat model of NAFLD. Groups of male rats were isocalorically overfed diets containing 10%, 35% or 70% total energy as corn oil or a 70% fat diet in which corn oil was replaced with increasing concentrations of saturated fat (18:82, beef tallow:MCT oil) from 20% to 65% for 21 days using total enteral nutrition (TEN). As dietary content of corn oil increased, hepatic steatosis and serum alanine amino transferases were elevated (P < 0.05). This was accompanied by greater expression of cytochrome P450 enzyme CYP2E1 (P < 0.05) and higher concentrations of polyunsaturated 18:2 and 20:4 fatty acids (FA) in the hepatic lipid fractions (P < 0.05). Keeping the total dietary fat at 70%, but increasing the proportion of MCT-enriched saturated fat resulted in a dose-dependent reduction in steatosis and necrosis without affecting CYP2E1 induction. There was no incorporation of C8-C10 FAs into liver lipids, but increasing the ratio of MCT to corn oil: reduced liver lipid 18:2 and 20:4 concentrations; reduced membrane susceptibility to radical attack; stimulated FA β- and ω-oxidation as a result of activation of peroxisomal proliferator activated receptor (PPAR)α, and appeared to increase mitochondrial respiration through complex III. These data suggest that replacing unsaturated fats like corn oil with MCT oil in the diet could be utilized as a potential treatment for NAFLD. PMID:23576797

  15. 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

  16. 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

  17. Dose-dependent regulation of cell proliferation and collagen degradation by estradiol on ligamentum flavum

    PubMed Central

    2014-01-01

    Background Estradiol plays an important role in the regulation of collagen metabolism. Deficiency of estradiol has been reported to be associated with the degeneration of many connective tissues. However, the association of estradiol and hypertrophy of the ligamentum flavum was seldom explored. Therefore, we studied the effects of estradiol on cultured cells from the ligamentum flavum. Methods Primary cultures of human ligamentum flavum cells obtained from surgical specimens of 14 patients undergoing spinal surgery were used to investigate the effect of estradiol on cell proliferation and the expression of collagen, elastin, and matrix metalloproteinases. Downstream pathways of estrogen receptor underlying the regulation of metalloproteinases were also investigated. Results In our study, we revealed the existence of estrogen receptors on both female and male ligamentum flavum cells with a gender difference. 17β-estradiol increased early (24 hours) proliferation of ligamentum flavum cells in a dose dependent manner and the effect could not be seen when the cell density increased. Estradiol with a concentration of 10-9 M decreased collagen levels and increased the expression of MMP-13. Adding an antagonist of PI3K downstream pathway could reverse the expression of MMP-13 caused by estradiol. Conclusions The results implied estradiol regulated the expression of MMP-13 via PI3K pathway and contributed to the homeostasis of extracellular matrix in the ligamentum flavum. PMID:25022571

  18. Dose-dependent ``activation energy`` for blistering phenomena in hydrogen-implanted silicon

    SciTech Connect

    Bedell, S.W.; Lanford, W.A.

    1998-12-31

    Silicon samples were implanted with 100 keV hydrogen at doses ranging from 4.9 to 9.9 {times} 10{sup 16} H/cm{sup 2}. The samples were then annealed in an argon atmosphere using a special furnace mounted on a microscope stage. The time required to observe the onset of Si blistering was then measured as a function of temperature for the various hydrogen doses. An Arrhenius plot of the time-temperature data was made and an activation energy was calculated for each dose. The measured activation energies range from 2.6 to 1.1 eV corresponding to 4.9 to 9.9 {times} 10{sup 16} H/cm{sup 2}, respectively. A qualitative explanation of the dose dependence is given in terms of a stress-induced lowering of the Si-Si bond energy. The hydrogen distribution as a function of annealing temperature was monitored using the {sup 1}H({sup 15}N,{alpha}{gamma}){sup 12}C nuclear reaction. The results from the hydrogen profiling indicate that the hydrogen profile flattens at 500 C and concentrates at 550 C.

  19. Dose dependence of acetylcholinesterase activity in neuroblastoma cells exposed to modulated radio-frequency electromagnetic radiation.

    PubMed

    Dutta, S K; Das, K; Ghosh, B; Blackman, C F

    1992-01-01

    Radio-frequency electromagnetic radiation (RFR) at 915 and 147 MHz, when sinusoidally amplitude modulated (AM) at 16 Hz, has been shown to enhance release of calcium ions from neuroblastoma cells in culture. The dose-response relation is unusual, consisting of two power-density "windows" in which enhanced efflux occurs, separated by power-density regions in which no effect is observed. To explore the physiological importance of these findings, we have examined the impact of RFR exposure on a membrane-bound enzyme, acetylcholinesterase (AChE), which is intimately involved with the acetylcholine (ACh) neurotransmitter system. Neuroblastoma cells (NG108), exposed for 30 min to 147-MHz radiation, AM at 16 Hz, demonstrated enhanced AChE activity, as assayed by a procedure using 14C-labeled ACh. Enhanced activity was observed within a time window between 7.0 and 7.5 h after the cells were plated and only when the exposure occurred at power densities identified in a previous report as being effective for altering the release of calcium ions. Thus RFR affects both calcium-ion release and AChE activity in nervous system-derived cells in culture in a common dose-dependent manner. PMID:1510740

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

    PubMed Central

    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. PMID:25516976

  1. 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. PMID:25516976

  2. [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

  3. Dose-dependent establishment of Trichuris suis larvae in Göttingen minipigs.

    PubMed

    Vejzagić, Nermina; Roepstorff, Allan; Kringel, Helene; Thamsborg, Stig Milan; Nielsen, Mads Pårup; Kapel, Christian M O

    2015-03-15

    Embryonated eggs of the pig whipworm Trichuris suis (TSOee) constitute the active pharmaceutical ingredient (API) in a medicinal product explored in human clinical trials against several immune-mediated diseases. The measurement of TSO biological potency (hatchability and infectivity) is a requirement for the assessment of TSO's pharmacological potency in human clinical trials. The present study aims to validate the dose-dependent establishment of T. suis larvae in Göttingen minipigs and eventual clinical implication of a dose range (1000-10,000 TSO). Four groups of 5 minipigs were inoculated with doses of 1000, 2500, 7500, and 10,000 TSOee, respectively, to evaluate a range of concentrations of TSOee in a minipig infectivity model. Unembryonated eggs (TSOue) were added to keep the total egg number in the inoculum constant at 10,000 eggs. Two groups received 2500 and 7500 TSOee per pig without the addition of TSOue as controls. The intestinal larval establishment at 21 days post inoculation (dpi) demonstrated a clear positive linear dose-response relationship between numbers of inoculated TSOee and recovered larvae. There was a low level of variation in larval counts in all study groups. Thus, the infectivity model in minipigs within the tested dose range offers a reliable, sensitive and accurate assay for testing biological potency of TSO. PMID:25700937

  4. 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

  5. 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

  6. 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

  7. Dose-dependent surface endothelialization and biocompatibility of polyurethane noble metal nanocomposites.

    PubMed

    Hess, Christian; Schwenke, Andreas; Wagener, Philipp; Franzka, Steffen; Laszlo Sajti, Csaba; Pflaum, Michael; Wiegmann, Bettina; Haverich, Axel; Barcikowski, Stephan

    2014-06-01

    Surface pre-endothelialization is a promising approach to improve the hemocompatibility of implants, medical devices, and artificial organs. To promote the adhesive property of thermoplastic polyurethane (TPU) for endothelial cells (ECs), up to 1 wt % of gold (Au) or platinum (Pt) nanoparticles, fabricated by pulsed laser ablation in polymer solution, were embedded into the polymer matrix. The analysis of these nanocomposites showed a homogenous dispersion of the nanoparticles, with average diameters of 7 nm for Au or 9 nm for Pt. A dose-dependent effect was found when ECs were seeded onto nanocomposites comprising different nanoparticle concentrations, resulting in a fivefold improvement of proliferation at 0.1 wt % nanoparticle load. This effect was associated with a nanoparticle concentration-dependent hydrophilicity and negative charge of the nanocomposite. In dynamic flow tests, nanocomposites containing 0.1 wt % Au or Pt nanoparticles allowed for the generation of a confluent and resistant EC layer. Real-time polymerase chain reaction quantification of specific markers for EC activation indicated that ECs cultivated on nanocomposites remain in an inactivated, nonthrombogenic and noninflammatory state; however, maintain the ability to trigger an inflammatory response upon stimulation. These findings were confirmed by a platelet and leukocyte adhesion assay. The results of this study suggest the possible applicability of TPU nanocomposites, containing 0.1 wt % Au or Pt nanoparticles, for the generation of pre-endothelialized surfaces of medical devices. PMID:23852964

  8. 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

  9. Dose-Dependent Response of Tissue-Engineered Intervertebral Discs to Dynamic Unconfined Compressive Loading

    PubMed Central

    Hudson, Katherine D.; Mozia, Robert I.

    2015-01-01

    Because of the limitations of current surgical methods in the treatment of degenerative disc disease, tissue-engineered intervertebral discs (TE-IVDs) have become an important target. This study investigated the biochemical and mechanical responses of composite TE-IVDs to dynamic unconfined compression. TE-IVDs were manufactured by floating an injection molded alginate nucleus pulposus (NP) in a type I collagen annulus fibrosus (AF) that was allowed to contract for 2 weeks before loading. The discs were mechanically stimulated at a range of strain amplitude (1–10%) for 2 weeks with a duty cycle of 1 h on–1 h off–1 h on before being evaluated for their biochemical and mechanical properties. Mechanical loading increased all properties in a dose-dependent manner. Glycosaminoglycans (GAGs) increased between 2.8 and 2.2 fold in the AF and NP regions, respectively, whereas the hydroxyproline content increased between 1.2 and 1.8 fold. The discs also experienced a 2-fold increase in the equilibrium modulus and a 4.3-fold increase in the instantaneous modulus. Full effects for all properties were seen by 5% strain amplitude. These data suggest that dynamic loading increases the functionality of our TE-IVDs with region-dependent responses using a method that may be scaled up to larger disc models to expedite maturation for implantation. PMID:25277703

  10. 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

  11. Dose-dependent effects of the herbicide mesotrione on soil cyanobacterial communities.

    PubMed

    Crouzet, Olivier; Wiszniowski, Jarosław; Donnadieu, Florence; Bonnemoy, Frédérique; Bohatier, Jacques; Mallet, Clarisse

    2013-01-01

    This study aimed to investigate the dose-response effects of an herbicide on soil photosynthetic microbial communities, particularly cyanobacteria, using a microcosm approach. Pure mesotrione (active ingredient), and Callisto (a commercial formulation of this triketone herbicide), were spread at different rates on soil microcosm surfaces. Soil Chlorophyll concentrations were quantified to assess the photosynthetic biomass, and the genetic structure and diversity of the cyanobacterial community were investigated by a group-specific polymerase chain reaction followed by denaturing gradient gel electrophoresis. Dose-dependent responses were evidenced for both functional and structural parameters. No effect was detected in soils treated with 1 × AR (1-fold recommended application rate) irrespective of the herbicide formulation. At 10 × AR (10-fold recommended application rate), only Callisto treatment induced significant decreases of photosynthetic biomass, whereas structural parameters were less affected. At the 100 × AR (100-fold recommended application rate), both pure mesotrione and Callisto had strong negative impacts on soil chlorophyll concentrations and cyanobacterial genetic structure and diversity. At both the 10 × AR and 100 × AR treatments, Callisto induced significant stronger effects than pure mesotrione. In addition, indicators of photosynthetic biomass, compared with structural parameters of cyanobacterial communities (within 14 days), responded (within 7 days) more quickly to herbicide stress. The results of this study underscore the relevance of soil photosynthetic microbial communities to develop indicators for herbicide risk assessment. PMID:23014935

  12. Capecitabine-phenytoin interaction is dose dependent with an unexpected time course.

    PubMed

    Privitera, Michael; de Los Ríos la Rosa, Felipe

    2011-11-01

    The main objective of this study was to further analyze the drug interaction between capecitabine and phenytoin with special emphasis on magnitude, timing, and the dose effect. A single patient had multiple phenytoin levels at various doses of capecitabine. Phenytoin levels were subjected to analysis of variance and the dose effect was approached using a multiple comparison test. All phenytoin levels meeting the criteria for steady state were subjected to box plot analysis. Analysis of 35 phenytoin levels over a 25-month period demonstrated a statistically significant interaction between the medications. The interaction onset was delayed by 4 weeks and persisted up to 9 weeks after capecitabine dose increases or decreases. The magnitude of interaction was directly proportional to the capecitabine dosage. We concluded that capecitabine caused a marked increase in phenytoin levels that was capecitine dose dependent, with a delayed time course not predicted by phenytoin kinetics, suggesting a novel interaction mechanism. The magnitude and complexity of this interaction suggest that alternate antiepileptic medications should be used in combination with capecitabine. PMID:21909021

  13. 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

  14. 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. PMID:25254931

  15. 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. PMID:20601038

  16. A mixture of prebiotic oligosaccharides reduces the incidence of atopic dermatitis during the first six months of age

    PubMed Central

    Moro, G; Arslanoglu, S; Stahl, B; Jelinek, J; Wahn, U; Boehm, G

    2006-01-01

    Background Oligosaccharides may alter postnatal immune development by influencing the constitution of gastrointestinal bacterial flora. Aims To investigate the effect of a prebiotic mixture of galacto‐ and long chain fructo‐oligosaccharides on the incidence of atopic dermatitis (AD) during the first six months of life in formula fed infants at high risk of atopy. Methods Prospective, double‐blind, randomised, placebo controlled trial; 259 infants at risk for atopy were enrolled. A total of 102 infants in the prebiotic group and 104 infants in the placebo group completed the study. If bottle feeding was started, the infant was randomly assigned to one of two hydrolysed protein formula groups (0.8 g/100 ml prebiotics or maltodextrine as placebo). All infants were examined for clinical evidence of atopic dermatitis. In a subgroup of 98 infants, faecal flora was analysed. Results Ten infants (9.8%; 95 CI 5.4–17.1%) in the intervention group and 24 infants (23.1%; 95 CI 16.0–32.1%) in the control group developed AD. The severity of the dermatitis was not affected by diet. Prebiotic supplements were associated with a significantly higher number of faecal bifidobacteria compared with controls but there was no significant difference in lactobacilli counts. Conclusion Results show for the first time a beneficial effect of prebiotics on the development of atopic dermatitis in a high risk population of infants. Although the mechanism of this effect requires further investigation, it appears likely that oligosaccharides modulate postnatal immune development by altering bowel flora and have a potential role in primary allergy prevention during infancy. PMID:16873437

  17. Sentinel lymph node biopsy reduces the incidence of secondary neck metastasis in patients with oral squamous cell carcinoma

    PubMed Central

    HIRAKI, AKIMITSU; FUKUMA, DAIKI; NAGATA, MASASHI; SHIRAISHI, SHINYA; KAWAHARA, KENTA; MATSUOKA, YUICHIRO; NAKAGAWA, YOSHIHIRO; YOSHIDA, RYOJI; TANAKA, TAKUYA; YOSHITAKE, YOSHIHIRO; SHINOHARA, MASANORI; YAMASHITA, YASUYUKI; NAKAYAMA, HIDEKI

    2016-01-01

    It has recently been established that sentinel node biopsy (SNB) is an applicable and feasible procedure for the prediction of neck lymph node status in patients with early oral squamous cell carcinoma (OSCC) who are clinically negative for neck metastasis (cN0). The aim of this study was to retrospectively compare excision followed by watchful waiting with excision and SNB, in order to determine the effectiveness of SNB. A total of 125 patients with cN0 early OSCC were divided into two groups, namely the excision alone (n=78) and excision with SNB (n=47) groups. The clinical data of these two groups between 2006 and 2013 were analyzed. In the excision with SNB group, the negative predictive value and false-negative rate of SNB were 94% (30/32) and 18% (2/11), respectively. Secondary neck metastasis, also known as delayed neck metastasis, occurred in 24.2% of the patients in the excision alone group and 4.9% of the patients in the excision with SNB group. The 5-year overall survival (OS) rates were 84.0 and 97.5% in the excision alone and excision with SNB groups, respectively. Significant differences were found in the rate of secondary neck metastasis and OS between the two groups. SNB may be effective in the detection of occult neck lymph node metastasis, with a reduction in the incidence of secondary neck metastasis and improvements in the 5-year OS in patients with early-stage (stage I/II) oral cancer. PMID:27330766

  18. 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.

  19. Dose Dependent Side Effect of Superparamagnetic Iron Oxide Nanoparticle Labeling on Cell Motility in Two Fetal Stem Cell Populations

    PubMed Central

    Diana, Valentina; Bossolasco, Patrizia; Moscatelli, Davide; Silani, Vincenzo; Cova, Lidia

    2013-01-01

    Multipotent stem cells (SCs) could substitute damaged cells and also rescue degeneration through the secretion of trophic factors able to activate the endogenous SC compartment. Therefore, fetal SCs, characterized by high proliferation rate and devoid of ethical concern, appear promising candidate, particularly for the treatment of neurodegenerative diseases. Super Paramagnetic Iron Oxide nanoparticles (SPIOn), routinely used for pre-clinical cell imaging and already approved for clinical practice, allow tracking of transplanted SCs and characterization of their fate within the host tissue, when combined with Magnetic Resonance Imaging (MRI). In this work we investigated how SPIOn could influence cell migration after internalization in two fetal SC populations: human amniotic fluid and chorial villi SCs were labeled with SPIOn and their motility was evaluated. We found that SPIOn loading significantly reduced SC movements without increasing production of Reactive Oxygen Species (ROS). Moreover, motility impairment was directly proportional to the amount of loaded SPIOn while a chemoattractant-induced recovery was obtained by increasing serum levels. Interestingly, the migration rate of SPIOn labeled cells was also significantly influenced by a degenerative surrounding. In conclusion, this work highlights how SPIOn labeling affects SC motility in vitro in a dose-dependent manner, shedding the light on an important parameter for the creation of clinical protocols. Establishment of an optimal SPIOn dose that enables both a good visualization of grafted cells by MRI and the physiological migration rate is a main step in order to maximize the effects of SC therapy in both animal models of neurodegeneration and clinical studies. PMID:24244310

  20. 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

  1. Steroids as an adjunct for reducing the incidence of proliferative vitreoretinopathy after rhegmatogenous retinal detachment surgery: a systematic review and meta-analysis

    PubMed Central

    Shi, Hui; Guo, Tao; Liu, Peng-Cheng; Wang, Qian-Yi; Du, Ya-Ru; Liu, Qing-Yu; He, Meng-Mei; Liu, Jun-Ling; Yu, Jing

    2015-01-01

    Background This meta-analysis was performed to determine the effectiveness of steroids as an adjunct following rhegmatogenous retinal detachment (RRD) surgery. Methods RRD patients with or without proliferative vitreoretinopathy (PVR) were included. The treatment group included patients in whom steroids were used as an adjunct and a control group in which placebo was used. Only randomized controlled trials were included. We searched the main electronic databases and included studies published until July 2014. PVR odds ratio, visual acuity, retinal reattachment rate, and complications were evaluated in three trials. Results Three randomized controlled trials were included in the meta-analysis. There was no significant difference in the incidence of postoperative PVR between groups (heterogeneity I2=48%, P=0.14). However, the incidence of postoperative PVR was lower in the treatment group (I2=0%, P<0.0001) than in the control group when a PVR grade C study was excluded. There was no statistically significant difference in postoperative visual acuity between the treatment and control groups (odds ratio −0.18; 95% confidence interval −0.38, 0.02; P=0.08). The two groups had similar results for primary/final retinal reattachment and reoperation rate. There was no significant difference in postoperative intraocular pressure. Conclusion This systematic review demonstrates that steroids may significantly reduce the incidence of postoperative PVR grade B or lower following RRD surgery. PMID:25834397

  2. Sodium citrate reduces the incidence of corneal ulcerations and perforations in extreme alkali-burned eyes--acetylcysteine and ascorbate have no favorable effect.

    PubMed

    Pfister, R R; Nicolaro, M L; Paterson, C A

    1981-09-01

    Alkali-burned eyes (45 sec, 12 mm, 4N NaOH) were subjected to topical treatment with 10% ascorbate, 20% acetylcysteine, 10% ascorbate together with 20% acetylcysteine, 10% citrate, or Adsorbotear vehicle. Only citrate-treated eyes showed a significant decrease in corneal ulcerations and perforations (17%) compared with ascorbate (88%), acetylcysteine (81%), ascorbate/acetyl-cysteine (100%), or Adsorbotear (75%). In the citrate-treated eyes there was a significantly reduced incidence of band keratopathy (17%) but an increased incidence of hyphema (100%). Both groups receiving acetylcysteine developed acellular corneal caps, the result of peripheral ulceration undermining the central cornea. Polymorphonuclear neutrophils (PMN) were substantially increased at the base of the cap in the acetylcysteine- and acetylcysteine/ascorbate-treated eyes at day 56. At the end of the experiment, citrate-treated eyes showed substantially fewer stromal PMN than any other group. These results show that topical citrate has a most favorable effect on the incidence of corneal ulceration and perforation after alkali burning. PMID:7275534

  3. 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

  4. 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

  5. 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

  6. 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.

  7. Dose-dependent role of claudin-1 in vivo in orchestrating features of atopic dermatitis.

    PubMed

    Tokumasu, Reitaro; Yamaga, Kosuke; Yamazaki, Yuji; Murota, Hiroyuki; Suzuki, Koya; Tamura, Atsushi; Bando, Kana; Furuta, Yasuhide; Katayama, Ichiro; Tsukita, Sachiko

    2016-07-12

    Atopic dermatitis (AD) is a chronic inflammatory skin disease in humans. It was recently noted that the characteristics of epidermal barrier functions critically influence the pathological features of AD. Evidence suggests that claudin-1 (CLDN1), a major component of tight junctions (TJs) in the epidermis, plays a key role in human AD, but the mechanism underlying this role is poorly understood. One of the main challenges in studying CLDN1's effects is that Cldn1 knock-out mice cannot survive beyond 1 d after birth, due to lethal dehydration. Here, we established a series of mouse lines that express Cldn1 at various levels and used these mice to study Cldn1's effects in vivo. Notably, we discovered a dose-dependent effect of Cldn1's expression in orchestrating features of AD. In our experimental model, epithelial barrier functions and morphological changes in the skin varied exponentially with the decrease in Cldn1 expression level. At low Cldn1 expression levels, mice exhibited morphological features of AD and an innate immune response that included neutrophil and macrophage recruitment to the skin. These phenotypes were especially apparent in the infant stages and lessened as the mice became adults, depending on the expression level of Cldn1 Still, these adult mice with improved phenotypes showed an enhanced hapten-induced contact hypersensitivity response compared with WT mice. Furthermore, we revealed a relationship between macrophage recruitment and CLDN1 levels in human AD patients. Our findings collectively suggest that CLDN1 regulates the pathogenesis, severity, and natural course of human AD. PMID:27342862

  8. 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

  9. Dose-dependent control of proliferation and sperm specification by FOG-1/CPEB

    PubMed Central

    Thompson, Beth E.; Bernstein, David S.; Bachorik, Jennifer L.; Petcherski, Andrei G.; Wickens, Marvin; Kimble, Judith

    2005-01-01

    SUMMARY RNA-binding proteins control germline development in metazoans. This work focuses on control of the C. elegans germ line by two RNA-binding proteins: FOG-1, a CPEB homolog, and FBF, a PUF family member. Previous studies showed that FOG-1 specifies the sperm fate and that FBF promotes proliferation. Here we report that FOG-1 also promotes proliferation. Whereas fbf-1 fbf-2 double mutants make ∼120 germ cells, fog-1; fbf-1 fbf-2 triple mutants make only ∼10 germ cells. The triple mutant germ line divides normally until early L2, when germ cells prematurely enter meiosis and begin oogenesis. Importantly, fog-1/+; fbf-1 fbf-2 animals make more germ cells than fbf-1 fbf-2 double mutants, demonstrating that one dose of wild-type fog-1 promotes proliferation more effectively than two doses – at least in the absence of FBF. FOG-1 protein is barely detectable in proliferating germ cells, but abundant in germ cells destined for spermatogenesis. Based on fog-1 dosage effects together with the gradient of FOG-1 protein abundance, we suggest that low FOG-1 promotes proliferation and high FOG-1 specifies spermatogenesis. FBF binds specifically to regulatory elements in the fog-13′UTR, and FOG-1 increases in animals lacking FBF. Therefore, FBF represses fog-1 expression. We suggest that FBF promotes continued proliferation, at least in part, by maintaining FOG-1 at a low level appropriate for proliferation. The dose-dependent control of proliferation and cell fate by FOG-1 has striking parallels with Xenopus CPEB, suggesting a conserved mechanism in animal development. PMID:16000383

  10. Nitrous oxide persistently alleviates pain hypersensitivity in neuropathic rats: A dose-dependent effect

    PubMed Central

    Ben Boujema, Meric; Laboureyras, Emilie; Pype, Jan; Bessière, Baptiste; Simonnet, Guy

    2015-01-01

    BACKGROUND: Despite numerous pharmacological approaches, there are no common analgesic drugs that produce meaningful relief for the majority of patients with neuropathic pain. Although nitrous oxide (N2O) is a weak analgesic that acts via opioid-dependent mechanisms, it is also an antagonist of the N-methyl-D-aspartate receptor (NMDAR). The NMDAR plays a critical role in the development of pain sensitization induced by nerve injury. OBJECTIVE: Using the chronic constriction injury of the sciatic nerve in male rats as a preclinical model of neuropathic pain, the first aim of the present study was to evaluate the lowest N2O concentration and the shortest time of N2O postinjury exposure that would produce persistent relief of neuropathic pain. The second aim was to compare the effects of N2O with gabapentin, a reference drug used in human neuropathic pain relief. METHODS: Changes in the nociceptive threshold were evaluated using the paw pressure vocalization test in rats. RESULTS: Among the various N2O concentrations tested, which ranged from 25% to 50%, only 50% N2O single exposure for 1 h 15 min induced a persistent (minimum of three weeks) and significant (60%) reduction in pain hypersensitivity. A single gabapentin dose (75 mg/kg to 300 mg/kg, intraperitoneally) induced an acute (1 h to 1 h 30 min) dose-dependent effect, but not a persistent effect such as that observed with N2O. CONCLUSIONS: These preclinical results suggest that N2O is advantageous for long-lasting neuropathic pain relief after sciatic nerve injury compared with other drugs used in humans such as gabapentinoids or NMDAR antagonists. The present preclinical study provides a rationale for developing comparative clinical studies. PMID:26371891

  11. Epidural methadone results in dose-dependent analgesia in cancer pain, further enhanced by epidural dexamethasone

    PubMed Central

    Lauretti, G R; Rizzo, C C; Mattos, A L; Rodrigues, S W

    2013-01-01

    Background: This study was designed to evaluate the role of epidural methadone-lidocaine in cancer pain combined or not to epidural dexamethasone. Methods: In all, 72 cancer patients, 32- to 67-year-old were randomized to six groups (n=12) and prospectively studied to examine analgesia and adverse effects for 3 weeks. Patients received single-dose protocol epidural test drugs: Control group (CG) received epidural 40-mg lidocaine diluted to 10-ml volume with saline. Dexamethasone group (DG) 40-mg lidocaine plus 10-mg dexamethasone. The 2.5MetG 2.5-mg epidural methadone with 40-mg lidocaine; the 5MetG, 5-mg epidural methadone plus 40-mg lidocaine, the 7.5MetG, 7.5-mg epidural methadone plus 40-mg lidocaine and finally the 7.5Met-DexG, 7.5-mg methadone with 40-mg lidocaine and 10-mg dexamethasone. Results: Groups CG, DG and 2.5MetG were similar regarding analgesia and side effects. Patients from 5MetG and 7.5MetG took 3±1 and 5±1 days, respectively, to restart oral morphine. Patients from 7.5MetDG took 14±2 to restart oral morphine (P<0.001). Daily somnolence and appetite improved in the 7.5MetDG during 2-week evaluation (P<0.005). Fatigue improved for both DG and 7.5MetDG during 2-week evaluation (P<0.005). By the third week of evaluation, all patients were similar. Conclusions: Epidural methadone plus lidocaine resulted in dose-dependent analgesia, further improved by epidural dexamethasone, which also improved fatigue. PMID:23322191

  12. 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

  13. Nitric oxide triggers specific and dose-dependent cytosolic calcium transients in Arabidopsis

    PubMed Central

    Aboul-Enein, Ahmed M; Loake, Gary J

    2009-01-01

    Calcium (Ca2+) transients have been shown to take place in response to diverse developmental and physiological cues. Also, it is involved in biotic and abiotic stress signaling. Nitric oxide (NO) is an important signaling molecule that plays a crucial role in plant growth and development, starting from germination to flowering, ripening of fruit and senescence of organs. Moreover, it plays a pivotal role in several biotic and abiotic stress signaling processes. In the present work, the ability of NO to trigger increases in cytosolic calcium concentration ([Ca2+]cyt) was investigated. For this purpose, transgenic Arabidopsis seedlings constitutively expressing the luminescent Ca2+-sensitive protein apoaequorin (35S::APOAEQUORIN) was employed. In chemiluminescence and in vivo Ca2+ imaging assays, the NO-donor sodium nitroprusside (SNP) triggered a strong, instantaneous, reproducible, and dose-dependent rise in [Ca2+]cyt. Moreover, the observed rise in [Ca2+]cyt was shown to be NO-specific and not associated with decomposition products of SNP, as the NO-scavenger 2-4-carboxyphenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3 oxide (C-PTIO) significantly blunted the observed NO-mediated spike in [Ca2+]cyt. Interestingly, preincubation of 35S::APOAEQUORIN Arabidopsis seedlings with the plasma membrane channel blocker lanthanum chloride resulted in partial concentration-dependent blocking of the NO-specific Ca2+ transient. This observation indicates that, in addition to the mobilization of [Ca2+]cyt, as an external source in response to NO treatment, there also exists an appreciable contribution of an as yet unidentified internal pool. PMID:19721746

  14. Antibody response against Trichinella spiralis in experimentally infected rats is dose dependent

    PubMed Central

    2011-01-01

    Domestic pigs are the main representatives of the domestic cycle of Trichinella spiralis that play a role in transmission to humans. In Europe, backyard pigs of small household farms are the most important risks for humans to obtain trichinellosis. Rats might play a role in the transmission of Trichinella spiralis from domestic to sylvatic animals and vice versa. In order to be able to investigate the role of wild rats in the epidemiology of T. spiralis in The Netherlands, we studied the dynamics of antibody response after T. spiralis infections in experimental rats, using infection doses ranging from very low (10 muscle larvae, ML, per rat) to very high (16 000 ML per rat). To evaluate the feasibility of rats surviving high infection doses with T. spiralis, clinical and pathological parameters were quantified. Serological tools for detecting T. spiralis in rats were developed to quantitatively study the correlation between parasite load and immunological response. The results show that an infection dose-dependent antibody response was developed in rats after infection with as low as 10 ML up to a level of 10 000 ML. A positive correlation was found between the number of recovered ML and serum antibody levels, although specific measured antibody levels correspond to a wide range of LPG values. Serum antibodies of rats that were infected even with 10 or 25 ML could readily be detected by use of the T. spiralis western blot 2 weeks post infection. We conclude that based on these low infection doses, serologic tests are a useful tool to survey T. spiralis in wild rats. PMID:22129040

  15. 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

  16. 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.

  17. Calorie restriction reduces the incidence of myeloid leukemia induced by a single whole-body radiation in C3H/He mice.

    PubMed

    Yoshida, K; Inoue, T; Nojima, K; Hirabayashi, Y; Sado, T

    1997-03-18

    Dietary restriction, especially caloric restriction, is a major modifier in experimental carcinogenesis and is known to decrease significantly the incidence of neoplasms. Gross and Dreyfuss [Gross, L. & Dreyfuss, Y. (1984) Proc. Natl. Acad. Sci. USA 81, 7596-7598; Gross, L. & Dreyfuss, Y. (1986) Proc. Natl. Acad. Sci. USA 83, 7928-7931] reported that a 36% restriction in caloric intake dramatically decreased the radiation-induced solid tumors and/or leukemias. Their protocol predominantly produced lymphatic neoplasms. It is of interest to observe the effect of caloric restriction on radiation-induced myeloid leukemia, because the disease was observed to have been increased in the survivors of the atomic bombs in Hiroshima and Nagasaki. The spontaneous incidence of myeloid leukemia in C3H/He male mice is 1%, and the incidence increased to 23.3% when 3 Gy of whole-body x-ray irradiation was given. However, the incidence of myeloid leukemia was found to be significantly decreased by caloric restriction; it was reduced to 7.9% and 10.7% when restriction was started before (6 weeks old) and after (10 weeks old) irradiation, respectively. In addition, the onset of the myeloid leukemia in both restricted groups was prolonged to a greater extent as compared with the control diet group. Caloric restriction demonstrated a significant prolongation of the life span in the groups on a restricted diet after having been exposed to irradiation, either before or after dietary restriction, in comparison with mice that were only irradiated. PMID:9122244

  18. 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...

  19. Thyroid-hormone-disrupting chemicals: evidence for dose-dependent additivity or synergism.

    PubMed

    Crofton, Kevin M; Craft, Elena S; Hedge, Joan M; Gennings, Chris; Simmons, Jane E; Carchman, Richard A; Carter, W Hans; DeVito, Michael J

    2005-11-01

    ) and the experimentally observed mixture response (the empirical model). A likelihood-ratio test revealed statistically significant departure from dose additivity. There was no deviation from additivity at the lowest doses of the mixture, but there was a greater-than-additive effect at the three highest mixtures doses. At high doses the additivity model underpredicted the empirical effects by 2- to 3-fold. These are the first results to suggest dose-dependent additivity and synergism in TDCs that may act via different mechanisms in a complex mixture. The results imply that cumulative risk approaches be considered when assessing the risk of exposure to chemical mixtures that contain TDCs. PMID:16263510

  20. 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. PMID:27373561

  1. 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

  2. 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

  3. A managed protocol for treatment of deceased potential donors reduces the incidence of cardiac arrest before organ explant

    PubMed Central

    Westphal, Glauco Adrieno; Zaclikevis, Viviane Renata; Vieira, Kalinca Daberkow; Cordeiro, Rodrigo de Brito; Horner, Marina Borges W.; de Oliveira, Thamy Pellizzaro; Duarte, Robson; Sperotto, Geonice; da Silveira, Georgiana; Caldeira, Milton; Coll, Elisabeth; Yus-Teruel, Santiago

    2012-01-01

    Objective To assess the effect of the application of a managed protocol for the maintenance care of deceased potential multiple organ donors at two hospitals. Methods A before (Phase 1)/after (Phase 2) study conducted at two general hospitals, which included consecutively potential donors admitted to two intensive care units. In Phase 1 (16 months), the data were collected retrospectively, and the maintenance care measures of the potential donors were instituted by the intensivists. In Phase 2 (12 months), the data collection was prospective, and a managed protocol was used for maintenance care. The two phases were compared in terms of their demographic variables, physiological variables at diagnosis of brain death and the end of the process, time to performance of brain death confirmatory test and end of the process, adherence to bundles of maintenance care essential measures, losses due to cardiac arrest, family refusal, contraindications, and the conversion rate of potential into actual donors. Student's t- and chi-square tests were used, and p-value < 0.05 was considered to be significant. Results A total of 42 potential donors were identified (18 in Phase 1 and 24 in Phase 2). The time interval between the first clinical assessment and the recovery decreased in Phase 2 (Phase 1: 35.0±15.5 hours versus Phase 2: 24.6±6.2 hours; p = 0.023). Adherence increased to 10 out of the 19 essential items of maintenance care, and losses due to cardiac arrest also decreased in Phase 2 (Phase 1: 27.8 versus 0% in Phase 2; p = 0.006), while the convertion rate increased (Phase 1: 44.4 versus 75% in Phase 2; p = 0.044). The losses due to family refusal and medical contraindication did not vary. Conclusion The adoption of a managed protocol focused on the application of essential measures for the care of potential deceased donors might reduce the loss of potential donors due to cardiac arrest. PMID:23917929

  4. 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.

  5. Reduced-dose methotrexate in combination with tacrolimus was associated with rapid engraftment and recovery from oral mucositis without affecting the incidence of GVHD.

    PubMed

    Matsukawa, Toshihiro; Hashimoto, Daigo; Sugita, Junichi; Nakazawa, Seitarou; Matsushita, Takae; Kashiwazaki, Haruhiko; Goto, Hideki; Onozawa, Masahiro; Kahata, Kaoru; Fujimoto, Katsuya; Endo, Tomoyuki; Kondo, Takeshi; Hashino, Satoshi; Yamazaki, Yutaka; Teshima, Takanori

    2016-07-01

    Allogeneic hematopoietic stem cell transplantation is a curable treatment for hematological diseases. Graft-versus-host disease (GVHD) causes morbidity and mortality after HSCT. Methotrexate (MTX) is used for GVHD prophylaxis, but its appropriate dose remains unclear. In the present study, we compared the efficacy and toxicity of 15-10-10 MTX (day +1: 15 mg/m(2); days +3 and +6: 10 mg/m(2)) with 10-7-7 MTX (day +1: 10 mg/m(2); day +3 and +6: 7 mg/m(2)) in combination with tacrolimus. The cumulative incidence rates of grades II-IV acute GVHD, grades III-IV acute GVHD and chronic GVHD in the 15-10-10 MTX and 10-7-7 MTX groups did not differ to a statistically significant extent. The median time for neutrophil engraftment in the 15-10-10 MTX group was 16 days (range, 11-31 days), while that in the 10-7-7 group was 15 days (range, 12-19 days) (P = 0.024). Moreover, the median time for platelet recovery was significantly shorter in the 10-7-7 MTX group (22 days; range, 13-49 days) than that in the 15-10-10 MTX group (27 days; range, 9-405 days) (P = 0.027). The duration of oral mucositis was significantly shorter in the patients who received a reduced dose of MTX (median, 4.5 vs 13.0 days; P = 0.013). In conclusion, GVHD prophylaxis with a reduced dose of MTX was associated with earlier engraftment and earlier recovery from mucositis in comparison to a standard dose of MTX, without affecting the incidence of GVHD. PMID:27119977

  6. 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

  7. 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

  8. 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

  9. Effect of intravenous ondansetron on reducing the incidence of hypotension and bradycardia events during shoulder arthroscopy in sitting position under interscalene brachial plexus block: A prospective randomized trial

    PubMed Central

    Nallam, Srinivasa Rao; Dara, Sudheer

    2015-01-01

    Background and Aims: Sudden, profound hypotension and bradycardia events (HBEs) have been reported in more than 20% of patients undergoing shoulder arthroscopy in the sitting position. The present study was designed to know whether intravenous (IV) ondansetron (selective 5-hydroxy tryptamine 3-antagonist) can help in reducing the HBEs associated with shoulder arthroscopy performed in sitting position under interscalene brachial plexus block (ISBPB). Methods: A total of 100 patients (age 20–50 years) undergoing shoulder arthroscopy performed in the sitting position under ISBPB were assigned randomly to one of the two groups: Group C received 10 ml of normal saline and Group T received 4 mg of ondansetron diluted in 10 ml of normal saline` IV. All patients received ISBPB using levobupivacaine 0.5%. Assessment of motor and sensory blockade, pulse rate, systolic blood pressure, respiration, and side effects were noted every 5 min for first 30 min and every 10 min till the end of surgery. HBEs were recorded in both groups. Results: IV injection of ondansetron significantly reduces the incidence of HBEs from 11 (22.44% in Group C) to 3 (6.1% in Group T). The duration of analgesia was significantly longer in Group C (8.1 ± 3.3) in comparison with Group T (6.3 ± 4.2 h). Conclusion: We conclude that 4 ml of IV ondansetron can significantly reduce the HBEs during shoulder arthroscopy done in the sitting position under ISBPB. PMID:26195831

  10. Low-dose interleukin-2 fosters a dose-dependent regulatory T cell tuned milieu in T1D patients.

    PubMed

    Rosenzwajg, Michelle; Churlaud, Guillaume; Mallone, Roberto; Six, Adrien; Dérian, Nicolas; Chaara, Wahiba; Lorenzon, Roberta; Long, S Alice; Buckner, Jane H; Afonso, Georgia; Pham, Hang-Phuong; Hartemann, Agnès; Yu, Aixin; Pugliese, Alberto; Malek, Thomas R; Klatzmann, David

    2015-04-01

    Most autoimmune diseases (AID) are linked to an imbalance between autoreactive effector T cells (Teffs) and regulatory T cells (Tregs). While blocking Teffs with immunosuppression has long been the only therapeutic option, activating/expanding Tregs may achieve the same objective without the toxicity of immunosuppression. We showed that low-dose interleukin-2 (ld-IL-2) safely expands/activates Tregs in patients with AID, such HCV-induced vasculitis and Type 1 Diabetes (T1D). Here we analyzed the kinetics and dose-relationship of IL-2 effects on immune responses in T1D patients. Ld-IL-2 therapy induced a dose-dependent increase in CD4(+)Foxp3(+) and CD8(+)Foxp3(+) Treg numbers and proportions, the duration of which was markedly dose-dependent. Tregs expressed enhanced levels of activation markers, including CD25, GITR, CTLA-4 and basal pSTAT5, and retained a 20-fold higher sensitivity to IL-2 than Teff and NK cells. Plasma levels of regulatory cytokines were increased in a dose-dependent manner, while cytokines linked to Teff and Th17 inflammatory cells were mostly unchanged. Global transcriptome analyses showed a dose-dependent decrease in immune response signatures. At the highest dose, Teff responses against beta-cell antigens were suppressed in all 4 patients tested. These results inform of broader changes induced by ld-IL-2 beyond direct effects on Tregs, and relevant for further development of ld-IL-2 for therapy and prevention of T1D, and other autoimmune and inflammatory diseases. PMID:25634360

  11. Nickel nanoparticle-induced dose-dependent cyto-genotoxicity in human breast carcinoma MCF-7 cells

    PubMed Central

    Ahamed, Maqusood; Alhadlaq, Hisham A

    2014-01-01

    Despite the widespread application of nickel nanoparticles (Ni NPs) in industrial, commercial, and biomedical fields, their response to human cells has not been clearly elucidated. In the study reported here, Ni NPs with a 28 nm diameter were used to study their interaction with human breast carcinoma (MCF-7) cells. Dose-dependent decreased cell viability and damaged cell membrane integrity showed the cytotoxic potential of the Ni NPs. We further found that Ni NPs induce oxidative stress in a dose-dependent manner, as evidenced by glutathione depletion and reactive oxygen species (ROS) generation. Comet assay indicated the dose-dependent induction of DNA damage due to Ni NP exposure. The level of messenger RNA, as well as activity of caspase-3 enzyme, was higher in MCF-7 cells exposed to Ni NPs than in control cells. Moreover, we observed statistically significant correlations of ROS with cell viability (R2=0.984), DNA damage (% tail DNA) (R2=0.982), and caspase-3 enzyme activity (R2=0.991). To the best of our knowledge, this is the first study on human breast cancer cells to have shown the cyto-genotoxicity of Ni NPs, which seems to be mediated through ROS. PMID:24627639

  12. 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

  13. 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

  14. 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

  15. Dose-dependent carcinogenicity and frequent Ki-ras proto-oncogene activation by dietary N-nitrosodiethylamine in rainbow trout.

    PubMed

    Hendricks, J D; Cheng, R; Shelton, D W; Pereira, C B; Bailey, G S

    1994-07-01

    While the experimental data upon which current concepts in mechanistically based risk assessment and molecular epidemiology are grounded derive almost entirely from rodent models, fish models have several attributes (e.g., low background incidence, extremely low cost tumor studies, nonmammalian comparative status for extrapolation of mechanisms to humans) that make them valuable adjuncts for addressing these concepts. This report provides an initial characterization of the dose dependency of dietary N-nitrosodiethylamine (DEN) hepatocarcinogenicity in Shasta strain rainbow trout (Oncorhynchus mykiss) and the potential of DEN to elicit ras proto-oncogene activation in this species. Carcinogen was administered in the diet at five concentrations for 12 months. Necropsies were performed at 9, 12, and 18 months, the latter on fish maintained on control diet for 6 months after cessation of DEN exposure. The incidence of hepatic neoplasms at the lower dietary concentrations (< or = 70 ppm) did not consistently exceed that for control groups, which were higher in this particular study (2%) than expected (historically 0.1%). For the higher DEN concentrations, a linear relationship between the hepatic tumor incidence (expressed as log odds, log [p/(1-p)], where p = proportion of fish bearing tumors), and the logarithm of total cumulative dose was observed, with response being independent of the length of time (9 or 12 months) during which the dose was accumulated. The dose-response curve for fish maintained an additional 6 months postexposure was shifted toward higher incidence but was parallel to the curve for fish killed at cessation of exposure. The model predicts that doubling the dose will produce somewhat more than a doubling of the odds (p/(100-p)) for tumor incidence and that the odds for lesions 6 months postexposure will be approximately double those at cessation of exposure. Comparison of these results with previous studies using rats suggests an overall

  16. How Human Brucellosis Incidence in Urban Kampala Can Be Reduced Most Efficiently? A Stochastic Risk Assessment of Informally-Marketed Milk

    PubMed Central

    Makita, Kohei; Fèvre, Eric M.; Waiswa, Charles; Eisler, Mark C.; Welburn, Susan C.

    2010-01-01

    Background In Kampala, Uganda, studies have shown a significant incidence of human brucellosis. A stochastic risk assessment involving two field surveys (cattle farms and milk shops) and a medical record survey was conducted to assess the risk of human brucellosis infection through consumption of informally marketed raw milk potentially infected with Brucella abortus in Kampala and to identify the best control options. Methodology/Principal Findings In the cattle farm survey, sera of 425 cows in 177 herds in the Kampala economic zone were sampled and tested for brucellosis using a competitive enzyme-linked immunosorbent assay (CELISA). Farmers were interviewed for dairy information. In the milk shop surveys, 135 milk sellers in the urban areas were interviewed and 117 milk samples were collected and tested using an indirect enzyme-linked immunosorbent assay (IELISA). A medical record survey was conducted in Mulago National Referral Hospital for serological test results. A risk model was developed synthesizing data from these three surveys. Possible control options were prepared based on the model and the reduction of risk was simulated for each scenario. Overall, 12.6% (6.8–18.9: 90%CI) of informally marketed milk in urban Kampala was contaminated with B.abortus at purchase and the annual incidence rate was estimated to be 5.8 (90% CI: 5.3–6.2) per 10,000 people. The best control option would be the construction of a milk boiling centre either in Mbarara, the largest source of milk, or in peri-urban Kampala and to ensure that milk traders always sell milk to the boiling centre; 90% success in enforcing these two options would reduce risk by 47.4% (21.6–70.1: 90%CI) and 82.0% (71.0–89.0: 90%CI), respectively. Conclusion/Significance This study quantifies the risk of human brucellosis infection through informally marketed milk and estimates the incidence rate in Kampala for the first time; risk-based mitigation strategies are outlined to assist in developing

  17. 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

  18. 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.

  19. Bovine meniscal tissue exhibits age- and interleukin-1 dose-dependent degradation patterns and composition-function relationships.

    PubMed

    Ling, Carrie H-Y; Lai, Janice H; Wong, Ivan J; Levenston, Marc E

    2016-05-01

    Despite increasing evidence that meniscal degeneration is an early event in the development of knee osteoarthritis, relatively little is known regarding the sequence or functional implications of cytokine-induced meniscal degradation or how degradation varies with age. This study examined dose-dependent patterns of interleukin-1 (IL-1)-induced matrix degradation in explants from the radially middle regions of juvenile and adult bovine menisci. Tissue explants were cultured for 10 days in the presence of 0, 1.25, 5, or 20 ng/ml recombinant human IL-1α. Juvenile explants exhibited immediate and extensive sulfated glycosaminoglycan (sGAG) loss and subsequent collagen release beginning after 4-6 days, with relatively little IL-1 dose-dependence. Adult explants exhibited a more graded response to IL-1, with dose-dependent sGAG release and a lower fraction of sGAG released (but greater absolute release) than juvenile explants. In contrast to juvenile explants, adult explants exhibited minimal collagen release over the 10-day culture. Compressive and shear moduli reflected the changes in explant composition, with substantial decreases for both ages but a greater relative decrease in juvenile tissue. Dynamic moduli exhibited stronger dependence on explant sGAG content for juvenile tissue, likely reflecting concomitant changes to both proteoglycan and collagen tissue components. The patterns of tissue degradation suggest that, like in articular cartilage, meniscal proteoglycans may partially protect collagen from cell-mediated degeneration. A more detailed view of functional changes in meniscal tissue mechanics with degeneration will help to establish the relevance of in vitro culture models and will advance understanding of how meniscal degeneration contributes to overall joint changes in early stage osteoarthritis. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:801-811, 2016. PMID:26519862

  20. Breaks of dose dependence of transient creep as result of competing influence of defects’ fluxes on climb of dislocations

    NASA Astrophysics Data System (ADS)

    Selyshchev, P.

    2015-04-01

    In the framework of climb-glide model a theoretical approach is developed to describe transient creep under irradiation. It is obtained the explicit expression for creep rate which describes experimentally observed breaks of dose dependence of creep. It is shown that the breaks arise as result of competition of radiation and thermal fluxes of defects to dislocation. When interstitial and vacancy fluxes become equal, the dislocation cannot overcome the obstacle via climbing and cannot continue glide. Climb-glide mechanism does not contribute to the creep. The creep rate drops. Numbers of breaks depend on initial state of material and conditions of irradiation. Dose (time) of break appearance are obtained.

  1. 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

  2. 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.

  3. 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

  4. Transcutaneous continuous carbon dioxide tension monitoring reduced incidence, degree and duration of hypercapnia during combined regional anaesthesia and monitored anaesthesia care in shoulder surgery patients.

    PubMed

    Baulig, Werner; Keselj, Marija; Baulig, Barbara; Guzzella, Sandra; Borgeat, Alain; Aguirre, José

    2015-08-01

    We studied the impact of transcutaneous continuous carbon dioxide tension (PtcCO2) monitoring on ventilation and oxygenation during monitored anaesthesia care (MAC) in patients scheduled for shoulder surgery with continuous interscalene block. 50 patients were randomised either to the intervention (I-group) or the control (C-group) group. In both groups MAC was performed using target controlled infusion of propofol and remifentanil. MAC regimen was adapted to PtcCO2 values in the I-group, whereas the C-group was blinded for these values. Primary outcome was the incidence, degree and duration of hypoventilation stages. In the I-group and the C-group the mean ± SD [range] of PtcCO2 and PaCO2 was 5.79 ± 0.84 [4.37] and 5.44 ± 0.59 [2.78] kPa, as well as 6.41 ± 1.17 [6.29] and 6.01 ± 0.96 [7.15] kPa. Periods of PtcCO2/PaCO2 > 6.5 kPa were 21.0 ± 35.7/1.2 ± 4.2 min in the I-group and 45.6 ± 40.0/18.6 ± 26.8 min in the C-group. Severe hypercapnia (PtcCO2 and/or PaCO2 > 7.5 kPa) was dected in 3/0 patients of the I-group and in 10/3 patients of the C-group. PtcCO2 and PaCO2 showed a strong correlation (r = 0.78), but only moderate agreement with a mean bias (LOA) of -0.37 (-1.69; +0.95) kPa showing an overestimation of the PaCO2. Sensitivity and specificity of PtcCO2 to detect changes of PaCO2 was 0.94 and 0.56, respectively. In no patient SpO2 or SaO2 values lower than 90% were measured. Despite a moderate agreement between PaCO2 and PtcCO2 the PtcCO2 monitoring significantly reduced incidence, degree and duration of hypercapnia in shoulder surgery patients with MAC. PMID:25312782

  5. A pilot study of respiratory muscle training to improve cough effectiveness and reduce the incidence of pneumonia in acute stroke: study protocol for a randomized controlled trial

    PubMed Central

    2014-01-01

    Background After stroke, pneumonia is a relevant medical complication that can be precipitated by aspiration of saliva, liquids, or solid food. Swallowing difficulty and aspiration occur in a significant proportion of stroke survivors. Cough, an important mechanism protecting the lungs from inhaled materials, can be impaired in stroke survivors, and the likely cause for this impairment is central weakness of the respiratory musculature. Thus, respiratory muscle training in acute stroke may be useful in the recovery of respiratory muscle and cough function, and may thereby reduce the risk of pneumonia. The present study is a pilot study, aimed at investigating the validity and feasibility of this approach by exploring effect size, safety, and patient acceptability of the intervention. Methods/design Adults with moderate to severe stroke impairment (National Institutes of Health Stroke Scale (NIHSS) score 5 to 25 at the time of admission) are recruited within 2 weeks of stroke onset. Participants must be able to perform voluntary respiratory maneuvers. Excluded are patients with increased intracranial pressure, uncontrolled hypertension, neuromuscular conditions other than stroke, medical history of asthma or chronic obstructive pulmonary disease, and recent cardiac events. Participants are randomized to receive inspiratory, expiratory, or sham respiratory training over a 4-week period, by using commercially available threshold resistance devices. Participants and caregivers, but not study investigators, are blind to treatment allocation. All participants receive medical care and stroke rehabilitation according to the usual standard of care. The following assessments are conducted at baseline, 4 weeks, and 12 weeks: Voluntary and reflex cough flow measurements, forced spirometry, respiratory muscle strength tests, incidence of pneumonia, assessments of safety parameters, and self-reported activity of daily living. The primary outcome is peak expiratory cough flow

  6. Mast cell chymase promotes cell proliferation and expression of certain cytokines in a dose-dependent manner.

    PubMed

    Dong, Xianglin; Chen, Junjie; Zhang, Yange; Cen, Ying

    2012-06-01

    Wound healing is a complex process, with various intracellular molecules and cytokines involved. Chymase is a chymotrypsin-like serine protease originally found to be a mast cell protease. In this study, to further investigate the role of chymase in the process of wound healing, the effects of chymase on cell proliferation and cytokine activation in human skin fibroblasts were determined. To determine cell proliferation, MTT assay was employed. The cells were harvested and total proteins were extracted and detected by western blotting. It was found that in vitro cell treatments with chymase led to dose-dependent increases of skin fibroblast proliferation. Moreover, the treatment of cells with chymase for 6 h induced dose-dependent increases in the expression levels of transforming growth factor (TGF)-β1 and interleukin (IL)-1β, although higher doses (120 ng/ml for TGF-β1; 60 and 120 ng/ml for IL-1β) did not facilitate the detected cytokine expression. In addition, treatment for longer periods of time (12 or 24 h) did not increase TGF-β1 or IL-1β expression. The results from our study will strongly facilitate the understanding of the roles of chymase in the process of wound healing. PMID:22470087

  7. 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

  8. 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.

  9. 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. PMID:26610393

  10. Phasing in the presence of severe site-specific radiation damage through dose-dependent modelling of heavy atoms.

    PubMed

    Schiltz, M; Dumas, P; Ennifar, E; Flensburg, C; Paciorek, W; Vonrhein, C; Bricogne, G

    2004-06-01

    The case of a brominated RNA crystal structure determination in which standard three-wavelength MAD phasing was unsuccessful because of fast X-ray-induced debromination was reinvestigated [Ennifar et al. (2002), Acta Cryst. D58, 1262-1268]. It was found that if the data are kept unmerged and if a dose-stamp is associated with each reflection measurement, dose-dependent occupancies can be refined for the Br atoms. Such a parametrization has been implemented in the macromolecular phasing program SHARP. Refining such dose-dependent occupancies on an unmerged data set gave a dramatic improvement, even for SAD phases from only the first wavelength (peak), and resulted in a good electron-density map after solvent flattening. The adverse effect of radiation damage has been turned into a beneficial one. The crucial difference is made by the use of unmerged data: phasing power is generated through the intensity differences of symmetry-related reflections recorded at different doses, i.e. corresponding to different states of the X-ray-induced debromination. This approach should prove useful in all situations of experimental phasing where site-specific radiation damage occurs unavoidably and undesirably and not only in cases in which radiation damage is purposely being created in order to demonstrate its potential usefulness. PMID:15159561

  11. 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

  12. Iron dose-dependent differentiation and enucleation of human erythroblasts in serum-free medium.

    PubMed

    Byrnes, Colleen; Lee, Y Terry; Meier, Emily R; Rabel, Antoinette; Sacks, David B; Miller, Jeffery L

    2016-02-01

    Improvements in ex vivo generation of enucleated red blood cells are being sought for erythroid biology research, toward the ultimate goal of erythrocyte engineering for clinical use. Based upon the high levels of iron-saturated transferrin in plasma serum, it was hypothesized that terminal differentiation in serum-free media may be highly dependent on the concentration of iron. Here adult human CD34(+) cells were cultured in a serum-free medium containing dosed levels of iron-saturated transferrin (holo-Tf, 0.1-1.0 mg/ml). Iron in the culture medium was reduced, but not depleted, with erythroblast differentiation into haemoglobinized cells. At the lowest holo-Tf dose (0.1 mg/ml), terminal differentiation was significantly reduced and the majority of the cells underwent apoptotic death. Cell survival, differentiation and enucleation were enhanced as the holo-Tf dose increased. These data suggest that adequate holo-Tf dosing is critical for terminal differentiation and enucleation of human erythroblasts generated ex vivo in serum-free culture conditions. Published 2013. This article is a US Government work and is in the public domain in the USA. PMID:23606586

  13. Dose-dependent functions of Fgf8 in regulating telencephalic patterning centers.

    PubMed

    Storm, Elaine E; Garel, Sonia; Borello, Ugo; Hebert, Jean M; Martinez, Salvador; McConnell, Susan K; Martin, Gail R; Rubenstein, John L R

    2006-05-01

    Mouse embryos bearing hypomorphic and conditional null Fgf8 mutations have small and abnormally patterned telencephalons. We provide evidence that the hypoplasia results from decreased Foxg1 expression, reduced cell proliferation and increased cell death. In addition, alterations in the expression of Bmp4, Wnt8b, Nkx2.1 and Shh are associated with abnormal development of dorsal and ventral structures. Furthermore, nonlinear effects of Fgf8 gene dose on the expression of a subset of genes, including Bmp4 and Msx1, correlate with a holoprosencephaly phenotype and with the nonlinear expression of transcription factors that regulate neocortical patterning. These data suggest that Fgf8 functions to coordinate multiple patterning centers, and that modifications in the relative strength of FGF signaling can have profound effects on the relative size and nature of telencephalic subdivisions. PMID:16613831

  14. 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

  15. Time- and dose-dependent effects of total-body ionizing radiation on muscle stem cells.

    PubMed

    Masuda, Shinya; Hisamatsu, Tsubasa; Seko, Daiki; Urata, Yoshishige; Goto, Shinji; Li, Tao-Sheng; Ono, Yusuke

    2015-04-01

    Exposure to high levels of genotoxic stress, such as high-dose ionizing radiation, increases both cancer and noncancer risks. However, it remains debatable whether low-dose ionizing radiation reduces cellular function, or rather induces hormetic health benefits. Here, we investigated the effects of total-body γ-ray radiation on muscle stem cells, called satellite cells. Adult C57BL/6 mice were exposed to γ-radiation at low- to high-dose rates (low, 2 or 10 mGy/day; moderate, 50 mGy/day; high, 250 mGy/day) for 30 days. No hormetic responses in proliferation, differentiation, or self-renewal of satellite cells were observed in low-dose radiation-exposed mice at the acute phase. However, at the chronic phase, population expansion of satellite cell-derived progeny was slightly decreased in mice exposed to low-dose radiation. Taken together, low-dose ionizing irradiation may suppress satellite cell function, rather than induce hormetic health benefits, in skeletal muscle in adult mice. PMID:25869487

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

    PubMed Central

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

    2015-01-01

    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 Ca2+ 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. PMID:25407270

  17. 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. PMID:25407270

  18. Time- and dose-dependent changes in neuronal activity produced by x radiation in brain slices

    SciTech Connect

    Not Available

    1990-01-01

    A new method of exposing tissues to X rays in a lead Faraday cage has made it possible to examine directly radiation damage is isolated neuronal tissue. Thin slices of hippocampus from brains of euthanized guinea pigs were exposed to 17.4 keV X radiation. Electrophysiological recordings were made before, during and after exposure to doses between 5 and 65 Gy at a dose rate of 1.54 Gy/min. Following exposure to doses of 40 Gy and greater, the synaptic potential was enhanced, reaching a steady level soon after exposure. The ability of the synaptic potential to generate a spike was reduced and damage progressed after termination of the radiation exposure. Recovery was not observed following termination of exposure. These results demonstrated that an isolated neuronal network can show complex changes in electrophysiological properties following moderate doses of ionizing radiation. An investigation of radiation damage directly to neurons in vitro will contribute to the understanding of the underlying mechanisms of radiation-induced nervous system dysfunction.

  19. Time- and dose-dependent changes in neuronal activity produced by X radiation in brain slices

    SciTech Connect

    Pellmar, T.C.; Schauer, D.A.; Zeman, G.H. )

    1990-05-01

    A new method of exposing tissues to X rays in a lead Faraday cage has made it possible to examine directly radiation damage to isolated neuronal tissue. Thin slices of hippocampus from brains of euthanized guinea pigs were exposed to 17.4 ke V X radiation. Electrophysiological recordings were made before, during, and after exposure to doses between 5 and 65 Gy at a dose rate of 1.54 Gy/min. Following exposure to doses of 40 Gy and greater, the synaptic potential was enhanced, reaching a steady level soon after exposure. The ability of the synaptic potential to generate a spike was reduced and damage progressed after termination of the radiation exposure. Recovery was not observed following termination of exposure. These results demonstrate that an isolated neuronal network can show complex changes in electrophysiological properties following moderate doses of ionizing radiation. An investigation of radiation damage directly to neurons in vitro will contribute to the understanding of the underlying mechanisms of radiation-induced nervous system dysfunction.

  20. 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

  1. 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

  2. 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

  3. Polycystin-1 maturation requires polycystin-2 in a dose-dependent manner.

    PubMed

    Gainullin, Vladimir G; Hopp, Katharina; Ward, Christopher J; Hommerding, Cynthia J; Harris, Peter C

    2015-02-01

    Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited nephropathy responsible for 4%-10% of end-stage renal disease cases. Mutations in the genes encoding polycystin-1 (PC1, PKD1) or polycystin-2 (PC2, PKD2) cause ADPKD, and PKD1 mutations are associated with more severe renal disease. PC1 has been shown to form a complex with PC2, and the severity of PKD1-mediated disease is associated with the level of the mature PC1 glycoform. Here, we demonstrated that PC1 and PC2 first interact in the ER before PC1 cleavage at the GPS/GAIN site and determined that PC2 acts as an essential chaperone for PC1 maturation and surface localization. The chaperone function of PC2 was dependent on the presence of the distal coiled-coil domain and was disrupted by pathogenic missense mutations. In Pkd2-/- mice, complete loss of PC2 prevented PC1 maturation. In Pkd2 heterozygotes, the 50% PC2 reduction resulted in a nonequimolar reduction (20%-25%) of the mature PC1 glycoform. Interbreeding between various Pkd1 and Pkd2 models revealed that animals with reduced levels of functional PC1 and PC2 in the kidney exhibited severe, rapidly progressive disease, illustrating the importance of complexing of these proteins for function. Our results indicate that PC2 regulates PC1 maturation; therefore, mature PC1 levels are a determinant of disease severity in PKD2 as well as PKD1. PMID:25574838

  4. 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

  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. PMID:25701025

  6. The protein corona protects against size- and dose-dependent toxicity of amorphous silica nanoparticles

    PubMed Central

    Bantz, Christoph; Westmeier, Dana; Galla, Hajo J; Wang, Qiangbin; Kirkpatrick, James C; Nielsen, Peter; Maskos, Michael; Stauber, Roland H

    2014-01-01

    Summary Besides the lung and skin, the gastrointestinal (GI) tract is one of the main targets for accidental exposure or biomedical applications of nanoparticles (NP). Biological responses to NP, including nanotoxicology, are caused by the interaction of the NP with cellular membranes and/or cellular entry. Here, the physico-chemical characteristics of NP are widely discussed as critical determinants, albeit the exact mechanisms remain to be resolved. Moreover, proteins associate with NP in physiological fluids, forming the protein corona potentially transforming the biological identity of the particle and thus, adding an additional level of complexity for the bio–nano responses. Here, we employed amorphous silica nanoparticles (ASP) and epithelial GI tract Caco-2 cells as a model to study the biological impact of particle size as well as of the protein corona. Caco-2 or mucus-producing HT-29 cells were exposed to thoroughly characterized, negatively charged ASP of different size in the absence or presence of proteins. Comprehensive experimental approaches, such as quantifying cellular metabolic activity, microscopic observation of cell morphology, and high-throughput cell analysis revealed a dose- and time-dependent toxicity primarily upon exposure with ASP30 (Ø = 30 nm). Albeit smaller (ASP20, Ø = 20 nm) or larger particles (ASP100; Ø = 100 nm) showed a similar zeta potential, they both displayed only low toxicity. Importantly, the adverse effects triggered by ASP30/ASP30L were significantly ameliorated upon formation of the protein corona, which we found was efficiently established on all ASP studied. As a potential explanation, corona formation reduced ASP30 cellular uptake, which was however not significantly affected by ASP surface charge in our model. Collectively, our study uncovers an impact of ASP size as well as of the protein corona on cellular toxicity, which might be relevant for processes at the nano–bio interface in general. PMID:25247121

  7. Different dose-dependent effects of ebselen in -sciatic nerve ischemia-reperfusion injury in rats

    PubMed Central

    Ozyigit, Filiz; Kucuk, Aysegul; Akcer, Sezer; Tosun, Murat; Kocak, Fatma Emel; Kocak, Cengiz; Kocak, Ahmet; Metineren, Hasan; Genc, Osman

    2015-01-01

    Ebselen is an organoselenium compound which has strong antioxidant and anti-inflammatory effects. We investigated the neuroprotective role of ebselen pretreatment in rats with experimental sciatic nerve ischemia-reperfusion (I/R) injury. Adult male Sprague Dawley rats were divided into four groups (N = 7 in each group). Before sciatic nerve I/R was induced, ebselen was injected intraperitoneally at doses of 15 and 30 mg/kg. After a 2 h ischemia and a 3 h reperfusion period, sciatic nerve tissues were excised. Tissue levels of malondialdehyde (MDA) and nitric oxide (NO), and activities of superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) were measured. Sciatic nerve tissues were also examined histopathologically. The 15 mg/kg dose of ebselen reduced sciatic nerve damage and apoptosis (P < 0.01), levels of MDA, NO, and inducible nitric oxide synthase (iNOS) positive cells (P < 0.01, P < 0.05, respectively), and increased SOD, GPx, and CAT activities (P < 0.001, P < 0.01, P < 0.05, respectively) compared with the I/R group that did not receive ebselen. Conversely, the 30 mg/kg dose of ebselen increased sciatic nerve damage, apoptosis, iNOS positive cells (P < 0.01, P < 0.05, P < 0.001) and MDA and NO levels (P < 0.05, P < 0.01) and decreased SOD, GPx, and CAT activities (P < 0.05) compared with the sham group. The results of this study suggest that ebselen may cause different effects depending on the dose employed. Ebselen may be protective against sciatic nerve I/R injury via antioxidant and antiapoptotic activities at a 15 mg/kg dose, conversely higher doses may cause detrimental effects. PMID:26614850

  8. 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

  9. 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

  10. Sensitivity and dose dependency of radiation-induced injury in hematopoietic stem/progenitor cells in mice.

    PubMed

    Guo, Chang-Ying; Luo, Lan; Urata, Yoshishige; Goto, Shinji; Huang, Wen-Jing; Takamura, Syu; Hayashi, Fumiko; Doi, Hanako; Kitajima, Yuriko; Ono, Yusuke; Ogi, Tomoo; Li, Tao-Sheng

    2015-01-01

    We evaluated the sensitivity and dose dependency of radiation-induced injury in hematopoietic stem/progenitor cells. Adult C57BL/6 mice were daily exposed to 0, 2, 10, 50, and 250 mGy γ-ray for 1 month in succession, respectively. The damage of hematopoietic stem/progenitor cells in bone marrow were investigated within 2 hours (acute phase) or at 3 months (chronic phase) after the last exposure. Daily exposure to over 10 mGy γ-ray significantly decreased the number and colony-forming capacity of hematopoietic stem/progenitor cells at acute phase, and did not completely recover at chronic phase with 250 mGy exposure. Interestingly, the daily exposure to 10 or 50 mGy γ-ray decreased the formation of mixed types of colonies at chronic phase, but the total number of colonies was comparable to control. Immunostaining analysis showed that the formation of 53BP1 foci in c-kit(+) stem/progenitor cells was significantly increased with daily exposure to 50 and 250 mGy at acute phase, and 250 mGy at chronic phase. Many genes involved in toxicity responses were up- or down-regulated with the exposures to all doses. Our data have clearly shown the sensitivity and dose dependency of radiation-induced injury in hematopoietic stem/progenitor cells of mice with daily exposures to 2 ~ 250 mGy γ-ray. PMID:25623887

  11. Dose-Dependent Dual Role of PIT-1 (POU1F1) in Somatolactotroph Cell Proliferation and Apoptosis

    PubMed Central

    Jullien, Nicolas; Roche, Catherine; Brue, Thierry; Figarella-Branger, Dominique; Graillon, Thomas; Barlier, Anne; Herman, Jean-Paul

    2015-01-01

    To test the role of wtPIT-1 (PITWT) or PIT-1 (R271W) (PIT271) in somatolactotroph cells, we established, using inducible lentiviral vectors, sublines of GH4C1 somatotroph cells that allow the blockade of the expression of endogenous PIT-1 and/or the expression of PITWT or PIT271, a dominant negative mutant of PIT-1 responsible for Combined Pituitary Hormone Deficiency in patients. Blocking expression of endogenous PIT-1 induced a marked decrease of cell proliferation. Overexpressing PITWT twofold led also to a dose-dependent decrease of cell proliferation that was accompanied by cell death. Expression of PIT271 induced a strong dose-dependent decrease of cell proliferation accompanied by a very pronounced cell death. These actions of PIT271 are independent of its interaction/competition with endogenous PIT-1, as they were unchanged when expression of endogenous PIT-1 was blocked. All these actions are specific for somatolactotroph cells, and could not be observed in heterologous cells. Cell death induced by PITWT or by PIT271 was accompanied by DNA fragmentation, but was not inhibited by inhibitors of caspases, autophagy or necrosis, suggesting that this cell death is a caspase-independent apoptosis. Altogether, our results indicate that under normal conditions PIT-1 is important for the maintenance of cell proliferation, while when expressed at supra-normal levels it induces cell death. Through this dual action, PIT-1 may play a role in the expansion/regression cycles of pituitary lactotroph population during and after lactation. Our results also demonstrate that the so-called “dominant-negative” action of PIT271 is independent of its competition with PIT-1 or a blockade of the actions of the latter, and are actions specific to this mutant variant of PIT-1. PMID:25822178

  12. 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

  13. 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

  14. Dose-dependent genotoxicity of copper oxide nanoparticles stimulated by reactive oxygen species in human lung epithelial cells.

    PubMed

    Akhtar, Mohammad Javed; Kumar, Sudhir; Alhadlaq, Hisham A; Alrokayan, Salman A; Abu-Salah, Khalid M; Ahamed, Maqusood

    2016-05-01

    Copper oxide nanoparticles (CuO NPs) are of great interest in nanoscience and nanotechnology because of their broad industrial and commercial applications. Therefore, toxicity of CuO NPs needs to be thoroughly understood. The aim of this study was to investigate the cytotoxicity, genotoxicity, and oxidative stress induced by CuO NPs in human lung epithelial (A549) cells. CuO NPs were synthesized by solvothermal method and the size of NPs measured under transmission electron microscopy (TEM) was found to be around 23 nm. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) and lactate dehydrogenase (LDH) assays showed that CuO NPs (5-15 µg/ml) exert cytotoxicity in A549 cells in a dose-dependent manner. Comet assay suggested concentration-dependent induction of DNA damage due to the exposure to CuO NPs. The comet tail moment was 27% at 15 µg/ml of CuO NPs, whereas it was 5% in control (p < 0.05). The flow cytometry data revealed that CuO NPs induced micronuclei (MN) in A549 cells dose dependently. The frequency of MN was 25/10(3) cells at 15 µg/ml of CuO NPs, whereas it was 2/10(3) cells for control. CuO NPs were also found to induce oxidative stress in a concentration-dependent manner, which was indicated by induction of reactive oxygen species (ROS) and lipid peroxidation along with glutathione depletion. Moreover, MN induction and DNA damage were significantly correlated with ROS (R(2) = 0.937 for ROS vs. olive tail moment, and R(2) = 0.944 for ROS vs. MN). Taken together, this study suggested that CuO NPs induce genotoxicity in A549 cells, which is likely to be mediated through ROS generation and oxidative stress. PMID:24311626

  15. Dose-dependent effects of polyphenolic extracts from green tea, blue-berried honeysuckle, and chokeberry on rat caecal fermentation processes.

    PubMed

    Frejnagel, Slawomir; Juskiewicz, Jerzy

    2011-06-01

    The physiological status of the colon or ceacum is known to be very important for the host organism. Therefore, the aim of this study was to estimate the influence of high doses of polyphenolic extracts from chokeberry (CH), blue-berried honeysuckle (H), and green tea (GT) on fermentation processes in the caecum and caecal parameters of rats fed casein diets. In a 4-week experiment, 35-day-old rats were fed diets containing 0.4, 0.8, and 1.2 % of pure polyphenols. The greatest weight of digesta was recorded in rats fed 1.2 % of GT extract, and these animals were also characterised by having the lowest content of dry matter. Supplementation of diets with the extracts of interest caused a reduction in pH values and ammonia concentrations in caecal digesta in comparison to control animals. The results of a two-way analysis of variance indicated dose-dependent (except for 0.4 % supplementation) inhibition of enzymatic activity compared to control animals. Introduction of CH and H extracts significantly reduced the activity of β-glucuronidase compared to rats fed tea diets. Two-way analysis of variance showed a significant decrease in volatile fatty acids concentration in rats fed diets supplemented with H and CH extracts in comparison to control and tea-fed rats. The obtained results showed that the extracts tested can distinctly influence caecal parameters and metabolism. PMID:21240841

  16. The Ranger First Responder Program and Tactical Emergency Casualty Care Implementation: A Whole-Community Approach to Reducing Mortality From Active Violent Incidents.

    PubMed

    Fisher, Andrew D; Callaway, David W; Robertson, Josh N; Hardwick, Shane A; Bobko, Joshua P; Kotwal, Russ S

    2015-01-01

    Active violent incidents are dynamic and challenging situations that can produce a significant amount of preventable deaths. Lessons learned from the military?s experience in Afghanistan and Iraq through the Committee on Tactical Combat Casualty Care and the 75th Ranger Regiment?s Ranger First Responder Program have helped create the Committee for Tactical Emergency Casualty Care (C-TECC) to address the uniqueness of similar wounding patterns and to end preventable deaths. We propose a whole-community approach to active violent incidents, using the C-TECC Trauma Chain of Survival and a tiered approach for training and responsibilities: the first care provider, nonmedical professional first responders, medical first responders, and physicians and trauma surgeons. The different tiers are critical early links in the Chain of Survival and this approach will have a significant impact on active violent incidents. PMID:26360353

  17. 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.

  18. 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

  19. Dose-dependent modulation of the in vitro cytokine production of human immune competent cells by lead salts.

    PubMed

    Hemdan, Nasr Y A; Emmrich, Frank; Adham, Khadiga; Wichmann, Gunnar; Lehmann, Irina; El-Massry, Azza; Ghoneim, Hossam; Lehmann, Jörg; Sack, Ulrich

    2005-07-01

    Lead pollution constitutes a major health problem that has been intensively debated. To reveal its effects on the immune response, the influence of lead on the in vitro cytokine production of human peripheral mononuclear blood cells was investigated. Isolated cells were exposed to lead acetate or lead chloride for 24 h in the presence of either heat-killed Salmonella enteritidis (hk-SE) or monoclonal antibodies (anti-CD3, anti-CD28, anti-CD40) as cell activators. Our results showed that while higher lead doses are toxic, lower ones evoke immunomodulatory effects. All tested lead doses significantly reduced cell vitality and/or proliferation and affected secretion of proinflammatory, T helper cell type (T(H))1 and T(H)2 cytokines. Expression of interferon (IFN)-gamma, interleukin (IL)-1beta, and tumor necrosis factor (TNF)-alpha was reduced at lower lead doses in both models of cell stimulation. Although hk-SE failed to induce detectable IL-4 levels, monoclonal antibody-induced IL-4, IL-6, and IL-10 secretion increased in the presence of lower lead doses. Also, levels of hk-SE-induced IL-10 and IL-6 secretion were increased at lower lead doses. Thus, exposure to lower doses leads to suppression of the T(H)1 cytokine IFN-gamma and the proinflammatory cytokines TNF-alpha and IL-1beta. The elevated production of IL-4 and/or IL-10 can induce and maintain a T(H)2 immune response and might contribute to increased susceptibility to pathologic agents as well as the incidence of allergic hypersensitivity and/or T(H)2-dominated autoimmune diseases. PMID:15843504

  20. 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

  1. 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

  2. Comparative Analysis of Temporal and Dose-Dependent TCDD-Elicited Gene Expression in Human, Mouse, and Rat Primary Hepatocytes

    PubMed Central

    Zacharewski, Timothy R.

    2013-01-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)–elicited time- and dose-dependent differential gene expression was compared in human, mouse, and rat primary hepatocytes. Comprehensive time course (10 nM TCDD or dimethyl sulfoxide vehicle control for 1, 2, 4, 8, 12, 24, and 48h) studies identified 495, 2305, and 711 differentially expressed orthologous genes in human, mouse, and rat hepatocytes, respectively. However, only 16 orthologs were differentially expressed across all three species, with the majority of orthologs exhibiting species-specific expression (399 human, 2097 mouse, and 533 rat), consistent with species-specific expression reported in other in vitro and in vivo comparative studies. TCDD also elicited the dose-dependent induction of 397 human, 100 mouse, and 443 rat genes at 12h and 615 human, 426 mouse, and 314 rat genes at 24h. Comparable EC50 values were obtained for AhR battery genes including Cyp1a1 (0.1 nM human, 0.05 nM mouse, 0.08 nM rat at 24h) and Tiparp (0.97 nM human, 0.63 nM mouse, 0.14 nM rat at 12h). Overrepresented functions and pathways included amino acid metabolism in humans, immune response in mice, and energy homeostasis in rats. Differentially expressed genes functionally associated with lipid transport, processing, and metabolism were overrepresented in all three species but exhibited species-specific expression consistent with the induction of hepatic steatosis in mice but not in rats following a single oral gavage of TCDD. Furthermore, human primary hepatocytes showed lipid accumulation following 48h of treatment with TCDD, suggesting that AhR-mediated steatosis in mice more closely resembles human hepatic fat accumulation compared with that in rats. Collectively, these results suggest that species-specific gene expression profiles mediate the species-specific effects of TCDD despite the conservation of the AhR and its signaling mechanism. PMID:23418086

  3. 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

  4. 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

  5. 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

  6. 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

  7. Dose-dependent neuroprotective effect of caffeine on a rotenone-induced rat model of parkinsonism: A histological study.

    PubMed

    Soliman, Amira M; Fathalla, Ahmed M; Moustafa, Ahmed A

    2016-06-01

    Several lines of evidence have demonstrated an inverse relationship between caffeine utilization and Parkinson's disease (PD) progression. Caffeine is a methylxanthine known as a non-specific inhibitor of adenosine (A2A and A1) receptors in the cerebrum and demonstrated to be a neuroprotective medication. In this study, the neuroprotective efficacy of two different doses of caffeine ranging above the usual consumption dose and below the toxic dose was investigated using histopathological and immunohistochemical methods. Thirty-two male rats were randomly divided into 4 groups, with 8 in each group: vehicle control (1ml/kg/48h for 12 days), rotenone (1.5mg/kg/48h, s.c. for 12 days), low-dose Caffeine-treated: (10mg/kg IP. daily for 12 days), high-dose Caffeine-treated (20mg IP daily for 12 days). Twenty-four hours after the last rotenone injection, animals were sacrificed and brains were sectioned and prepared for histopathological staining with hematoxylinand eosin, cresyl violet and Mallory's phosphotungestic acid haematoxylinand for immunohistochemical staining of tyrosine hydroxylase. Our study showed that the treatment with caffeine improved histopathological degeneration in the substantia nigra parts compacta (SNpc) neurons and hindered the reduction in dopamine concentration caused by rotenone. We also found that a higher dose of caffeine was more effective against histopathological degeneration. These results suggest that caffeine has a dose-dependent neuroprotective effect. PMID:27132082

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

    NASA Astrophysics Data System (ADS)

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

    2009-07-01

    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 (~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.

  9. Investigation of Dose-Dependent Factors Limiting Oral Bioavailability: Case Study With the PI3K-δ Inhibitor.

    PubMed

    Chiang, Po-Chang; Sutherlin, Daniel; Pang, Jodie; Salphati, Laurent

    2016-06-01

    It is understood that a potential issue for drugs with poor aqueous solubility is low oral absorption. If oral exposure issues arise when working with a low solubility drug candidate, the common action is to rely on enabling formulations to solve the issue. However, this approach becomes troublesome in the pre-clinical setting where compound absorption, distribution, metabolism, excretion properties are suboptimal and more factors limiting bioavailability may be at play. A narrow focus on solubility enhancement without a full understanding of compound absorption, distribution, metabolism, excretion properties can produce data that cloak the actual phenomena driving exposure. Compound 1 is a potent and selective PI3Kdelta inhibitor with poor aqueous solubility. In a pharmacokinetic study on dogs, exposure was found to be less than dose-linear. Besides the solubility, further investigations were conducted to identify other factors limiting oral exposure. It was observed that these limiting factors are dose dependent. Results from modeling pharmacokinetic under low-dose conditions suggest that exposure is significantly limited by metabolism and no exposure improvements should be expected from enabled formulations. Furthermore, enabling formulations are expected to exert a beneficial influence at higher doses. An in vivo test was conducted in dogs to verify this phenomenon. PMID:27238480

  10. 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. PMID:25637568

  11. 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

  12. 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.

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

    PubMed

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

    2014-08-15

    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

  14. Dose-dependent effect of the CYP2D6 genotype on the steady-state fluvoxamine concentration.

    PubMed

    Watanabe, Junzo; Suzuki, Yutaro; Fukui, Naoki; Sugai, Takuro; Ono, Shin; Inoue, Yoshimasa; Someya, Toshiyuki

    2008-12-01

    Several studies have reported that the cytochrome P450 (CYP) 2D6 plays an important role in the fluvoxamine metabolism. However, some other studies have reported that the CYP2D6 genotype has no major impact on the fluvoxamine concentration. This study investigated the dose-dependent effect of CYP2D6-variant alleles on the steady-state fluvoxamine concentration. There were 23 patients whose plasma concentrations of fluvoxamine were measured at 4 doses (50, 100, 150, and 200 mg/d). The differences in the plasma fluvoxamine concentration were analyzed between 2 genotype groups divided by the number of CYP2D6-variant alleles (with 0 and 1 or 2 variant alleles). The results demonstrated the nonlinear kinetics of fluvoxamine metabolism, and the degree of nonlinear kinetics decreased as the dose was increased. Significant differences in fluvoxamine concentration were observed between the subjects with 0 variant alleles and the subjects with 1 or 2 variant alleles (P = 0.044) when they were treated by 50 mg of fluvoxamine. There were no significant differences in the plasma concentration of fluvoxamine at 100, 150, and 200 mg/d. The present study suggests that the effect of the CYP2D6 genotype on fluvoxamine metabolism is greater at lower doses of fluvoxamine. PMID:18978520

  15. Dose-Dependent Bidirectional Effect of Angiotensin IV on Abdominal Aortic Aneurysm via Variable Angiotensin Receptor Stimulation.

    PubMed

    Kong, Jing; Zhang, Kai; Meng, Xiao; Zhang, Yun; Zhang, Cheng

    2015-09-01

    Angiotensin IV (Ang IV), as an effector peptide of the rennin-angiotensin system, possesses many biological properties yet not completely known. In this study, we aimed to investigate the role of Ang IV in the development of Ang II-induced abdominal aortic aneurysm (AAA) in apolipoprotein E-knockout mice. We used Ang II infusion to induce AAA, and animals were treated with Ang II (1.44 mg/kg per day) plus no treatment, Ang II (1.44 mg/kg per day) plus low-, medium-, and high-dose Ang IV (0.72, 1.44, and 2.88 mg/kg per day, respectively). The incidence of AAA was 87.5%, 66.7%, 37.5%, and 83.3% in the no treatment, the low-, medium-, or high-dose Ang IV group, respectively. Compared with the no treatment group, medium-dose Ang IV treatment markedly reduced macrophage infiltration; levels of proinflammatory cytokines, including monocyte chemoattractant protein 1, interleukin 6, and intercellular adhesion molecule 1; the expression and activity of metalloproteinases 2 and 9; but increased smooth muscle cells, and collagen content in AAA. However, high-dose Ang IV treatment did not have obvious protective effect. The beneficial effect of medium-dose Ang IV may be contributed to the stimulation of type 4 angiotensin receptor (AT4R) and AT2R with suppression of AT1R, activation of Akt, and inhibition of nuclear factor-κB, as these beneficial effects were largely reversed by cotreatment with the AT4R antagonist divalinal-Ang IV in Ang II-infused mice or with the Akt inhibitor A6730 in Ang II-stimulated human smooth muscle cells. Therefore, medium dose of Ang IV may provide a novel and promising approach to the treatment of AAA. PMID:26238445

  16. 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

  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. 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.

  19. 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

  20. Current Smoking Dose-Dependently Associated with Decreased β-Cell Function in Chinese Men without Diabetes

    PubMed Central

    Wang, Chun; Wang, Yijun; Wu, Junxia; Liu, Suyi; Zhu, Ying; Lv, Shurong; Lin, Ping; Wang, Xiaoke; Xu, Yan; Yu, Shali; Chen, Gang; Xiang, Quanyong

    2015-01-01

    The aim of this study was to evaluate the associations between chronic smoking and insulin resistance and β-cell function in Chinese men without diabetes. A total of 1,568 participants were recruited by multistage sampling. Using homeostatic model assessment (HOMA), geometric means of insulin resistance (HOMA-IR) and β-cell function (HOMA-β) with 95% confidence interval (CI) were calculated by general linear model. Odds ratios (ORs) with 95% CI were estimated to evaluate the associations between smoking status and insulin resistance and β-cell deficiency under a logistic regression model. Current smokers had higher levels of 2 h glucose (6.66 versus 6.48 mmol/L) for oral glucose tolerance test and lower levels of fasting insulin (5.68 versus 6.03 mU/L) than never smokers. The adjusted means for HOMA-β (%) were 54.86 in current smokers and 58.81 in never smokers (P = 0.0257). Current smoking was associated with β-cell deficiency (OR 1.29, 95% CI 1.01–1.64) compared to never smoking. The β-cell function gradually decreased with increasing smoking intensity (Ptrend = 0.0026), and the differences were statistically significant when the pack-year of smoking was 20 or above. No association was observed between smoking status and HOMA-IR. Our study suggested that chronic smoking may dose-dependently suppress insulin secretion in Chinese men. PMID:26236748

  1. 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

  2. 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

  3. Dose-dependent effects of small-molecule antagonists on the genomic landscape of androgen receptor binding

    PubMed Central

    2012-01-01

    Background The androgen receptor plays a critical role throughout the progression of prostate cancer and is an important drug target for this disease. While chromatin immunoprecipitation coupled with massively parallel sequencing (ChIP-Seq) is becoming an essential tool for studying transcription and chromatin modification factors, it has rarely been employed in the context of drug discovery. Results Here we report changes in the genome-wide AR binding landscape due to dose-dependent inhibition by drug-like small molecules using ChIP-Seq. Integration of sequence analysis, transcriptome profiling, cell viability assays and xenograft tumor growth inhibition studies enabled us to establish a direct cistrome-activity relationship for two novel potent AR antagonists. By selectively occupying the strongest binding sites, AR signaling remains active even when androgen levels are low, as is characteristic of first-line androgen ablation therapy. Coupled cistrome and transcriptome profiling upon small molecule antagonism led to the identification of a core set of AR direct effector genes that are most likely to mediate the activities of targeted agents: unbiased pathway mapping revealed that AR is a key modulator of steroid metabolism by forming a tightly controlled feedback loop with other nuclear receptor family members and this oncogenic effect can be relieved by antagonist treatment. Furthermore, we found that AR also has an extensive role in negative gene regulation, with estrogen (related) receptor likely mediating its function as a transcriptional repressor. Conclusions Our study provides a global and dynamic view of AR’s regulatory program upon antagonism, which may serve as a molecular basis for deciphering and developing AR therapeutics. PMID:22849360

  4. Parkin depletion delays motor decline dose-dependently without overtly affecting neuropathology in α-synuclein transgenic mice

    PubMed Central

    2013-01-01

    Background Mutations of the gene encoding the major component of Lewy bodies (LB), α-synuclein (α-syn), cause autosomal dominant forms of Parkinson’s disease (PD), whereas loss-of-function mutations of the gene encoding the multifunctional E3 ubiquitin-protein ligase Parkin account for autosomal recessive forms of the disease. Parkin overproduction protects against α-syn-dependent neurodegeneration in various in vitro and in vivo models, but it remains unclear whether this process is affected by Parkin deficiency. We addressed this issue, by carrying out more detailed analyses of transgenic mice overproducing the A30P variant of human α-syn (hA30Pα-syn) and with two, one or no parkin knockout alleles. Results Longitudinal behavioral follow-up of these mice indicated that Parkin depletion delayed disease-predictive sensorimotor impairment due to α-syn accumulation, in a dose-dependent fashion. At the end stage of the disease, neuronal deposits containing fibrillar α-syn species phosphorylated at S129 (PS129α-syn) were the predominant neuropathological feature in hA30Pα-syn mice, regardless of their parkin expression. Some of these deposits colocalized with the LB markers ubiquitin and α-syn truncated at D135 (α-synD135), indicating that PS129α-syn is subjected to secondary posttranslational modification (PTM); these features were not significantly affected by parkin dysfunction. Conclusions These findings suggest that Parkin deficiency acts as a protective modifier in α-syn-dependent neurodegeneration, without overtly affecting the composition and characteristics of α-syn deposits in end-stage disease. PMID:24192137

  5. Neonatal Binge Alcohol Exposure Produces Dose Dependent Deficits in Interstimulus Interval Discrimination Eyeblink Conditioning in Juvenile Rats

    PubMed Central

    Brown, Kevin L.; Burman, Michael A.; Duong, Huan B.; Stanton, Mark E.

    2009-01-01

    Alcohol consumption in neonatal rats produces cerebellar damage and is widely used to model 3rd-trimester human fetal alcohol exposure. Neonatal “binge-like” exposure to high doses of alcohol (5 g/kg/day or more) impairs acquisition of eyeblink classical conditioning (EBC), a cerebellar-dependent Pavlovian motor learning task. We have recently found impairments in interstimulus interval (ISI) discrimination – a complex task variant of EBC - in adult rats following postnatal day (PD) 4–9 alcohol exposure at doses of 3, 4, and 5 g/kg/day. Because robust developmental differences in conditioned response (CR) generation and CR latency measures are present between untreated juveniles and adults in this task, we sought to extend alcohol findings to juvenile rats (PD30). Five neonatal treatment groups were used: (1) undisturbed controls, (2) sham intubation controls, (3) 3 g/kg/day of alcohol (blood alcohol concentration {BAC} = 139.9 mg/dl), (4) 4 g/kg/day of alcohol (BAC = 237.3 mg/dl), or (5) 5 g/kg/day of alcohol (BAC = 301.8 mg/dl). Intubations occurred over PD4-9. ISI discrimination training in juveniles (PD30-33) revealed dose-dependent CR deficits in all three alcohol-exposed groups relative to controls. Contrary to expected outcomes, CR latency measures were not significantly affected as a function of neonatal treatment. Comparison of these findings with our recent study in adults suggests that alcohol-induced impairments in ISI discrimination EBC may be greater in adults relative to juveniles. The present findings provide further evidence that ISI discrimination may provide greater sensitivity to functional deficits resulting from moderate levels of neonatal alcohol exposure relative to single-cue EBC paradigms. PMID:19007754

  6. 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

  7. 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

  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. Therapeutic success and efficacy of nonviral liposomal cDNA gene transfer to the skin in vivo is dose dependent.

    PubMed

    Jeschke, M G; Richter, G; Herndon, D N; Geissler, E K; Hartl, M; Hofstätter, F; Jauch, K W; Perez-Polo, J R

    2001-12-01

    It is well documented that responses to growth factor treatment typically display bell-shaped dose responses that can significantly affect efficacy. Here we tested the hypothesis that nonviral liposomal gene delivery also displays this characteristic. We chose two different growth factors, keratinocyte growth factor (KGF) and insulin-like growth factor-I (IGF-I) CMV-driven transfecting constructs at three different concentrations and assessed efficacy on several physiological parameters that are descriptive of wound healing progress in a burn-wound healing model. Rats were given a 60% TBSA scald burn and randomly divided into one of seven groups to receive weekly subcutaneous injections of liposomes containing the cDNA for KGF (0.2 microg, 2.2 microg, or 22.2 microg), or liposomes containing the cDNA for IGF-I (0.2 microg, 2.2 microg, or 22.2 microg) at various concentrations, but constant liposome:DNA ratios and a LacZ gene (0.2 microg) CMV-driven construct for beta-galactosidase as vehicle and marker gene. Transfection was confirmed by histology for beta-galactosidase. Physiological efficacy was evaluated by measuring the wound healing parameters that define dermal and epidermal regeneration. Transfection products were found in the cytoplasm of rapidly dividing cells of the granulation tissue. Different doses of the nonviral cDNA gene transfer coding for KGF or IGF-I resulted in different outcomes for dermal and epidermal regeneration. There was a dose-dependent response to both growth factor gene transfers that was not dissimilar from that typically displayed by treatment with growth factor proteins. Both concentrations below and above the optimal concentration of DNA:liposomal preparations did not yield the results observed at the optimal concentration. PMID:11803397

  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. 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

  12. 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

  13. 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

  14. In vitro cytotoxicity evaluation of HDAC inhibitor Apicidin in pancreatic carcinoma cells subsequent time and dose dependent treatment.

    PubMed

    Bauden, Monika; Tassidis, Helena; Ansari, Daniel

    2015-07-01

    Apicidin is a potent histone deacetylase inhibitor (HDACI) that selectively binds to histone deacetylases (HDACs) class I and interferes with the deacetylation process, which results in modification of acetylation level of cellular proteins. The aim of the study was to investigate the potential time and dose dependent cytotoxicity of the test compound, Apicidin, in pancreatic cancer cells Capan-1 and Panc-1 as well as estimate maximal tolerable dose (MTD) of the test agent and determine EC50 using four complementary colorimetric cytotoxicity or viability assays. The cells were treated with increasing concentrations of Apicidin (0-5000nM) for 2, 4 and 6h (short term exposure) or 24, 48 and 72h (long term exposure) before conducting cytotoxic analyses with lactate dehydrogenase assay or viability analyses with sulforhodamine B (SRB), methyl tetrazolium (MTT) and crystal violet (CV) assays. In order to investigate whether Apicidin irreversibly affects the cells already during the short term exposure, the medium containing Apicidin was removed and replaced with fresh culturing medium after 6h of treatment. The cells were then incubated for additional 24, 48 or 72h before carrying out the analysis. The results obtained from cytotoxicity and viability assays indicated, that Apicidin was well tolerated by both cell lines at concentrations below 100nM at any given time point and at all applied concentrations during the short term (6h or less) treatment. Continuous prolonged term exposures (48h or greater) of the cells to Apicidin with concentration exceeding 100nM resulted in significantly increasing cytotoxicity and sustained significant loss of cell viability. Moreover, long term exposure of pancreatic cancer cells Capan-1 and Panc-1 to Apicidin concentrations exceeding 100nM showed an initial anti-proliferative effect before cytotoxicity onset. In summary, MTD was exposure time dependent and estimated to 100nM for long term treatment and to at least 5000nM for treatment

  15. 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

  16. 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

  17. Lactobacillus reuteri strains reduce incidence and severity of experimental necrotizing enterocolitis via modulation of TLR4 and NF-κB signaling in the intestine.

    PubMed

    Liu, Yuying; Fatheree, Nicole Y; Mangalat, Nisha; Rhoads, Jon Marc

    2012-03-15

    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

  18. 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

  19. Identification of quality management practices to reduce the incidence of retail beef tenderness problems: development and evaluation of a prototype quality system to produce tender beef.

    PubMed

    Tatum, J D; Belk, K E; George, M H; Smith, G C

    1999-08-01

    A prototype quality system for ensuring beef tenderness was designed and tested. The test population of cattle was genetically diverse, but it was constrained to include youthful (14- to 17-mo-old) steers with no more than 3/8 Bos indicus inheritance. Feeding and preharvest management of the cattle were consistent with procedures recommended for production of grain-finished beef of an acceptable quality level. In addition, the target endpoint for harvest (11-mm external fat thickness over the longissimus at the 12th rib) resulted in production of mostly Select and low Choice beef carcasses; 92% of the resulting carcasses qualified for these two grade levels. Application of the prototype quality system reduced the expected rate of nonconformance to desired tenderness specifications from about one in four loin steaks (23% for top sirloins and 26% for strip loins) to approximately one in eight loin steaks (13% for top sirloins and 12% for strip loins). Tenderness comparisons among sires suggested that the rate of nonconformance for strip loin steaks might be reduced even further by control of genetic inputs into the system. Use of process control in a quality management system was demonstrated to be an effective approach for assurance of beef tenderness. PMID:10461989

  20. Reduced incidence of postoperative symptoms following a novel bilateral supraclavicular approach to open thyroidectomy: a randomized clinical trial in a Chinese population

    PubMed Central

    Lv, Lin; Zhou, Miaomiao; Pan, Shenshen; Yang, Kai

    2015-01-01

    Transient postoperative symptoms, including pain, swelling, unnatural feelings during cervical movements, and incision adhesion formation are common in patients after open thyroidectomy, especially in those with bilateral lesions. Therefore, we proposed a new bilateral supraclavicular approach to reduce such complications, and compared it with the conventional transcervical approach to verify its safety and efficacy. Forty-four patients were recruited and randomized into either a conventional transcervical group (CT) or a bilateral supraclavicular (BS) group. Surgically-related variables, duration of postoperative symptoms, and incision adhesion formation status were recorded and evaluated. There were no statistically significance differences in sex, age, extent of surgery, pathological type, intraoperative blood loss, and operation duration between the two groups. The BS group had a slightly longer total incision length, but exhibited a significantly shorter period of postoperative symptoms (P=0.012) and lower risk for adhesion formation (P=0.035 in the 1st month, P=0.047 in the 10th month) compared to the CT group. In conclusion, the bilateral supraclavicular approach is a safe and effective method for reducing postoperative symptoms and adhesion formation in patients with bilateral thyroid lesions. PMID:26221276

  1. 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...

  2. White button and shiitake mushrooms reduce the incidence and severity of collagen-induced arthritis in dilute brown non-agouti mice.

    PubMed

    Chandra, Lawrance; Alexander, Heather; Traoré, Djibril; Lucas, Edralin A; Clarke, Stephen L; Smith, Brenda J; Lightfoot, Stanley A; Kuvibidila, Solo

    2011-01-01

    Exotic mushrooms have been used in ancient Chinese medicine due to their immunomodulatory properties for the treatment and/or prevention of chronic diseases. However, only limited data exist on the health benefits of white button mushrooms (WBM), the most common in the American diet. In the current study, we investigated the effects of WBM and shiitake mushrooms (SM) on collagen-induced arthritis (CIA) using a 2 x 3 factorial design in 8-wk-old female dilute brown non-agouti mice that were fed a control diet (n = 37) or the same diet supplemented with 5% lyophilized WBM or SM (n = 27) for 6 wk. CIA was induced by immunizing mice with 100 µg bovine collagen followed by 50 µg LPS on d 20 post-collagen injection. CIA was assessed by mononuclear cell infiltration, bone erosion, plasma IL-6, TNFα, and intercellular adhesion molecule-1 (sICAM-1) concentrations. Compared with the control diet, WBM and SM tended to reduce the CIA index from 5.11 ± 0.82 to 3.15 ± 0.95 (P = 0.06) (median, 6-9 to 1-2) 31 d post-collagen injection. Whereas 58% of control mice had a CIA index ≥ 7, only 23% of WBM and 29% of SM mice did (P = 0.1). Although both types of mushrooms reduced plasma TNFα (34%, WBM; 64%, SM), only SM increased plasma IL-6 by 1.3-fold (P < 0.05). The CIA index was positively correlated with sICAM1 (r = 0.55; P < 0.05) but negatively correlated with TNFα (r = 0.34; P < 0.05). Whether mushrooms are beneficial for arthritis management remains to be investigated. To our knowledge, this is the first report demonstrating a possible health benefit of WBM in arthritis treatment. PMID:21106932

  3. Dose-dependent effects of ethanol extract of Salvia haematodes Wall roots on reproductive function and copulatory behaviour in male rats.

    PubMed

    Bansode, F W; Rajendran, S M; Singh, R K

    2015-04-01

    This study was aimed to investigate the dose-dependent effects of Salvia haematodes Wall roots (SHW) extract on male reproductive function and copulatory behaviour in rats. Sexually mature males were assigned to four groups: control and treated (5, 50 and 300 mg kg(-1)  day(-1) for 30 days). At the end of treatment regimes, the reproductive activity viz. body/organ weights, testicular spermatogenesis, daily sperm production rate (DSP) and epididymal sperm counts, and sexual behaviour including mounting latency (ML), mounting frequency (MF), intromission latency (IL), intromission frequency (IF), ejaculation latency (EL), post-ejaculatory interval (PEI) and penile reflexes (PE) were assessed. Results showed significant increase in body weight (at 300 mg kg(-1) ), testis/epididymis weights (at 50 and 300 mg kg(-1) ), testicular spermatids, DSP, tubular diameter and epididymal sperm counts (at 50 and 300 mg kg(-1) doses) in treated compared with control rats. It also produced dose-dependant changes in sexual behaviour. The 5 mg kg(-1) dose of extract increased MF and PE, whereas 50 and 300 kg(-1) doses caused significant increase in MF, IF, PE, EL (but less than sildenafil citrate treatment), hit rate and seminal plug weight. It is concluded that SHW extract enhances anabolic activity, testicular function and sexual behavioural performance in a dose-dependant manner. PMID:24621398

  4. Anatomy of an incident

    DOE PAGESBeta

    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

  5. Comparable incidence and severity of cytomegalovirus infections following T cell-depleted allogeneic stem cell transplantation preceded by reduced intensity or myeloablative conditioning.

    PubMed

    Kalpoe, J S; van der Heiden, P L J; Vaessen, N; Claas, E C J; Barge, R M; Kroes, A C M

    2007-07-01

    Reports on infectious complications following reduced intensity conditioning (RIC) before allogeneic stem cell transplantation (allo-SCT) are equivocal. This prospective follow-up study compared the impact of cytomegalovirus (CMV) infections following RIC with fludarabine, ATG and busulphan or conventional myeloablative conditioning (MAC). Forty-eight RIC and 59 MAC patients were enrolled. The occurrence and severity of CMV infections within 100 days following allo-SCT were assessed, using plasma CMV DNA load kinetics. CMV DNAemia was observed in 21 RIC (60%) and in 19 MAC (44%) patients at risk for CMV. The mean CMV DNAemia free survival time was comparable following RIC and MAC: 70 days (95% (confidence interval) CI: 59-80 days) and 77 days (95% CI: 68-86 days), respectively (P=0.24). Parameters indicative for the level of CMV reactivation, including the area under the curve of CMV DNA load over time as well as the onset, the peak values and duration of CMV infection episodes, the numbers and duration of CMV treatment episodes and recurrent infections, were not different in both groups. During follow-up, none of the patients developed CMV disease. RIC with fludarabine, ATG and busulphan demonstrated safety comparable to conventional MAC with regard to frequency and severity of CMV infections within 100 days following T cell-depleted allo-SCT. PMID:17530007

  6. 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

  7. Dietary supplementation with high doses of regular vitamin D3 safely reduces diabetes incidence in NOD mice when given early and long term.

    PubMed

    Takiishi, Tatiana; Ding, Lei; Baeke, Femke; Spagnuolo, Isabella; Sebastiani, Guido; Laureys, Jos; Verstuyf, Annemieke; Carmeliet, Geert; Dotta, Francesco; Van Belle, Tom L; Gysemans, Conny A; Mathieu, Chantal

    2014-06-01

    High doses of the active form of vitamin D3, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], prevent diabetes in the NOD mouse but also elicit unwanted calcemic side effects. Because immune cells themselves can convert vitamin D3 into 1,25(OH)2D3 locally, we hypothesized that dietary vitamin D3 can also prevent disease. Thus, we evaluated whether dietary administration of high doses of regular vitamin D3 (800 IU/day) during different periods of life (pregnancy and lactation, early life [3-14 weeks of age], or lifelong [3-35 weeks of age]) safely prevents diabetes in NOD mice. We found that only lifelong treatment raised serum 25-hydroxyvitamin D3 from 173 nmol/L in controls to 290 nmol/L, without inducing signs of calcemic or bone toxicity, and significantly reduced diabetes development in both male and female NOD mice. This diabetes protection by vitamin D3 correlated with preserved pancreatic insulin content and improved insulitis scores. Moreover, vitamin D3 treatment decreased interferon-γ-positive CD8(+) T cells and increased CD4(+)(CD25(+))FoxP3(+) T cells in pancreatic draining lymph nodes. In conclusion, this study shows for the first time that high doses of regular dietary vitamin D3 can safely prevent diabetes in NOD mice when administered lifelong, although caution is warranted with regards to administering equivalently high doses in humans. PMID:24550187

  8. Incidence of sudden cardiac death associated with coronary artery occlusion in dogs with hypertension and left ventricular hypertrophy is reduced by chronic beta-adrenergic blockade.

    PubMed

    Dellsperger, K C; Martins, J B; Clothier, J L; Marcus, M L

    1990-09-01

    Because beta-adrenergic blockade has as one of its many effects altered electrophysiological abnormalities after dogs with left ventricular hypertrophy have been subjected to coronary occlusion, we tested the hypothesis that metoprolol (200-400 mg/day) would reduce mortality rates in dogs with one-kidney, one clip left ventricular hypertrophy while a similar reduction in arterial pressure with enalapril (20-40 mg/day) would not. Dogs with left ventricular hypertrophy were given metoprolol or enalapril for 5-7 days before a 3-hour coronary occlusion. Infarct size and risk area were measured with triphenyltetrazolium chloride stain and barium angiography, respectively. For control (n = 15), left ventricular hypertrophy (n = 17), left ventricular hypertrophy plus metoprolol (n = 12), and left ventricular hypertrophy plus enalapril (n = 15) groups, mean arterial pressure, ratio of infarct size to risk area, and dogs experiencing sudden death were 110 +/- 4, 142 +/- 4, 121 +/- 7, and 120 +/- 3 mm Hg; 44 +/- 5%, 65 +/- 5%, 44 +/- 7%, and 30 +/- 4%; and 27%, 65%, 17%, and 53%, respectively. Thus, the excessive increase in early mortality occurring when dogs with hypertension and left ventricular hypertrophy undergo coronary occlusion is interrupted with beta-blockade, possibly via electrophysiological effects rather than by changes in arterial pressure or infarct size. PMID:1975521

  9. Low Incidence of Miscarriage Induced by the Scent of Male Littermates of Original Mates: Male Kinship Reduces the Bruce Effect in Female Mice, Mus musculus

    PubMed Central

    Wang, Yuting; Liu, Dingzhen

    2013-01-01

    The scent of a novel male can elicit pregnancy block in recently mated female mice (Mus musculus), a phenomenon known as the Bruce effect. Despite abundant literature on the Bruce effect in rodents, it remains unclear whether males related to a female’s original mate can induce the Bruce effect in out-bred, communally living mice. We investigated this question using Kunming (KM) male mice of varying genetic relatedness. Recently mated females were subjected to three treatments: exposure to the urine of the mate, urine of the mate’s male littermate, and urine of a male unrelated to the mate. It was found that the urine of male littermates of the females’ mates did not elicit more pregnancy block than that of the females’ mates. However, the urine of novel males caused a higher rate of female miscarriage than that of the females’ mates. By using a habituation-dishabituation paradigm, we found that unmated females could discriminate the urine scents of two male littermates from those of a novel male unrelated to the littermates. To understand how females use urinary cues to discriminate between males with different genetic relationships, we used gas chromatography coupled with mass spectrometry (GC-MS) to examine the volatile composition of urine from males with varying relatedness. It was found that KM male littermates shared similar volatile compositions in their urine. Our results suggest that male kinship reduces the Bruce effect in female KM mice, and provide additional evidence for mate choice being partly mediated by the Bruce effect in KM mice. PMID:23874716

  10. Low incidence of miscarriage induced by the scent of male littermates of original mates: male kinship reduces the bruce effect in female mice, Mus musculus.

    PubMed

    Wang, Yuting; Liu, Dingzhen

    2013-01-01

    The scent of a novel male can elicit pregnancy block in recently mated female mice (Mus musculus), a phenomenon known as the Bruce effect. Despite abundant literature on the Bruce effect in rodents, it remains unclear whether males related to a female's original mate can induce the Bruce effect in out-bred, communally living mice. We investigated this question using Kunming (KM) male mice of varying genetic relatedness. Recently mated females were subjected to three treatments: exposure to the urine of the mate, urine of the mate's male littermate, and urine of a male unrelated to the mate. It was found that the urine of male littermates of the females' mates did not elicit more pregnancy block than that of the females' mates. However, the urine of novel males caused a higher rate of female miscarriage than that of the females' mates. By using a habituation-dishabituation paradigm, we found that unmated females could discriminate the urine scents of two male littermates from those of a novel male unrelated to the littermates. To understand how females use urinary cues to discriminate between males with different genetic relationships, we used gas chromatography coupled with mass spectrometry (GC-MS) to examine the volatile composition of urine from males with varying relatedness. It was found that KM male littermates shared similar volatile compositions in their urine. Our results suggest that male kinship reduces the Bruce effect in female KM mice, and provide additional evidence for mate choice being partly mediated by the Bruce effect in KM mice. PMID:23874716

  11. Dose-dependent attenuation of intravenous nalbuphine on epidural morphine-induced pruritus and analgesia after cesarean delivery.

    PubMed

    Chen, Mao-Kai; Chau, Siu-Wah; Shen, Ya-Chun; Sun, Yu-Ning; Tseng, Kuang-Yi; Long, Chen-Yu; Feng, Yu-Tung; Cheng, Kuang-I

    2014-05-01

    Epidural morphine in patient-controlled analgesia regimens controls postoperative pain well but easily induces pruritus and other epidural morphine-related side effects. With 90 pregnant American Society of Anesthesiologists physical status II females scheduled for elective cesarean delivery, the present study was designed to evaluate the efficacy and safety profile of patient-controlled antipruritus (PCP) use of intravenous nalbuphine-based regimens for attenuation of postoperative pruritus and related side effects in combination with epidural morphine patient-controlled analgesia with regard to the quality of postoperative pain management. Patients were randomly assigned to two nalbuphine groups (5 μg/kg/hour, Group N5 or 10 μg/kg/hour, Group N10) and bolus dose of 1.6 μg/kg for PCP or the control (normal saline) group. Comparable visual analog scale scores for rest pain at each measured time interval among the three groups demonstrated that adequate pain relief was offered; however, the cumulative dose of nalbuphine administered to the patients in Group N10 attenuated the analgesic effect of epidural morphine in moving pain at POh24 only. Fewer episodes and milder severity of pruritus were observed in patients in Groups N5 and N10 at all postoperative time intervals. Epidural morphine provided good postoperative pain relief but with incommodious side effects. In addition, intravenous nalbuphine not only attenuated the incidence of pruritus but also decreased total morphine consumption. In conclusion, intravenous administration of low-dose nalbuphine (5 μg/kg/hour) for PCP maintained analgesia produced by epidural morphine and offered low pruritus incidence. PMID:24751388

  12. Efficacy of prophylactic intravenous ondansetron on the prevention of hypotension during cesarean delivery: a dose-dependent study

    PubMed Central

    Wang, Meng; Zhuo, Lang; Wang, Qun; Shen, Ming-Kun; Yu, Yan-Yun; Yu, Jun-Jing; Wang, Zhi-Ping

    2014-01-01

    Objective: This study was to determine the optimal dosage of ondansetron for preventing maternal hypotension during cesarean delivery. Methods: One hundred and fifty parturient women scheduled for elective cesarean section were randomly assigned to five groups (n=30). Five minutes prior to spinal anesthesia, women were injected with 5 ml of physiological saline (S), 2 mg (O2), 4 mg (O4), 6 mg (O6), or 8 mg (O8) of ondansetron in saline, respectively. Maternal blood pressure and heart rate were measured at 2-min intervals for 30 min. The serum parameters in umbilical cord blood were analyzed after delivery. Results: Compared with group S, the incidence of maternal hypotension was significantly lower in groups O4 and O6 (P < 0.05). The umbilical venous pH was significantly higher in group O4 (P < 0.05); while the partial pressure of carbon dioxide (Pco2) was significantly lower in groups O4, O6, and O8 (P < 0.05); and the bicarbonate (Hco3 -) and base excess in extracellular fluid (BEecf) were significantly lower in groups O6 and O8 (P < 0.05). Moreover, minimal changes of systolic blood pressure, diastolic blood pressure, and mean arterial blood pressure were observed in group O4 (P < 0.05). Conclusion: The optimal dose of ondansetron preloading was 4 mg during cesarean delivery. PMID:25664023

  13. 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...

  14. Analysis of the ACTN3 heterozygous genotype suggests that α-actinin-3 controls sarcomeric composition and muscle function in a dose-dependent fashion.

    PubMed

    Hogarth, Marshall W; Garton, Fleur C; Houweling, Peter J; Tukiainen, Taru; Lek, Monkol; Macarthur, Daniel G; Seto, Jane T; Quinlan, Kate G R; Yang, Nan; Head, Stewart I; North, Kathryn N

    2016-03-01

    A common null polymorphism (R577X) in ACTN3 causes α-actinin-3 deficiency in ∼ 18% of the global population. There is no associated disease phenotype, but α-actinin-3 deficiency is detrimental to sprint and power performance in both elite athletes and the general population. However, despite considerable investigation to date, the functional consequences of heterozygosity for ACTN3 are unclear. A subset of studies have shown an intermediate phenotype in 577RX individuals, suggesting dose-dependency of α-actinin-3, while others have shown no difference between 577RR and RX genotypes. Here, we investigate the effects of α-actinin-3 expression level by comparing the muscle phenotypes of Actn3(+/-) (HET) mice to Actn3(+/+) [wild-type (WT)] and Actn3(-/-) [knockout (KO)] littermates. We show reduction in α-actinin-3 mRNA and protein in HET muscle compared with WT, which is associated with dose-dependent up-regulation of α-actinin-2, z-band alternatively spliced PDZ-motif and myotilin at the Z-line, and an incremental shift towards oxidative metabolism. While there is no difference in force generation, HET mice have an intermediate endurance capacity compared with WT and KO. The R577X polymorphism is associated with changes in ACTN3 expression consistent with an additive model in the human genotype-tissue expression cohort, but does not influence any other muscle transcripts, including ACTN2. Overall, ACTN3 influences sarcomeric composition in a dose-dependent fashion in mouse skeletal muscle, which translates directly to function. Variance in fibre type between biopsies likely masks this phenomenon in human skeletal muscle, but we suggest that an additive model is the most appropriate for use in testing ACTN3 genotype associations. PMID:26681802

  15. Orally administered betaine has an acute and dose-dependent effect on serum betaine and plasma homocysteine concentrations in healthy humans.

    PubMed

    Schwab, Ursula; Törrönen, Anneli; Meririnne, Esa; Saarinen, Markku; Alfthan, Georg; Aro, Antti; Uusitupa, Matti

    2006-01-01

    Betaine, i.e., trimethylglycine, is linked to homocysteine metabolism. A 3-mo daily betaine supplementation decreased even normal plasma total homocysteine (tHcy) concentrations in humans. The pharmacokinetic characteristics and metabolism of betaine in humans have not been investigated in detail. The aim of this study was to assess the pharmacokinetics of orally administered betaine and its acute effect on plasma tHcy concentrations. Healthy volunteers (n = 10; 3 men, 7 women) with normal body weight (mean +/- SD, 69.5 +/- 17.0 kg), 40.8 +/- 12.4 y old, participated in the study. The betaine doses were 1, 3, and 6 g. The doses were mixed with 150 mL of orange juice and ingested after a 12-h overnight fast by each volunteer according to a randomized double-blind crossover design. Blood samples were drawn for 24 h and a 24-h urine collection was performed. Orally administered betaine had an immediate and dose-dependent effect on serum betaine concentration. Single doses of 3 and 6 g lowered plasma tHcy concentrations (P = 0.019 and P < 0.001, respectively), unlike the 1-g dose. After the highest dose, the concentrations remained low during the 24 h of monitoring. The change in plasma tHcy concentration was linearly associated with betaine dose (P = 0.006) and serum betaine concentration (R2 = 0.17, P = 0.025). The absorption and elimination of betaine were dose dependent. The urinary excretion of betaine seemed to increase with an increasing betaine dose, although a very small proportion of ingested betaine was excreted via urine. In conclusion, a single dose of orally administered betaine had an acute and dose-dependent effect on serum betaine concentration and resulted in lowered plasma tHcy concentrations within 2 h in healthy subjects. PMID:16365055

  16. 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

  17. Parathyroid hormone linked to a collagen binding domain promotes hair growth in a mouse model of chemotherapy-induced alopecia in a dose-dependent manner.

    PubMed

    Katikaneni, Ranjitha; Ponnapakkam, Tulasi; Seymour, Andrew; Sakon, Joshua; Gensure, Robert

    2014-08-01

    Chemotherapy-induced alopecia is a major source of psychological stress in patients undergoing cancer chemotherapy, and it can influence treatment decisions. Although there is currently no therapy for alopecia, a fusion protein of parathyroid hormone and collagen binding domain (PTH-CBD) has shown promise in animal models. The aim of this study was to determine whether there are dose-dependent effects of PTH-CBD on chemotherapy-induced alopecia in a mouse model. 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); and treated on day 9 with vehicle or cyclophosphamide (150 mg/kg intraperitoneally). Mice were photographed every 3-4 days and killed on day 63 for histological analysis. Photographs were quantified by gray scale analysis to assess hair content. Mice not receiving chemotherapy showed regrowth of hair 2 weeks after 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. Histological analysis 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 gray 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 that in mice that did not receive chemotherapy. Single-dose subcutaneous administration of PTH-CBD showed dose-dependent effects in minimizing hair loss and speeding up recovery from chemotherapy-induced alopecia. PMID:24710191

  18. 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…

  19. Dose-dependent effects of the caspase inhibitor Q-VD-OPh on different apoptosis-related processes.

    PubMed

    Kuželová, Kateřina; Grebeňová, Dana; Brodská, Barbora

    2011-11-01

    The effects of the pan-caspase inhibitor Q-VD-OPh on caspase activity, DNA fragmentation, PARP cleavage, 7A6 exposition, and cellular adhesivity to fibronectin were analyzed in detail in three different apoptotic systems involving two cell lines (JURL-MK1 and HL60) and two apoptosis inducers (imatinib mesylate and suberoylanilide hydroxamic acid). Q-VD-OPh fully inhibited caspase-3 and -7 activity at 0.05  µM concentration as indicated both by the measurement of the rate of Ac-DEVD-AFC cleavage and anti-caspase immunoblots. Caspase-8 was also inhibited at low Q-VD-OPh concentrations. On the other hand, significantly higher Q-VD-OPh dose (10 µM) was required to fully prevent the cleavage of PARP-1. DNA fragmentation and disruption of the cell membrane functionality (Trypan blue exclusion test) were both prevented at 2 µM Q-VD-OPh while 10 µM inhibitor was needed to inhibit the drug-induced loss of cellular adhesivity to fibronectin which was observed in JURL-MK1 cells. The exposition of the mitochondrial antigen 7A6 occurred independently of Q-VD-OPh addition and may serve to the detection of cumulative incidence of the cells which have initiated the apoptosis. Our results show that Q-VD-OPh efficiency in the inhibition of caspase-3 activity and DNA fragmentation in the whole-cell environment is about two orders of magnitude higher than that of z-VAD-fmk. This difference is not due to a slow permeability of the latter through the cytoplasmic membrane. PMID:21751237

  20. Obliquely incident ion beam figuring

    NASA Astrophysics Data System (ADS)

    Zhou, Lin; Dai, Yifan; Xie, Xuhui; Li, Shengyi

    2015-10-01

    A new ion beam figuring (IBF) technique, obliquely incident IBF (OI-IBF), is proposed. In OI-IBF, the ion beam bombards the optical surface obliquely with an invariable incident angle instead of perpendicularly as in the normal IBF. Due to the higher removal rate in oblique incidence, the process time in OI-IBF can be significantly shortened. The removal rates at different incident angles were first tested, and then a test mirror was processed by OI-IBF. Comparison shows that in the OI-IBF technique with a 30 deg incident angle, the process time was reduced by 56.8%, while keeping the same figure correcting ability. The experimental results indicate that the OI-IBF technique is feasible and effective to improve the surface correction process efficiency.

  1. Dose-dependent protection by tomato against 7,12-dimethylbenz[a]anthracene-induced genotoxicity and oxidative stress in mice.

    PubMed

    Chandra Mohan, K V P; Bhuvaneswari, V; Abraham, S K; Nagini, S

    2003-01-01

    This study was designed to investigate the protective role of pretreatment with graded doses of freshly prepared tomato paste against 7,12-dimethylbenz[a]anthracene (DMBA)-induced genetic damage and oxidative stress in male Swiss mice. The incidence of bone marrow micronuclei and the extent of hepatic lipid peroxidation and the antioxidants glutathione, glutathione peroxidase, and glutathione S-transferase were monitored. Three different concentrations (0.5, 1, and 2 g/kg body weight) of tomato paste were tested for their anticlastogenic effects against DMBA (35 mg/kg body weight). Increased frequency of micronuclei and enhanced lipid peroxidation accompanied by compromised antioxidant defenses were observed in DMBA-treated animals. Pretreatment with all three doses of tomato paste significantly reduced the frequencies of DMBA-induced micronuclei and oxidative stress. These findings demonstrate that administration of tomato paste protects against the clastogenic effects of DMBA by decreasing lipid peroxidation and enhancing the antioxidant status. PMID:14585182

  2. 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.

  3. 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

  4. Dose-Dependent Effects of the Cimicifuga racemosa Extract Ze 450 in the Treatment of Climacteric Complaints: A Randomized, Placebo-Controlled Study.

    PubMed

    Schellenberg, Ruediger; Saller, Reinhard; Hess, Lorenzo; Melzer, Jörg; Zimmermann, Christian; Drewe, Juergen; Zahner, Catherine

    2012-01-01

    Extracts from Cimicifuga racemosa (CR, synonym Actaea racemosa) have shown efficacy in trials in women with menopausal symptoms. Yet, dose dependency remains unclear. Therefore, 180 female outpatients with climacteric complaints were treated for 12 weeks in a randomized, double-blind, placebo-controlled, 3-armed trial (CR extract Ze 450 in 6.5 mg or 13.0 mg, or placebo). Primary outcome was the difference in menopausal symptoms (vasomotor, psychological, and somatic), assessed by the Kupperman Menopausal Index between baseline and week 12. Secondary efficacy variables were patients' self-assessments of general quality of life (QoL), responder rates, and safety. Compared to placebo, patients receiving Ze 450 showed a significant reduction in the severity of menopausal symptoms in a dose-dependent manner from baseline to endpoint (mean absolute differences 17.0 (95% CI 14.65-19.35) score points, P < 0.0001 for 13.0 mg; mean absolute differences 8.47 (95% CI 5.55-11.39) score points, P = 0.0003 for 6.5 mg). QoL and responder rates corresponded with the main endpoint. Changes in menopausal symptoms and QoL were inversely correlated. Reported adverse events and clinical laboratory testing did not raise safety concerns. The CR extract Ze 450 is an effective and well-tolerated nonhormonal alternative to hormone treatment for symptom relief in menopausal women. PMID:23346194

  5. Dose-Dependent Effects of the Cimicifuga racemosa Extract Ze 450 in the Treatment of Climacteric Complaints: A Randomized, Placebo-Controlled Study

    PubMed Central

    Schellenberg, Ruediger; Saller, Reinhard; Hess, Lorenzo; Melzer, Jörg; Zimmermann, Christian; Drewe, Juergen; Zahner, Catherine

    2012-01-01

    Extracts from Cimicifuga racemosa (CR, synonym Actaea racemosa) have shown efficacy in trials in women with menopausal symptoms. Yet, dose dependency remains unclear. Therefore, 180 female outpatients with climacteric complaints were treated for 12 weeks in a randomized, double-blind, placebo-controlled, 3-armed trial (CR extract Ze 450 in 6.5 mg or 13.0 mg, or placebo). Primary outcome was the difference in menopausal symptoms (vasomotor, psychological, and somatic), assessed by the Kupperman Menopausal Index between baseline and week 12. Secondary efficacy variables were patients' self-assessments of general quality of life (QoL), responder rates, and safety. Compared to placebo, patients receiving Ze 450 showed a significant reduction in the severity of menopausal symptoms in a dose-dependent manner from baseline to endpoint (mean absolute differences 17.0 (95% CI 14.65–19.35) score points, P < 0.0001 for 13.0 mg; mean absolute differences 8.47 (95% CI 5.55–11.39) score points, P = 0.0003 for 6.5 mg). QoL and responder rates corresponded with the main endpoint. Changes in menopausal symptoms and QoL were inversely correlated. Reported adverse events and clinical laboratory testing did not raise safety concerns. The CR extract Ze 450 is an effective and well-tolerated nonhormonal alternative to hormone treatment for symptom relief in menopausal women. PMID:23346194

  6. DOSE-DEPENDENT EFFECTS OF THE ANTIPROGESTIN, RU486, ON SEXUAL BEHAVIOR OF NATURALLY-CYCLING FISCHER RATS

    PubMed Central

    Uphouse, Lynda

    2015-01-01

    Regularly cycling Fischer female rats were treated with either a low (5 mg/kg) or high (5 mg/RAT; approximately 30 mg/kg) dose of the antiprogestin, RU486, before the morning of proestrus or on the morning of proestrus. The emergence of sexual behavior after treatment with RU486 was examined in a mating test with a sexually active male rat. Lordosis behavior was remarkably resistant to the effects of RU486. Only the high dose of RU486 given the evening before proestrus, approximately 22 hours before mating, reduced lordosis behavior. Independent of dose or time of treatment, proceptivity was reduced and resistance to the male’s attempts to mount was increased by RU486 treatment. In addition, the effect of a 5 min restraint stress on sexual behavior was examined. In contrast to the relative resistance of lordosis behavior of unrestrained rats to RU486 treatment, RU486 treated rats showed a significant decline in lordosis behavior after restraint. These findings allow the suggestion that the emergence of lordosis behavior is relatively resistant to the antiprogestin while the maintenance of lordosis behavior after restraint may require participation of intracellular progesterone receptors. PMID:25591479

  7. Development of a computational high-throughput tool for the quantitative examination of dose-dependent histological features.

    PubMed

    Nault, Rance; Colbry, Dirk; Brandenberger, Christina; Harkema, Jack R; Zacharewski, Timothy R

    2015-04-01

    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

  8. 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

  9. 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

  10. Exercise Training in Transgenic Mice Is Associated with Attenuation of Early Breast Cancer Growth in a Dose-Dependent Manner

    PubMed Central

    Goh, Jorming; Tsai, Jesse; Bammler, Theo K.; Farin, Frederico M.; Endicott, Emma; Ladiges, Warren C.

    2013-01-01

    Epidemiological research suggests that regular physical activity confers beneficial effects that mediate an anti-tumor response and may reduce cancer recurrence. It is unclear what amount of physical activity is necessary to exert such a protective effect and what mechanisms are involved. We investigated the effects of voluntary wheel running on tumor progression and cytokine gene expression in the transgenic polyoma middle T oncoprotein (PyMT) mouse model of invasive breast cancer. Runners showed significantly reduced tumor sizes compared with non-runners after 3 weeks of running (p≤0.01), and the greater the running distance the smaller the tumor size (Pearson's r = −0.61, p≤0.04, R2 = 0.38). Mice running greater than 150 km per week had a significantly attenuated tumor size compared with non-runners (p≤0.05). Adipose tissue mass was inversely correlated with tumor size in runners (Pearson's r = −0.77, p = 0.014) but not non-runners. Gene expression of CCL22, a cytokine associated with recruitment of immunosuppressive T regulatory cells, was decreased in tumors of runners compared to non-runners (p≤0.005). No differences in tumor burden or metastatic burden were observed between runners and non-runners after ten weeks of running when the study was completed. We conclude that voluntary wheel running in PyMT mice correlates with an attenuation in tumor progression early during the course of invasive breast cancer. This effect is absent in the later stages of overwhelming tumor burden even though cytokine signaling for immunosuppressive regulatory T cells was down regulated. These observations suggest that the initiation of moderate exercise training for adjunctive therapeutic benefit early in the course of invasive breast cancer should be considered for further investigation. PMID:24312199

  11. Near anastigmatic grazing incidence telescope

    NASA Technical Reports Server (NTRS)

    Korsch, D.

    1984-01-01

    A performance capability assessment is presently conducted for short versus long grazing incidence telescope designs, in view of the observation that the field curvature and astigmatism that are the primary residual aberrations of a Wolter-type incidence telescope can be substantially reduced through mirror length reduction. A major advantage of the short element telescope is that, if sufficiently short, both the paraboloid and hyperboloid surfaces may be fabricated as a single piece; this significantly facilitates the task of alignment.

  12. 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

  13. Thermal dose dependent optical property changes of ex vivo chicken breast tissues between 500 and 1100 nm

    NASA Astrophysics Data System (ADS)

    Adams, Matthew T.; Wang, Qi; Cleveland, Robin O.; Roy, Ronald A.

    2014-07-01

    This study examines the effectiveness of the thermal dose model in accurately predicting thermally induced optical property changes of ex vivo chicken breast between 500-1100 nm. The absorption coefficient, μa, and the reduced scattering coefficient, \\mu _s^\\prime, of samples are measured as a function of thermal dose over the range 50 °C-70 °C. Additionally, the maximum observable changes in μa and \\mu _s^\\prime are measured as a function of temperature in the range 50 °C-90 °C. Results show that the standard thermal dose model used in the majority of high-intensity focused ultrasound (HIFU) treatments is insufficient for modeling optical property changes, but that the isodose constant may be modified in order to better predict thermally induced changes. Additionally, results are presented that show a temperature dependence on changes in the two coefficients, with an apparent threshold effect occurring between 65 °C-70 °C.

  14. 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

  15. 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

  16. Dose dependence of x-ray luminescence from CaF{sub 2}:Eu{sup 2+}, Mn{sup 2+} phosphors

    SciTech Connect

    Chen Wei; Westcott, Sarah L.; Zhang Jun

    2007-11-19

    In CaF{sub 2}:Mn{sup 2+}, Eu{sup 2+}, the emission from Eu{sup 2+} decreases while the emission from Mn{sup 2+} increases in intensity as the x-ray duration time increases. The decrease of Eu{sup 2+} emission is due to the oxidation of Eu{sup 2+} to Eu{sup 3+} upon x-ray irradiation, while the increase of Mn{sup 2+} emission in intensity is likely due to the breakdown of the forbidden transition by the defects. This phenomenon has potential for dose-dependent radiation detection because utilizing the ratio of the two emissions from Mn{sup 2+} and Eu{sup 2+} for radiation dosimetry is more sensitive and more reliable than using emission intensity change only.

  17. 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

  18. Reduced LAK cytotoxicity of peripheral blood mononuclear cells in patients with bladder cancer: Decreased LAK cytotoxicity caused by a low incidence of CD56+ and CD57+ mononuclear blood cells

    SciTech Connect

    Hermann, G.G.; Petersen, K.R.; Steven, K.; Zeuthen, J. )

    1990-11-01

    The cytotoxicity of unstimulated peripheral blood mononuclear cells (US-PBMC), phytohemagglutinin (PHA)-stimulated PBMC (PS-PBMC) and interleukin-2 (IL-2)-activated PBMC (LAK cells) was assessed in patients with noninvasive and invasive transitional-cell bladder cancer and compared with those determined in healthy controls. The differences in the cytotoxicities were correlated with specific changes in the subsets of peripheral blood mononuclear cells (PBMC). PBMC from 37 patients and 13 healthy controls were tested against the bladder cancer cell line T24 in {sup 51}Cr-release assays. The PBMC subsets were analyzed using monoclonal antibodies against T cells, natural killer (NK) -cells, monocytes, and activation markers. The cytotoxicities of US-PBMC, PS-PBMC, and LAK cells were all significantly lower in the cancer patients than in the controls (P less than 0.05). The percentages of PBMC positive for the NK-cell markers CD56 and CD57 were lowest in the patients and were correlated to the decrease in cytotoxicity. Depletion of CD56+ or CD57+ cells from PBMC prior to or after 2 days stimulation with IL-2 demonstrated that these cells are the major source of LAK-cell cytotoxicity and showed that the reduced ability of bladder cancer patient PBMC to develop LAK-cell cytotoxicity is a result of a low incidence of CD56+ and CD57+ cells in the blood. These findings indicate that IL-2 therapy alone might not be a sufficient therapy of bladder cancer patients.

  19. Dose-dependent regulation of steroid receptor coactivator-1 and steroid receptors by testosterone propionate in the hippocampus of adult male mice.

    PubMed

    Qiu, Linli; Zhao, Yangang; Guo, Qiang; Zhang, Yuanyuan; He, Li; Li, Wei; Zhang, Jiqiang

    2016-02-01

    Androgens have been proposed to play important roles in the regulation of hippocampus function either directly, through the androgen receptor (AR), or indirectly, through estrogen receptors (ERs), after aromatization into estradiol. Steroid receptor coactivator-1 (SRC-1) is present in the hippocampus of several species, and its expression is regulated by development and aging, as well as by orchidectomy and aromatase inhibitor letrozole administration, while ovariectomy only transiently downregulated hippocampal SRC-1. However, whether the expression of hippocampal SRC-1 can be directly regulated by testosterone, the principal male sex hormone, remains unclear. In the present study, we investigated the expression of hippocampal SRC-1 after orchidectomy and testosterone treatment using immunohistochemistry and Western blot analysis. We found that while hippocampal SRC-1 was significantly downregulated by orchidectomy (ORX), its expression was rescued by treatment with testosterone in a dose-dependent manner. Furthermore, we noticed that the decreased expression of hippocampal AR, ERs and the synaptic proteins GluR-1 and PSD-95 induced by ORX was also rescued by testosterone treatment in a dose-dependent manner. However, we found that hippocampal membrane estrogen receptor GPR30 and dendritic spine marker spinophilin were not altered by ORX or testosterone treatment. Together, the above results provided the first direct evidence for the androgenic regulation on hippocampal SRC-1, indicating that SRC-1 may be a direct target of androgenic regulation on the hippocampus. Furthermore, because AR and ERs can be differentially regulated by testosterone, and the transcriptional activity requires the involvement of local SRC-1, and considering the complicated regulatory pathway of each individual receptor, the converged hub regulator SRC-1 of these nuclear receptor networks is worthy of further investigation. PMID:26607693

  20. 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

  1. Dose-dependent, saturable occupancy of the metabotropic glutamate subtype 5 receptor by fenobam as measured with [(11) C]ABP688 PET imaging.

    PubMed

    Mathews, William B; Kuwabara, Hiroto; Stansfield, Kirstie; Valentine, Heather; Alexander, Mohab; Kumar, Anil; Hilton, John; Dannals, Robert F; Wong, Dean F; Gasparini, Fabrizio

    2014-08-01

    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 X syndrome. This study examined whether [(11) C]ABP688, an antagonist PET radioligand, competes with fenobam for the same binding site in the nonhuman 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 [(11) C]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 [(11) C]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. Synapse, 2014. © 2014 Wiley Periodicals, Inc. PMID:25098663

  2. 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

  3. 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.

  4. 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.

  5. 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

  6. Opacity incident reduction corrective action

    SciTech Connect

    Levyash, I.G.; Benegal, S.D.; Claase, B.J.M.

    1998-07-01

    This paper illustrates some of the methods used to reduce the number of package boiler opacity incidents at the Consolidated Edison Company of New York, Inc. East River Generating Station. The principal objective was to reduce opacity exceedances caused by the design of boiler auxiliaries. Opacity causes were identified and grouped. A matrix was developed to keep track of repairs and corrections on all package boilers. A special maintenance program was developed to sustain opacity reduction.

  7. rAAV2/7 vector-mediated overexpression of alpha-synuclein in mouse substantia nigra induces protein aggregation and progressive dose-dependent neurodegeneration

    PubMed Central

    2013-01-01

    Background Alpha-synuclein is a key protein implicated in the pathogenesis of Parkinson's disease (PD). It is the main component of the Lewy bodies, a cardinal neuropathological feature in the disease. In addition, whole locus multiplications and point mutations in the gene coding for alpha-synuclein lead to autosomal dominant monogenic PD. Over the past decade, research on PD has impelled the development of new animal models based on alpha-synuclein. In this context, transgenic mouse lines have failed to reproduce several hallmarks of PD, especially the strong and progressive dopaminergic neurodegeneration over time that occurs in the patients. In contrast, viral vector-based models in rats and non-human primates display prominent, although highly variable, nigral dopaminergic neuron loss. However, the few studies available on viral vector-mediated overexpression of alpha-synuclein in mice report a weak neurodegenerative process and no clear Lewy body-like pathology. To address this issue, we performed a comprehensive comparative study of alpha-synuclein overexpression by means of recombinant adeno-associated viral vectors serotype 2/7 (rAAV2/7) at different doses in adult mouse substantia nigra. Results We noted a significant and dose-dependent alpha-synucleinopathy over time upon nigral viral vector-mediated alpha-synuclein overexpression. We obtained a strong, progressive and dose-dependent loss of dopaminergic neurons in the substantia nigra, reaching a maximum of 82% after 8 weeks. This effect correlated with a reduction in tyrosine hydroxylase immunoreactivity in the striatum. Moreover, behavioural analysis revealed significant motor impairments from 12 weeks after injection on. In addition, we detected the presence of alpha-synuclein-positive aggregates in the remaining surviving neurons. When comparing wild-type to mutant A53T alpha-synuclein at the same vector dose, both induced a similar degree of cell death. These data were supported by a biochemical

  8. 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. PMID:24612212

  9. 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.

  10. Adverse incident reporting in intensive care.

    PubMed

    Hart, G K; Baldwin, I; Gutteridge, G; Ford, J

    1994-10-01

    This prospective, observational, anonymous incident reporting study aimed to identify and correct factors leading to reduced patient safety in intensive care. An incident was any event which caused or had the potential to cause harm to the patient, but included problems in policy or procedure. Reports were discussed at monthly meetings. Of 390 incidents, 106 occasioned "actual" harm and 284 "potential" harm. There was one death, 86 severe complications and 88 complications of minor severity. Most were transient but the effects of 24 lasted up to a week. Most incidents affected cardiovascular and respiratory systems. Incident categories involved drugs, equipment, management or procedures. Incident causes were knowledge-based, rule-based, technical, slip/lapse, no error or unclassifiable. The study has identified some human and equipment performance problems in our intensive care unit. Correction of these should lead to a reduction in the future incidence of those events and hence an increased level of patient safety. PMID:7818059

  11. Dose-dependent stimulatory and inhibitory effects of luminal and serosal n-butyric acid on epithelial cell proliferation of pig distal colonic mucosa.

    PubMed

    Inagaki, Akiko; Sakata, Takashi

    2005-06-01

    Large bowel bacteria convert various carbohydrates into short-chain fatty acids (SCFA). SCFA stimulate epithelial cell proliferation of the large intestine in vivo and inhibit that of various cells in vitro. Supposing that too high concentration of SCFA on the serosal side is responsible for their inhibitory effect in vitro, we studied effects of luminal and serosal n-butyric acid (0, 0.1, 1, or 10 mmol/L, adjusted to neutral pH) on the epithelial cell proliferation rate of pig colonic mucosa in organ culture taking crypt cell production rate (CCPR) as the measure of proliferative activity. With 0 or 0.1 mmol/L n-butyric acid on the serosal side, luminal n-butyric acid increased CCPR at 1.0 mmol/L, and decreased CCPR at 10 mmol/L when compared to the luminal 0 mmol/L control. With 1.0 or 10 mmol/L serosal n-butyric acid, luminal n-butyric acid depressed CCPR dose-dependently. The above results indicated that n-butyric acid stimulated colonic epithelial cell proliferation at low concentration and inhibit it at high concentration with interaction effect to enhance the inhibitory action. The stimulatory effect of a low dose of serosal n-butyric acid may be responsible for the distant trophic effect of SCFA. PMID:16161765

  12. Dose-dependent inhibition of BACE-1 by the monoterpenoid 2,3,4,4-tetramethyl-5-methylenecyclopent-2-enone in cellular and mouse models of Alzheimer's disease.

    PubMed

    Videira, Rita; Castanheira, Pedro; Grãos, Mário; Resende, Rosa; Salgueiro, Lígia; Faro, Carlos; Cavaleiro, Carlos

    2014-06-27

    BACE-1 is an aspartic protease involved in the conversion of amyloid precursor protein (APP) to amyloid-β (Aβ) in vivo, which is one of the key steps in the development and progression of Alzheimer's disease. In a previous screening procedure for inhibitors of BACE-1 activity, the oil of Lavandula luisieri was identified as the most potent among several essential oils. The inhibitory effect of this essential oil on Aβ production was also demonstrated in a cellular assay. The composition of the volatile oil and the isolation of the compound responsible for the inhibitory activity were also reported. The present work focused on the characterization of the inhibition of BACE-1 by this active compound, a monoterpene necrodane ketone, 2,3,4,4-tetramethyl-5-methylenecyclopent-2-enone (1), with assessment of its Ki value and the type of inhibition. The dose-related effects of the compound were also evaluated using two different cell lines, with determinations of the respective EC50 values. The entire oil and the 2,3,4,4-tetramethyl-5-methylenecyclopent-2-enone (1) were tested on a triple transgenic mouse model of Alzheimer's disease. The overall results showed that compound 1 displayed a dose-dependent inhibition of BACE-1 in cellular and mouse models of Alzheimer's disease and is therefore capable of passing through cellular membranes and the blood-brain barrier. PMID:24921156

  13. Dexmedetomidine Dose-Dependently Attenuates Ropivacaine-Induced Seizures and Negative Emotions Via Inhibiting Phosphorylation of Amygdala Extracellular Signal-Regulated Kinase in Mice.

    PubMed

    Zhai, Ming-Zhu; Wu, Huang-Hui; Yin, Jun-Bin; Cui, Yuan-Yuan; Mei, Xiao-Peng; Zhang, Han; Zhu, Xia; Shen, Xue-Feng; Kaye, Alan David; Chen, Guo-Zhong

    2016-05-01

    Ropivacaine (Ropi), one of the newest and safest amino amide local anesthetics, is linked to toxicity, including the potential for seizures, changes in behavior, and even cardiovascular collapse. Dexmedetomidine (Dex), an α2-adrenergic receptor agonist, has been widely used in anesthesia and critical care practice. To date, the underlying mechanisms of the effects of Dex premedication on Ropi-induced toxicity have not been clearly identified. In the current study, we investigated the effects of increasing doses of Dex premedication on 50 % convulsive dose (CD50) of Ropi. With increasing doses of intraperitoneal (i.p.) Dex 10 min prior to each i.p. RopiCD50, the latency and duration of seizure activity were recorded. Open-field (OF) and elevated plus maze (EPM) test were used to measure negative behavioral emotions such as depression and anxiety. Immunohistochemistry and Western blot were utilized to investigate phosphorylation-extracellular regulated protein kinases (p-ERK) expression in the basolateral amygdala (BLA) on 2 h and in the central amygdala (CeA) on 24 h after convulsion in mice. The results of our investigation demonstrated that Dex dose-dependently increased RopiCD50, prolonged the latency and shortened the duration of each RopiCD50-induced seizure, improved the negative emotions revealed by both OF and EPM test, and inhibited p-ERK expression in the BLA and the CeA. PMID:26099305

  14. Dose dependence and temporal evolution of the T1 relaxation time and MRI contrast in the rat brain after subcutaneous injection of manganese chloride.

    PubMed

    Shazeeb, Mohammed Salman; Sotak, Christopher H

    2012-12-01

    Divalent manganese ion (Mn(2+)) is a widely used T(1) contrast agent in manganese-enhanced MRI studies to visualize functional neural tracts and anatomy in the brain in vivo. In animal studies, Mn(2+) is administered at a dose that will maximize the contrast, while minimizing its toxic effects. In rodents, systemic administration of Mn(2+) via intravenous injection has been shown to create unique MRI contrast in the brain at a maximum dose of 175 mg kg(-1). However, intravenous administration of Mn(2+) results in faster bioelimination of excess Mn(2+) from the plasma due to a steep concentration gradient between plasma and bile. By contrast, following subcutaneous injection (LD(50) value = 320 mg kg(-1)), Mn(2+) is released slowly into the bloodstream, thus avoiding immediate hepatic elimination resulting in prolonged accumulation of Mn(2+) in the brain via the choroid plexus than that obtained via intravenous administration. The goal of this study was to investigate MRI dose response of Mn(2+) in rat brain following subcutaneous administration of Mn(2+). Dose dependence and temporal dynamics of Mn(2+) after subcutaneous injection can prove useful for longitudinal in vivo studies that require brain enhancement to persist for a long period of time to visualize neuroarchitecture like in neurodegenerative disease studies. PMID:22294279

  15. Dose-dependent response of nitrogen stable isotope ratio to proportion of legumes in diet to authenticate lamb meat produced from legume-rich diets.

    PubMed

    Devincenzi, T; Delfosse, O; Andueza, D; Nabinger, C; Prache, S

    2014-01-01

    This study investigated the dose-dependent response in lamb meat of stable nitrogen isotope ratio to the dietary proportion of legumes, and the ability of the nitrogen isotope signature of the meat to authenticate meat produced from legume-rich diets. Four groups of nine male Romane lambs grazing a cocksfoot pasture were supplemented with different levels of fresh alfalfa forage to obtain four dietary proportions of alfalfa (0%, 25%, 50% and 75%) for 98 days on average before slaughter (groups L0, L25, L50 and L75). We measured the stable nitrogen isotope ratio in the forages and in the longissimus thoracis muscle. The δ(15)N value of the meat decreased linearly with the dietary proportion of alfalfa. The distribution of the δ(15)N values of the meat discriminated all the L0 lambs from the L75 lambs, and gave a correct classification score of 85.3% comparing lambs that ate alfalfa with those that did not. PMID:24444961

  16. 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.

  17. 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. PMID:25445295

  18. 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

  19. 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

  20. 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

  1. 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

  2. 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

  3. 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

  4. Reduce HIV Risk

    MedlinePlus

    ... incidence could be reduced if people changed their sexual behaviors. Our research has demonstrated remarkable success in reducing HIV risk-associated sexual behaviors among African American adolescents and adults." Spring 2008 ...

  5. 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.

  6. 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. PMID:22813713

  7. 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

  8. 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

  9. 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

  10. 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

    2015-04-01

    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

  11. Dose-dependent neuroprotective effect of ciliary neurotrophic factor delivered via tetracycline-regulated lentiviral vectors in the quinolinic acid rat model of Huntington's disease.

    PubMed

    Régulier, E; Pereira de Almeida, L; Sommer, B; Aebischer, P; Déglon, N

    2002-11-01

    The ability to regulate gene expression constitutes a prerequisite for the development of gene therapy strategies aimed at the treatment of neurologic disorders. In the present work, we used tetracycline (Tet)-regulated lentiviral vectors to investigate the dose-dependent neuroprotective effect of human ciliary neurotrophic factor (CNTF) in the quinolinic acid (QA) model of Huntington's disease (HD). The Tet system was split in two lentiviruses, the first one containing the CNTF or green fluorescent protein (GFP) cDNAs under the control of the Tet-response element (TRE) and a second vector encoding the transactivator (tTA). Preliminary coinfection study demonstrated that 63.8% +/- 2.0% of infected cells contain at least two viral copies. Adult rats were then injected with CNTF- and GFP-expressing viral vectors followed 3 weeks later by an intrastriatal administration of QA. A significant reduction of apomorphine-induced rotations was observed in the CNTF-on group. In contrast, GFP-treated animals or CNTF-off rats displayed an ipsilateral turning behavior in response to apomorphine. A selective sparing of DARPP-32-, choline acetyltransferase (ChAT)-, and NADPH-d-positive neurons was observed in the striatum of CNTF-on rats compared to GFP animals and CNTF-off group. Enzyme-linked immunosorbent assay (ELISA) performed on striatal samples of rats sacrificed at the same time point indicated that this neuroprotective effect was associated with the production of 15.5 +/- 4.7 ng CNTF per milligram of protein whereas the residual CNTF expression in the off state (0.54 +/- 0.02 ng/mg of protein) was not sufficient to protect against QA toxicity. These results establish the proof of principle of neurotrophic factor dosing for neurodegenerative diseases and demonstrate the feasibility of lentiviral-mediated tetracycline-regulated gene transfer in the brain. PMID:12427308

  12. 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

  13. Dose-Dependent Effects of a Soluble Dietary Fibre (Pectin) on Food Intake, Adiposity, Gut Hypertrophy and Gut Satiety Hormone Secretion in Rats

    PubMed Central

    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

  14. Dose-dependent pharmacokinetics and efficacy of MK-401 against old, and young-mature infections of Fasciola hepatica in the rat.

    PubMed

    Schulman, M D; Valentino, D; Cifelli, S; Ostlind, D A

    1982-08-01

    The dose-dependent pharmacokinetics and the efficacy of MK-401 (4-amino-6-trichloroethenyl-1,3-benzenedisulfonamide) against old and young-mature infections of Fasciola hepatica were studied in experimentally infected rats. Fractionation of the host's blood after administration of 14C-MK-401 (0.77-15.8 mg/kg) showed that MK-401 was bound predominately to erythrocytes at doses below 4 mg/kg and at higher doses was distributed equally between the red cells and the plasma. Maximum amounts of MK-401 in the blood occurred 2 to 4 hr postadministration and were a hyperbolic function of dose, increasing almost linearly with dose up to 6 mg/kg and then beginning to saturate. Drug uptake by F. hepatica occurred at all doses and increased in direct proportion to the blood level. A single oral dose of MK-401 at 5 mg/kg was found to be highly effective (89%) against older infections (39-44 wk) but was virtually ineffective (1.5%) against younger flukes (9-16 wk). After administration of 14C-MK-401 at 5 mg/kg, drug concentrations in the blood and flukes of rats harboring older infections were significantly higher than those in the blood and flukes of rats with younger infections. Virtually identical differences in the blood level of MK-401 were observed in young and in old, noninfected rats after administration of 14C-MK-401 at 5 mg/kg. The increased efficacy of MK-401 against older infections of F. hepatica in the rat may be related to the age of the host rather than the parasite. PMID:7119988

  15. Spliced stromal cell-derived factor-1α analog stimulates endothelial progenitor cell migration and improves cardiac function in a dose-dependent manner after myocardial infarction

    PubMed Central

    Hiesinger, William; Frederick, John R.; Atluri, Pavan; McCormick, Ryan C.; Marotta, Nicole; Muenzer, Jeffrey R.; Woo, Y. Joseph

    2011-01-01

    Objectives Stromal cell-derived factor (SDF)-1α is a potent endogenous endothelial progenitor cell (EPC) chemokine and key angiogenic precursor. Recombinant SDF-1α has been demonstrated to improve neovasculogenesis and cardiac function after myocardial infarction (MI) but SDF-1α is a bulky protein with a short half-life. Small peptide analogs might provide translational advantages, including ease of synthesis, low manufacturing costs, and the potential to control delivery within tissues using engineered biomaterials. We hypothesized that a minimized peptide analog of SDF-1α, designed by splicing the N-terminus (activation and binding) and C-terminus (extracellular stabilization) with a truncated amino acid linker, would induce EPC migration and preserve ventricular function after MI. Methods EPC migration was first determined in vitro using a Boyden chamber assay. For in vivo analysis, male rats (n=48) underwent left anterior descending coronary artery ligation. At infarction, the rats were randomized into 4 groups and received peri-infarct intramyocardial injections of saline, 3 μg/kg of SDF-1α, 3 μg/kg of spliced SDF analog, or 6 μg/kg spliced SDF analog. After 4 weeks, the rats underwent closed chest pressure volume conductance catheter analysis. Results EPCs showed significantly increased migration when placed in both a recombinant SDF-1α and spliced SDF analog gradient. The rats treated with spliced SDF analog at MI demonstrated a significant dose-dependent improvement in end-diastolic pressure, stroke volume, ejection fraction, cardiac output, and stroke work compared with the control rats. Conclusions A spliced peptide analog of SDF-1α containing both the N- and C- termini of the native protein induced EPC migration, improved ventricular function after acute MI, and provided translational advantages compared with recombinant human SDF-1α. PMID:20951261

  16. Analysis program based on finite element method, MULTI(FEM), for evaluation of dose-dependent local disposition of drug in liver.

    PubMed

    Fukumura, K; Yamaoka, K; Higashimori, M; Nakagawa, T

    1999-05-01

    A curve-fitting program based on the Finite Element Method, MULTI(FEM), was developed to model nonlinear local disposition of a drug in the liver under non-steady-state conditions. The program was written in FORTRAN on an IBM-compatible personal computer. The validity of MULTI(FEM) was confirmed by analyzing the outflow kinetics of oxacillin (a model drug) following a pulse input to isolated, perfused rat livers, according to both linear and nonlinear dispersion models. Four dose levels (300, 1000, 3000, and 5000 microg) of oxacillin were administered to observe the dose-dependency in the hepatic local disposition. First, the individual outflow time-profiles at the same dose were averaged, and the average time-profile was analyzed by MULTI(FEM) based on linear dispersion models to yield a single curve fit. The fitted parameters at each dose level were compared with parameters estimated using MULTI(FILT), a program based on fast inverse Laplace transform, to analyze linear pharmacokinetics. The estimated parameters by MULTI(FEM) were in good agreement with those by MULTI(FILT). The apparent elimination rate constant (ke) decreased with an increase in dose, whereas other parameters showed no discernible dependency on an increase of dose. Second, the average outflow time-profiles at the four dose levels were simultaneously analyzed by MULTI(FEM) based on dispersion models featuring Michaelis-Menten elimination. The outflow time-profiles of oxacillin were well approximated by a two-compartment dispersion model with central Michaelis-Menten elimination. The maximum elimination rate constant (Vmax) and the Michaelis constant (Km) were estimated to be 1520 microg/mL/min and 41.3 microg/mL, respectively. Thus, the capability of MULTI(FEM) was demonstrated in evaluating capacity-limited local disposition in the liver. PMID:10229646

  17. Dose-dependent influence of short-term intermittent ethanol intoxication on cerebral neurochemical changes in rats detected by ex vivo proton nuclear magnetic resonance spectroscopy.

    PubMed

    Lee, Do-Wan; Nam, Yoon-Ki; Kim, Tai-Kyung; Kim, Jae-Hwa; Kim, Sang-Young; Min, Jung-Whan; Lee, Jung-Hoon; Kim, Hwi-Yool; Kim, Dai-Jin; Choe, Bo-Young

    2014-03-14

    The aim of this study was to quantitatively assess the effects of short-term intermittent ethanol intoxication on cerebral metabolite changes among sham controls (CNTL), low-dose ethanol (LDE)-exposed, and high-dose ethanol (HDE)-exposed rats, which were determined with ex vivo high-resolution spectra. Eight-week-old male Wistar rats were divided into three groups. Twenty rats in the LDE (n=10) and the HDE (n=10) groups received ethanol doses of 1.5 and 2.5 g/kg, respectively, through oral gavage every 8h for 4days. At the end of the 4-day intermittent ethanol exposure, one-dimensional ex vivo 500-MHz ¹H nuclear magnetic resonance spectra were acquired from 30 samples of the frontal cortex region (from the three groups). Normalized total N-acetylaspartate (tNAA: NAA+NAAG [N-acetylaspartyl-glutamate]), GABA, and glutathione (GSH) levels were significantly lower in the frontal cortex of the HDE-exposed rats than that of the LDE-exposed rats. Moreover, compared to the CNTL group, the LDE rats exhibited significantly higher normalized GABA levels. The six pairs of normalized metabolite levels were positively (+) or negatively (-) correlated in the rat frontal cortex as follows: tNAA and GABA (+), tNAA and aspartate (Asp) (+), myo-Inositol (mIns) and Asp (-), mIns and alanine (+), mIns and taurine (+), and mIns and tNAA (-). Our results suggested that short-term intermittent ethanol intoxication might result in neuronal degeneration and dysfunction, changes in the rate of GABA synthesis, and oxidative stress in the rat frontal cortex. Our ex vivo(1)H high-resolution magic angle spinning nuclear magnetic resonance spectroscopy results suggested some novel metabolic markers for the dose-dependent influence of short-term intermittent ethanol intoxication in the frontal cortex. PMID:24406441

  18. Long-term low-level laser therapy promotes an increase in maximal oxygen uptake and exercise performance in a dose-dependent manner in Wistar rats.

    PubMed

    Perini, Júlia Luiza; Hentschke, Vítor Scotta; Sonza, Anelise; Dal Lago, Pedro

    2016-02-01

    The use of low-level laser therapy (LLLT) represents a new intervention modality that has been explored to enhance exercise performance. The aim of this study was to evaluate the influence of LLLT (GaAIAs-850 nm) at different doses on VO2max and on exercise performance in rats. Male Wistar rats were divided into three groups: "placebo" rats (P-LLLT, n = 10), rats at a dose of 0.315 J per treatment point of LLLT (8.7 J/cm(2)-LLLT, n = 10), and rats at a dose of 2.205 J per treatment point of LLLT (61.2 J/cm(2)-LLLT, n = 10). The LLLT was applied bilaterally at the biceps femoris, gluteus, lateral and medial gastrocnemius, iliopsoas, and adductor longus muscles. One spot in each muscle belly was applied, with a sum of 12 spots in each rat, once a day, for 10 days. All animals performed the maximal exercise test (ET) at a metabolic treadmill for rats, with simultaneous gas analysis. The distance covered was measured during ET, before and after the conclusion of the LLLT protocol. The data were compared by a repeated measures two-way ANOVA followed by the Student-Newman-Keuls post hoc tests (p < .05). The 61.2 J/cm(2)-LLLT group increased VO2basal (~40 %), VO2max (~24 %), VCO2max (~17 %), and distance covered (~34 %) after LLLT application on the skeletal muscle. No significant results were found comparing before and after conditions for the studied variables considering P-LLLT and 8.7 J/cm(2)-LLLT groups. The LLLT promoted in a dose-dependent manner an increase in oxygen consumption uptake and a performance increment of male Wistar rats. PMID:26714977

  19. Dose-dependent variations in blood flow evaluation of canine nerve, nerve graft, tendon, and ligament tissue by the radiolabeled-microsphere technique

    SciTech Connect

    Riggi, K.; Wood, M.B.; Ilstrup, D.M. )

    1990-11-01

    This study evaluates the dose-dependent accuracy of the radionuclide-labeled microsphere technique for blood flow evaluation in nerve, tendon, and ligament. In eight dogs, blood flows were determined for nerve, nerve graft, tendon, and ligament tissue by simultaneous injection of high- and low-dose microspheres with different radiolabels. The results demonstrated no significant differences in blood flow as measured from the small number of microspheres (less than 400) and the high number (more than 400) for nerve and tendon tissue. For nerve tissue, microsphere counts of 50 to 100, 100 to 200, 200 to 300, and more than 300 produced mean percentage errors of 12.74% (n = 5, SEM = 4.52), 5.45% (n = 13, SEM = 1.22), 10.22% (n = 6, SEM = 4.37), and 17.08% (n = 12, SEM = 3.30), respectively. For tendon tissue, the same microsphere subdivisions had mean percentage errors of 7.47% (n = 4, SEM = 2.66), 3.63% (n = 6, SEM = 1.34), 15.54% (n = 4, SEM = 4.43), and 12.91% (n = 1), respectively. For ligament tissue, percentage errors were consistently higher; microsphere counts of 30 to 100, 100 to 200, and 200 to 300 produced mean errors of 20.14% (n = 4, SEM = 6.38), 18.66% (n = 4, SEM = 6.24), and 25.78% (n = 2, SEM = 1.97), respectively. Although there was no direct relationship between percentage error and number of microspheres retrieved, we suggest that microsphere counts in the range of 100 to 200 should be considered acceptable for nerve and tendon in the canine. Ligament tissue seems to be less well suited to the microsphere technique; however, further study is warranted.

  20. 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

  1. 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...

  2. Incidence of Chromosome Disorders

    PubMed Central

    Valentine, G. H.

    1979-01-01

    A minority of conceptions result in live births. Of recognized conceptions, 15% result in spontaneous abortions, up to 60% of which are due to chromosome abnormalities. The incidence of the different disorders is given. Of live births, one in 200 suffers a chromosome abnormality. The common abnormalities are described with their incidence. The effect of maternal age on this incidence is pronounced, but even so must be kept in proportion for counselling purposes.

  3. 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).

  4. 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. PMID:24291194

  5. Cylindrical cloaking at oblique incidence with optimized finite multilayer parameters.

    PubMed

    Zhang, Baile; Wu, Bae-Ian

    2010-08-15

    We propose multilayer cylindrical invisibility cloaks that are optimized for oblique incidences through a combination of analytic formalism of scattering and genetic optimization. We show that by using only four layers of homogeneous and anisotropic metamaterials without large values of constitutive parameters, the scattering for oblique incidences can be reduced by 2 orders. Although the optimization is done at a single incident angle, the cloak provides reduced scattering over a large range of incident angles. PMID:20717422

  6. Electrical characteristics of Mo/4H-SiC Schottky diodes having ion-implanted guard rings: temperature and implant-dose dependence

    NASA Astrophysics Data System (ADS)

    Latreche, A.; Ouennoughi, Z.; Sellai, A.; Weiss, R.; Ryssel, H.

    2011-08-01

    The electrical characteristics of ion-implanted guard rings for molybdenum (Mo) Schottky diodes on 4H-SiC are analyzed on the basis of the standard thermionic emission model and the assumption of a Gaussian distribution of the barrier height. For edge termination, high-resistivity guard rings manufactured by carbon and aluminum ion-implanted areas were used. Extractions of barrier heights of molybdenum on silicon carbide (4H-SiC) Schottky diodes have been performed on structures with various gate metallization, using both current-voltage-temperature (I-V-T) and capacitance-voltage (C-V) measurements. Characteristic features of the Schottky barrier height (SBH) are considered in relation to the specific dose of the carbon- or aluminum-implanted guard ring. Contacts showed excellent Schottky behavior ideality factors between 1.02 and 1.24 in the range of 303-473 K. The measured SBHs were between 0.92 and 1.17 eV in the same temperature range from I-V-T characteristics. The variations in the barrier height, which is significantly temperature- and implantation-dose-dependent, are well fitted to a single Gaussian distribution function. Experimental results agree reasonably well by using this approach, particularly for carbon implantation dose of 1.75 × 1014 cm-2, and a mean barrier height (\\bar \\Phi _{B0} ) of 1.22 eV and zero bias standard deviation σ0 = 0.067 V have been obtained. Furthermore, the modified Richardson plot according to the Gaussian distribution model resulted in a mean barrier height (\\bar \\Phi _{B0} ) and a Richardson constant (A*) of 1.22 eV and 148 A cm-2 K-2, respectively. The A* value obtained from this plot is in very close agreement with the theoretical value of 146 A cm-2 K-2 for n-type 4H-SiC. Therefore, it has been concluded that the temperature dependence of the forward (I-V) characteristics of the Mo/4H-SiC contacts can be successfully explained on the basis of a thermionic emission conduction mechanism with Guassianly distributed

  7. Dose-dependent effects of morphine exposure on mRNA and microRNA (miR) expression in hippocampus of stressed neonatal mice.

    PubMed

    McAdams, Ryan M; McPherson, Ronald J; Beyer, Richard P; Bammler, Theo K; Farin, Frederico M; Juul, Sandra E

    2015-01-01

    Morphine is used to sedate critically ill infants to treat painful or stressful conditions associated with intensive care. Whether neonatal morphine exposure affects microRNA (miR) expression and thereby alters mRNA regulation is unknown. We tested the hypothesis that repeated morphine treatment in stress-exposed neonatal mice alters hippocampal mRNA and miR expression. C57BL/6 male mice were treated from postnatal day (P) 5 to P9 with morphine sulfate at 2 or 5 mg/kg ip twice daily and then exposed to stress consisting of hypoxia (100% N2 1 min and 100% O2 5 min) followed by 2h maternal separation. Control mice were untreated and dam-reared. mRNA and miR expression profiling was performed on hippocampal tissues at P9. Overall, 2 and 5 mg/kg morphine treatment altered expression of a total of 150 transcripts (>1.5 fold change, P<0.05) from which 100 unique mRNAs were recognized (21 genes were up- and 79 genes were down-regulated), and 5 mg/kg morphine affected 63 mRNAs exclusively. The most upregulated mRNAs were fidgetin, arginine vasopressin, and resistin-like alpha, and the most down-regulated were defensin beta 11, aquaporin 1, calmodulin-like 4, chloride intracellular channel 6, and claudin 2. Gene Set Enrichment Analysis revealed that morphine treatment affected pathways related to cell cycle, membrane function, signaling, metabolism, cell death, transcriptional regulation, and immune response. Morphine decreased expression of miR-204-5p, miR-455-3p, miR-448-5p, and miR-574-3p. Nine morphine-responsive mRNAs that are involved in neurodevelopment, neurotransmission, and inflammation are predicted targets of the aforementioned differentially expressed miRs. These data establish that morphine produces dose-dependent changes in both hippocampal mRNA and miR expression in stressed neonatal mice. If permanent, morphine-mediated neuroepigenetic effects may affect long-term hippocampal function, and this provides a mechanism for the neonatal morphine

  8. The Dose-Dependent Effect of Nesiritide on Renal Function in Patients with Acute Decompensated Heart Failure: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

    PubMed Central

    Xiong, Bo; Wang, Chunbin; Yao, Yuanqing; Huang, Yuwen; Tan, Jie; Cao, Yin; Zou, Yanke; Huang, Jing

    2015-01-01

    Background Conflicting renal effects of nesiritide have been reported in patients with acute decompensated heart failure. To answer this controversy, we performed a meta-analysis of randomized controlled trials to evaluate the influence of nesiritide on renal function in patients with acute decompensated heart failure. Methods Articles were obtained from PubMed, Medline, Cochrane Library and reference review. Randomized controlled studies that investigated the effects of continuous infusion of nesiritide on renal function in adult patients with acute decompensated heart failure were included and analyzed. Fixed-effect model was used to estimate relative risk (RR) and weight mean difference (WMD). The quality assessment of each study, subgroup, sensitivity, and publication bias analyses were performed. Results Fifteen randomized controlled trials were eligible for inclusion. Most of included studies had relatively high quality and no publication bias was found. Overall, compared to control therapies, nesiritide might increase the risk of worsening renal function in patients with acute decompensated heart failure (RR 1.08, 95% CI 1.01–1.15, P = 0.023). In subgroup analysis, high-dose nesiritide strongly associated with renal dysfunction (RR 1.54, 95% CI 1.19-2.00, P = 0.001), but no statistical differences were observed in standard-dose (RR 1.04, 95% CI 0.98-1.12, P = 0.213), low-dose groups (RR 1.01, 95% CI 0.74-1.37, P = 0.968) and same results were identified in the subgroup analysis of placebo controlled trials. Peak mean change of serum creatinine from baseline was no significant difference (WMD -2.54, 95% CI -5.76-0.67, P = 0.121). Conclusions In our meta-analysis, nesiritide may have a dose-dependent effect on renal function in patients with acute decompensated heart failure. High-dose nesiritide is likely to increase the risk of worsening renal function, but standard-dose and low-dose nesiritide probably have no impact on renal function. These findings

  9. Dose-Dependent Effects of Morphine Exposure on mRNA and microRNA (miR) Expression in Hippocampus of Stressed Neonatal Mice

    PubMed Central

    McAdams, Ryan M.; McPherson, Ronald J.; Beyer, Richard P.; Bammler, Theo K.; Farin, Frederico M.; Juul, Sandra E.

    2015-01-01

    Morphine is used to sedate critically ill infants to treat painful or stressful conditions associated with intensive care. Whether neonatal morphine exposure affects microRNA (miR) expression and thereby alters mRNA regulation is unknown. We tested the hypothesis that repeated morphine treatment in stress-exposed neonatal mice alters hippocampal mRNA and miR expression. C57BL/6 male mice were treated from postnatal day (P) 5 to P9 with morphine sulfate at 2 or 5 mg/kg ip twice daily and then exposed to stress consisting of hypoxia (100% N2 1 min and 100% O2 5 min) followed by 2h maternal separation. Control mice were untreated and dam-reared. mRNA and miR expression profiling was performed on hippocampal tissues at P9. Overall, 2 and 5 mg/kg morphine treatment altered expression of a total of 150 transcripts (>1.5 fold change, P<0.05) from which 100 unique mRNAs were recognized (21 genes were up- and 79 genes were down-regulated), and 5 mg/kg morphine affected 63 mRNAs exclusively. The most upregulated mRNAs were fidgetin, arginine vasopressin, and resistin-like alpha, and the most down-regulated were defensin beta 11, aquaporin 1, calmodulin-like 4, chloride intracellular channel 6, and claudin 2. Gene Set Enrichment Analysis revealed that morphine treatment affected pathways related to cell cycle, membrane function, signaling, metabolism, cell death, transcriptional regulation, and immune response. Morphine decreased expression of miR-204-5p, miR-455-3p, miR-448-5p, and miR-574-3p. Nine morphine-responsive mRNAs that are involved in neurodevelopment, neurotransmission, and inflammation are predicted targets of the aforementioned differentially expressed miRs. These data establish that morphine produces dose-dependent changes in both hippocampal mRNA and miR expression in stressed neonatal mice. If permanent, morphine–mediated neuroepigenetic effects may affect long-term hippocampal function, and this provides a mechanism for the neonatal morphine

  10. 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

  11. Incidence of syndesmotic injury.

    PubMed

    Vosseller, J Turner; Karl, John W; Greisberg, Justin K

    2014-03-01

    Injury to the tibiofibular syndesmosis can occur with ankle sprain or fracture. The incidence of syndesmotic injury has not been specifically studied at a population level. Data on syndesmotic injury were obtained from the Healthcare Cost and Utilization Project (HCUP), a federal-state-private partnership. It is administered by the Agency for Healthcare Research and Quality, a division of the US Department of Health and Human Services. Two HCUP databases were queried for 8 states: the State Inpatient Database and the State Emergency Department Database. The first 6 International Classification of Diseases, Ninth Edition (ICD-9) code diagnoses were searched for codes that are used for syndesmotic injury (ie, 845.03). These data, along with data from the 2010 US census, were used to yield incidence rates for syndesmosis injury, as well as for various demographic groups. National estimates of injury totals were also calculated. In the 8 states, there were a total of 1821 syndesmotic injuries. Given the population of these states, the incidence rate of syndesmotic injury was 2.09 syndesmotic injuries per 100,000 person-years. This incidence correlates to an estimated 6445 syndesmotic injuries per year in the United States. These data provide some baseline numbers as to the incidence of syndesmotic injury in the United States. Although the incidence was low relative to some other injuries, the fact that syndesmotic injuries tend to occur in younger patients may have a greater effect in terms of productive years of life lost. PMID:24762148

  12. 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

  13. 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, ...

  14. Incident Duration Modeling Using Flexible Parametric Hazard-Based Models

    PubMed Central

    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

  15. 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

  16. 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

  17. 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

  18. 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

  19. Measurements of the reduced force coefficients for H{sub 2}, N{sub 2}, CO, and CO{sub 2} incident upon a solar panel array material, SiO{sub 2}-coated Kapton, Kapton, and Z-93-coated Al

    SciTech Connect

    Cook, S.R.; Hoffbauer, M.A.; Clark, D.D.; Cross, J.B.

    1998-07-01

    The reduced force coefficients were measured for H{sub 2}, N{sub 2}, CO, and CO{sub 2} incident upon a solar panel array material, SiO{sub 2}-coated Kapton, Kapton, and Z-93-coated Al. The coefficients were determined by measuring both the magnitude and direction of the force exerted on the surfaces by molecular beams of the gases. Measurements were made at angles of incidence of 0{degree}, 25{degree}, 50{degree}, 75{degree}, and 85{degree}. The forces were measured using a torsion balance with the surfaces mounted on the end of the lever arm. The absolute flux densities of the molecular beams were measured using a second torsion balance with a beam stop mounted on the lever arm that nullified the force of the scattered molecules. Flux measurements were also made using the effusive method. Standard time-of-flight techniques were used to determine the flux-weighted average velocities of the molecular beams. These velocities ranged from 1670 to 4620 m/s. The overall uncertainty in the reduced force coefficient measurements was estimated to be less than {plus_minus}10{percent}. These measurements were used to obtain the magnitude and direction of the flux-weighted average velocity of the scattered molecules, and also the flux-weighted translational kinetic energy of the scattered molecules. Analysis of this information provided insight into the microscopic details of the gas-surface interaction potential energy surface. {copyright} {ital 1998} {ital The American Physical Society}

  20. XM02 is superior to placebo and equivalent to Neupogen™ in reducing the duration of severe neutropenia and the incidence of febrile neutropenia in cycle 1 in breast cancer patients receiving docetaxel/doxorubicin chemotherapy

    PubMed Central

    del Giglio, A; Eniu, A; Ganea-Motan, D; Topuzov, E; Lubenau, H

    2008-01-01

    Background Recombinant granulocyte colony-stimulating factors (G-CSFs) such as Filgrastim are used to treat chemotherapy-induced neutropenia. We investigated a new G-CSF, XM02, and compared it to Neupogen™ after myelotoxic chemotherapy in breast cancer (BC) patients. Methods A total of 348 patients with BC receiving docetaxel/doxorubicin chemotherapy were randomised to treatment with daily injections (subcutaneous 5 μg/kg/day) for at least 5 days and a maximum of 14 days in each cycle of XM02 (n = 140), Neupogen™ (n = 136) or placebo (n = 72). The primary endpoint was the duration of severe neutropenia (DSN) in cycle 1. Results The mean DSN in cycle 1 was 1.1, 1.1, and 3.9 days in the XM02, Neupogen™, and placebo group, respectively. Superiority of XM02 over placebo and equivalence of XM02 with Neupogen™ could be demonstrated. Toxicities were similar between XM02 and Neupogen™. Conclusion XM02 was superior to placebo and equivalent to Neupogen™ in reducing DSN after myelotoxic chemotherapy. Trial Registration Current Controlled Trials ISRCTN02270769 PMID:19014494

  1. 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 |

  2. 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. PMID:26236085

  3. BAY 50-4798, a novel, high-affinity receptor-specific recombinant interleukin-2 analog, induces dose-dependent increases in CD25 expression and proliferation among unstimulated, human peripheral blood mononuclear cells in vitro.

    PubMed

    Matthews, Lynn; Chapman, Sherita; Ramchandani, Meena S; Lane, H Clifford; Davey, Richard T; Sereti, Irini

    2004-12-01

    Interleukin-2 administration induces CD4 T cell expansion in HIV-infected patients, however, toxicity can limit dosing. BAY 50-4798 is a recombinant IL-2 analog with >1000-fold specificity for the high-affinity IL-2 receptor. The effects of this compound on unstimulated human PBMC were evaluated. PBMC from HIV(-) and HIV(+) donors were cultured in vitro with incremental doses of BAY 50-4798 or aldesleukin. CD25 expression and proliferation were evaluated with flow cytometry. Cytokine levels were measured by ELISA in culture supernatants. BAY 50-4798 induced dose-dependent increases in CD25 expression and proliferation of T cells, NK, and B cells and showed selectivity for CD4 T cells expressing CD25. Induction of pro-inflammatory cytokines was also dose-dependent and was observed at the concentrations of BAY 50-4798 with the highest biologic activity. These data suggest that BAY 50-4798 can induce proliferation of unstimulated T cells but loss of T cell selectivity and induction of pro-inflammatory cytokines occur at concentrations exerting the highest biologic activity. PMID:15507389

  4. 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. PMID:26440136

  5. 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.

  6. Sex and dose-dependent effects of developmental exposure to bisphenol A on anxiety and spatial learning in deer mice (Peromyscus maniculatus bairdii) offspring.

    PubMed

    Jašarević, Eldin; Williams, Scott A; Vandas, Gregory M; Ellersieck, Mark R; Liao, Chunyang; Kannan, Kurunthachalam; Roberts, R Michael; Geary, David C; Rosenfeld, Cheryl S

    2013-01-01

    Bisphenol A (BPA) is a widely produced, endocrine disrupting compound that is pervasive in the environment. Data suggest that developmental exposure to BPA during sexual differentiation of the brain leads to later behavioral consequences in offspring. Outbred deer mice (Peromyscus maniculatus bairdii) are an excellent animal model for such studies as they exhibit well-defined sex- and steroid-dependent behaviors. Here, dams during gestation and lactation were fed with a phytoestrogen-free control diet, the same diet supplemented with either ethinyl estradiol (0.1 ppb), or one of the three doses of BPA (50 mg, 5 mg, 50 μg/kg feed weight). After weaning, the pups were maintained on control diet until they reached sexual maturity and then assessed for both spatial learning capabilities and anxiety-like and exploratory behaviors. Relative to controls, males exposed to the two upper but not the lowest dose of BPA demonstrated similar impairments in spatial learning, increased anxiety and reduced exploratory behaviors as ethinyl estradiol-exposed males, while females exposed to ethinyl estradiol, but not to BPA, consistently exhibited masculinized spatial abilities. We also determined whether dams maintained chronically on the upper dose of BPA contained environmentally relevant concentrations of BPA in their blood. While serum concentrations of unconjugated BPA in controls were below the minimum level of detection, those from dams on the BPA diet were comparable (5.48±2.07 ng/ml) to concentrations that have been observed in humans. Together, these studies demonstrate that developmental exposure to environmentally relevant concentrations of BPA can disrupt adult behaviors in a dose- and sex-dependent manner. PMID:23051835

  7. 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…

  8. 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,…

  9. Developmental Exposure to TCDD Reduces Fertility and Negatively Affects Pregnancy Outcomes across Multiple Generations

    PubMed Central

    Bruner-Tran, Kaylon L.; Osteen, Kevin G.

    2010-01-01

    TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) is a ubiquitous environmental contaminant and known endocrine disruptor. Since humans and animals are most sensitive to toxicant exposure during development, we previously developed a mouse model of in utero TCDD exposure in order to examine the impact of this toxicant on adult reproductive function. Our initial in utero toxicant-exposure study revealed a dose-dependent reduction in uterine sensitivity to progesterone; however, we did not previously explore establishment or maintenance of pregnancy. Thus, in the current study, we examined pregnancy outcomes in adult C57BL/6 mice with a history of developmental TCDD exposure. Herein we demonstrate reduced fertility and an increased incidence of premature birth (PTB) in F1 mice exposed in utero to TCDD as well as in three subsequent generations. Finally, our studies revealed that mice with a history of developmental TCDD exposure exhibit an increased sensitivity to inflammation which further negatively impacted gestation length in all generations examined. PMID:20955784

  10. Silver Nanoparticles Exhibit the Dose-Dependent Anti-Proliferative Effect against Human Squamous Carcinoma Cells Attenuated in the Presence of Berberine.

    PubMed

    Dziedzic, Arkadiusz; Kubina, Robert; Bułdak, Rafał J; Skonieczna, Magda; Cholewa, Krzysztof

    2016-01-01

    The biological activity of nanosize silver particles towards oral epithelium-derived carcinoma seems to be still underinvestigated. We evaluated the influence of low doses of nanosize scale silver particles on the proliferation and viability of malignant oral epithelial keratinocytes in vitro, alone and in conjunction with the plant alkaloid berberine. Cells of human tongue squamous carcinoma SCC-25 (ATCC CRL-1628), cultivated with the mixture of Dulbecco's modified Eagle's medium, were exposed to silver nanoparticles alone (AgNPs, concentrations from 0.31 to 10 μg/mL) and to a combination of AgNPs with berberine chloride (BER, 1/2 IC50 concentration) during 24 h and 48 h. The cytotoxic activity of AgNPs with diameters of 10 nm ± 4 nm was measured by 3-(4,5-dimethyl-2-thiazyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Cell cycle analysis was performed by treating cells with propidium iodide followed by flow-activated cell sorting. RT-QPCR reaction was used to assess expression of anti-apoptotic proteins Bcl-2 and pro-apoptotic protein Bcl-2-associated X protein Bax genes expression. Monodisperse silver nanoparticles at a concentration of 10 μg/mL arrested SCC-25 cells cycle after 48 h at the G0/G1 phase in a dose- and time-dependent manner through disruption G0/G1 checkpoint, with increase of Bax/Bcl-2 ratio gene expression. AgNPs exhibit cytotoxic effects on SCC-25 malignant oral epithelial keratinocytes, which is diminished when combined with BER. The AgNPs concentration required to inhibit the growth of carcinoma cells by 50% (IC50) after 48 h was estimated at 5.19 μg/mL. AgNPs combined with BER increased the expression of Bcl-2 while decreasing the ratio of Bax/Bcl-2 in SCC-25 cells. Silver particles at low doses therefore reduce the proliferation and viability of oral squamous cell carcinoma cells. SCC-25 cells are susceptible to damage from AgNPs-induced stress, which can be regulated by the natural alkaloid berberine, suggesting that nanoparticles

  11. 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

  12. Combination chemoprophylaxis and immunoprophylaxis in reducing the incidence of leprosy.

    PubMed

    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

  13. 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 Central

    Marty, Mary S.

    2013-01-01

    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 (63mg/kg/day) for P1 males and between 200 and 400 ppm (14–27mg/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. PMID:24105888

  14. Oscillating cascade aerodynamics at large mean incidence

    SciTech Connect

    Buffum, D.H.; Capece, V.R.; King, A.J.; El-Aini, Y.M.

    1998-01-01

    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 and 10 deg; the Reynolds number was 0.9 {times} 10{sup 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.

  15. 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.

  16. 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.

  17. Idiot savants: rate of incidence.

    PubMed

    Hill, A L

    1977-02-01

    Based on the replies to a survey of 300 public residential facilities for the mentally retarded, an incidence rate for idiot savants was established. This rate of .06% is based on the reporting of 54 idiot savants within a population of 90,000 residents. Several reasons for caution in the acceptance of this incidence rate are discussed. PMID:840586

  18. 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…

  19. 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’.

  20. Serum fatty acids and breast cancer incidence.

    PubMed

    Rissanen, Harri; Knekt, Paul; Järvinen, Ritva; Salminen, Irma; Hakulinen, Timo

    2003-01-01

    Fatty acid composition of the diet may be essential to the development of breast cancer. We studied the ability of several fatty acids of serum total lipids to predict breast cancer incidence in a case-control study nested within a longitudinal population study. The proportions of fatty acids in serum total lipids were determined from stored serum samples collected at baseline for 127 incident breast cancer cases and 242 matched controls. Women with a higher proportion of total polyunsaturated fatty acids (PUFAs) in serum had a reduced risk of breast cancer. The odds ratio (OR) between the highest and lowest tertiles of serum PUFA was 0.31 (95% confidence interval, CI = 0.12-0.77). This association was mainly due to n-6 PUFAs and especially to linoleic acid. The ORs were 0.35 (CI = 0.14-0.84) and 0.29 (CI = 0.12-0.73), respectively. Of the monounsaturated fatty acids (MUFAs), higher trans-11-18:1 levels were related to an increased breast cancer risk (OR = 3.69, CI = 1.35-10.06). The association was stronger in postmenopausal than in premenopausal women. The present study suggests that higher serum proportions of the n-6 PUFA linoleic acid and lower proportions of the MUFA trans-11-18:1 fatty acid predict a reduced incidence of breast cancer. PMID:12881010

  1. Study Design of PROCEDURE Study. A Randomized Comparison of the Dose-Dependent Effects of Pitavastatin in Patients with Abdominal Aortic Aneurysm with Massive Aortic Atheroma: Prevention of Cholesterol Embolization during Endovascular and Open Aneurysm Repair with Pitavastatin (PROCEDURE) Study

    PubMed Central

    Nemoto, Masaru; Hashimoto, Takuya; Miura, Sumio; Urabe, Go; Nakazawa, Tatsu; Hosaka, Akihiro; Kato, Masaaki; Ohkubo, Nobukazu; Miyairi, Takeshi; Okamoto, Hiroyuki; Shigematsu, Kunihiro; Miyata, Tetsuro

    2013-01-01

    Outcomes of abdominal aortic aneurysm (AAA) repair have improved in the 2 decades since the emergence of endovascular aneurysm repair (EVAR). However, EVAR is considered a contraindication for shaggy aorta because of the high risk of shower embolization. Recently, statins have been implicated in preventing embolization in patients with shaggy aorta via its pleiotropic effects, including atheroma reduction and coronary artery stabilization. We selected pitavastatin, a statin with potent effects, discovered and developed by a Japanese company because it has shown excellent pleiotropic effects on atheromatous arteries in the Japanese population. A randomized comparison study of dose-dependent effects of pitavastatin in patients with AAA with massive atheromatous aortic thrombus (PROCEDURE study) has begun. PROCEDURE has an enrollment goal of up to 80 patients with AAA with massive aortic atheroma (excluding intrasac atheroma), randomly allocated into 2 groups receiving pitavastatin at a dose of 1 or 4 mg/day. The endpoints of the PROCEDURE study include change in atheroma volume, major adverse events related to shower embolization after aneurysm repair, and lipid-lowering effects. When complete, results of the PROCEDURE study should provide objective evidence to use statins preoperatively for AAA with massive aortic atheroma. PMID:23641286

  2. 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

  3. 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

    El-Sayed, Ibrahim; Bassiouny, Khalid; Nokaly, Aziz; Abdelghani, Ahmed S; Roshdy, Wael

    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

  4. 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

  5. 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)

  6. 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

  7. Predicted vitamin D status and incidence of tooth loss and periodontitis

    PubMed Central

    Jimenez, Monik; Giovannucci, Edward; Kaye, Elizabeth Krall; Joshipura, Kaumudi J; Dietrich, Thomas

    2016-01-01

    Objective Vitamin D insufficiency is highly prevalent, with particular subgroups at greater risk (e.g. the elderly and those with darker skin). Vitamin D insufficiency may partly explain US racial/ethnic disparities in the prevalence of periodontitis and tooth loss. We evaluated the association between a predictor score of plasma 25-hydroxyvitamin D (25(OH)D) and incidence of periodontitis and tooth loss. Design Detailed biennial questionnaires were collected on medical history, lifestyle practices and incident periodontitis and tooth loss. The predictor score was derived from variables known to influence circulating concentrations of plasma 25(OH)D and validated against plasma concentrations among a sub-sample. Multivariable Cox proportional-hazards models with time-varying covariates estimated the association between the predicted 25(OH)D score and time until first tooth loss. Subjects A total of 42 730 participants of the Health Professionals Follow-Up Study aged 40–75 years at baseline were followed from 1986 to 2006. Setting USA, representing all fifty states and the District of Columbia. Results We observed 13 581 incident tooth loss events from 539 335 person-years. There was a dose-dependent significant inverse association across quintiles of the predicted 25(OH)D score and incidence of tooth loss. In multivariable analyses, the highest quintile of the updated predicted 25(OH)D score compared with the lowest was associated with a 20 % lower incidence of tooth loss (hazard ratio 5 0·80, 95 % CI 0·76, 0·85; P value for trend <0·0 0 1); UV-B was also independently associated. Results for the predicted 25(OH)D score and periodontitis were similar. Conclusions These results are suggestive of an association between predictors of vitamin D and lower incidence of tooth loss and periodontitis. PMID:23469936

  8. Neonatal Incidence of Hip Dysplasia

    PubMed Central

    Peled, Eli; Eidelman, Mark; Katzman, Alexander

    2008-01-01

    The advantages of sonographic examination are well known, but its main disadvantage is that it might lead to overdiagnosis, which might cause overtreatment. Variations in the incidence of developmental dysplasia of the hip are well known. We ascertained the incidence of neonatal sonographic developmental dysplasia of the hip without considering the development of those joints during followup. All 45,497 neonates (90,994 hips) born in our institute between January 1992 and December 2001 were examined clinically and sonographically during the first 48 hours of life. Sonography was performed according to Graf’s method, which considers mild hip sonographic abnormalities as Type IIa. We evaluated the different severity type incidence pattern and its influence on the total incidence during and between the investigated years. According to our study, sonographic Type IIa has major effects on the incidence of overall developmental dysplasia of the hip with a correlation coefficient of 0.95, whereas more severe sonographic abnormalities show relatively stable incidence patterns. Level of Evidence: Level I, prognostic study. See the Guidelines for Authors for a complete description of levels of evidence. PMID:18288551

  9. The effect of antibacterial soap on impetigo incidence, Karachi, Pakistan.

    PubMed

    Luby, Stephen; Agboatwalla, Mubina; Schnell, Beverly M; Hoekstra, Robert M; Rahbar, Mohammad H; Keswick, Bruce H

    2002-10-01

    We conducted a study to determine if soap containing 1.2% triclocarban would be effective in reducing the incidence of impetigo. We randomized 162 households in a low-income neighborhood of Karachi, Pakistan, to receive a regular supply of 1.2% triclocarban-containing soap (n = 81) or an identically appearing placebo (n = 81); 79 households in a nearby neighborhood were enrolled as standard practice controls. After adjustment for household clustering and covariates, the incidence of impetigo among children living in households receiving triclocarban-containing soap (1.10 episodes per 100 person-weeks) was 23% lower than in households receiving placebo soap (P = 0.28) and 43% lower than the standard habit and practice controls (P = 0.02). The routine use of triclocarban-containing soap by children living in a community with a high incidence of impetigo was associated with a reduced incidence of impetigo. PMID:12452499

  10. 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

  11. 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

  12. 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

  13. 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

  14. The stage-specific testicular germ cell apoptotic response to low-dose radiation and 2,5-hexanedione combined exposure. II: qRT-PCR array analysis reveals dose dependent adaptive alterations in the apoptotic pathway.

    PubMed

    Catlin, Natasha R; Huse, Susan M; Boekelheide, Kim

    2014-12-01

    Testicular effects of chemical mixtures may differ from those of the individual chemical constituents. This study assessed the co-exposure effects of the model germ cell- and Sertoli cell-specific toxicants, X-irradiation (x-ray), and 2,5-hexanedione (HD), respectively. In high-dose studies, HD has been shown to attenuate x-ray-induced germ cell apoptosis. Adult rats were exposed to different levels of x-ray (0.5 Gy, 1 Gy, and 2 Gy) or HD (0.33%), either alone or in combination. To assess cell type-specific attenuation of x-ray effects with HD co-exposure, we used laser capture microdissection (LCM) to enrich the targeted cell population and examine a panel of apoptosis-related transcripts using PCR arrays. The apoptosis PCR arrays identified significant dose-dependent treatment effects on several genes, with downregulation of death receptor 5 (DR5), Naip2, Sphk2, Casp7, Aven, Birc3, and upregulation of Fas. The greatest difference in transcript response to exposure was seen with 0.5 Gy x-ray exposure, and the attenuation effect seen with the combined high-dose x-ray and HD did not persist into the low-dose range. Examination of protein levels in staged tubules revealed a significant upregulation in DR5, following high-dose co-exposure. These results provide insight into the testis cell-specific apoptotic response to low-dose co-exposures of model testicular toxicants. PMID:24670816

  15. 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. PMID:24430706

  16. Incidence and Burden of the Myelodysplastic Syndromes.

    PubMed

    Cogle, Christopher R

    2015-09-01

    Since 2001, cases of myelodysplastic syndromes (MDSs) have been tracked by cancer registries. Examining registry data in the USA, the reported age-adjusted incidence of MDS per 100,000 was 3.3 per year for 2001-2003 and 4.9 per year for 2007-2011, with increases likely a result of growing awareness of reporting requirements. However, active case-finding methods repeatedly demonstrate that population-based registries have underestimated the incidence of MDS due to underreporting and underdiagnosis. Using keyword search strategies of electronic pathology reports or other novel case capture methods, the true incidence of MDS has been estimated between 5.3 and 13.1 per 100,000. Using Medicare billing claims data, the incidence of MDS per 100,000 in patients aged ≥65 years has been estimated between 75 and 162. MDS prevalence is estimated to be 60,000 and -170,000 in the USA and projected to grow. Epidemiologic data can help estimate the burden of MDS and expose unmet clinical needs. For example, patients with MDS receiving transfusions had significantly higher reported health care costs versus those that did not (3-year mean of $88,824 vs $29,519). Epidemiologic data also revealed that most MDS patients receiving transfusions do not receive active therapies, despite strong evidence that hypomethylating agents and lenalidomide significantly reduce transfusion burden. Other unmet needs identified by epidemiologic studies include high need for treatment options after failing first-line therapy and shared decision making by older MDS patients. PMID:26134527

  17. Methamphetamine Lab Incidents, 2004-2014

    MedlinePlus

    ... Liderazgo de la DEA Resource Center » Statistics & Facts » Methamphetamine Lab Incidents Methamphetamine Lab Incidents, 2004-2014 NOTE: These maps include all meth incidents, including labs, "dumpsites" or "chemical and glassware" ...

  18. The incidence of scarlet fever.

    PubMed Central

    Perks, E. M.; Mayon-White, R. T.

    1983-01-01

    This study attempted to find the incidence of scarlet fever in the Oxford region, including the proportion of patients from whom Streptococcus pyogenes could be isolated. General practitioners collected throat swabs from patients with suspected scarlet fever. The swabs were examined for viral and bacterial pathogens. Children admitted to hospital were used as controls. Twenty-five of 105 patients with suspected scarlet fever grew Str. pyogenes; M type 4 was the commonest type. The clinical diagnosis of scarlet fever was not always confirmed by throat culture. The annual incidence of scarlet fever was estimated to be 0.3 cases per 1000 per year. PMID:6358344

  19. Vortioxetine dose-dependently reverses 5-HT depletion-induced deficits in spatial working and object recognition memory: a potential role for 5-HT1A receptor agonism and 5-HT3 receptor antagonism.

    PubMed

    du Jardin, Kristian Gaarn; Jensen, Jesper Bornø; Sanchez, Connie; Pehrson, Alan L

    2014-01-01

    We previously reported that the investigational multimodal antidepressant, vortioxetine, reversed 5-HT depletion-induced memory deficits while escitalopram and duloxetine did not. The present report studied the effects of vortioxetine and the potential impact of its 5-HT1A receptor agonist and 5-HT3 receptor antagonist properties on 5-HT depletion-induced memory deficits. Recognition and spatial working memory were assessed in the object recognition (OR) and Y-maze spontaneous alternation (SA) tests, respectively. 5-HT depletion was induced in female Long-Evans rats using 4-cholro-DL-phenylalanine methyl ester HCl (PCPA) and receptor occupancies were determined by ex vivo autoradiography. Rats were acutely dosed with vortioxetine, ondansetron (5-HT3 receptor antagonist) or flesinoxan (5-HT1A receptor agonist). The effects of chronic vortioxetine administration on 5-HT depletion-induced memory deficits were also assessed. 5-HT depletion reliably impaired memory performance in both the tests. Vortioxetine reversed PCPA-induced memory deficits dose-dependently with a minimal effective dose (MED) ≤0.1mg/kg (∼80% 5-HT3 receptor occupancy; OR) and ≤3.0mg/kg (5-HT1A, 5-HT1B, 5-HT3 receptor occupancy: ∼15%, 60%, 95%) in SA. Ondansetron exhibited a MED ≤3.0μg/kg (∼25% 5-HT3 receptor occupancy; OR), but was inactive in the SA test. Flesinoxan had a MED ≤1.0mg/kg (∼25% 5-HT1A receptor occupancy; SA); only 1.0mg/kg ameliorated deficits in the NOR. Chronic p.o. vortioxetine administration significantly improved memory performance in OR and occupied 95%, 66%, and 9.5% of 5-HT3, 5-HT1B, and 5-HT1A receptors, respectively. Vortioxetine's effects on SA performance may involve 5-HT1A receptor agonism, but not 5-HT3 receptor antagonism, whereas the effects on OR performance may involve 5-HT3 receptor antagonism and 5-HT1A receptor agonism. PMID:23916504

  20. 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

  1. Preclinical Dose-Escalation Study of Intravitreal AAV-RS1 Gene Therapy in a Mouse Model of X-linked Retinoschisis: Dose-Dependent Expression and Improved Retinal Structure and Function.

    PubMed

    Bush, Ronald A; Zeng, Yong; Colosi, Peter; Kjellstrom, Sten; Hiriyanna, Suja; Vijayasarathy, Camasamudram; Santos, Maria; Li, Jinbo; Wu, Zhijian; Sieving, Paul A

    2016-05-01

    Gene therapy for inherited retinal diseases has been shown to ameliorate functional and structural defects in both animal models and in human clinical trials. X-linked retinoschisis (XLRS) is an early-age onset macular dystrophy resulting from loss of an extracellular matrix protein (RS1). In preparation for a human clinical gene therapy trial, we conducted a dose-range efficacy study of the clinical vector, a self-complementary AAV delivering a human retinoschisin (RS1) gene under control of the RS1 promoter and an interphotoreceptor binding protein enhancer (AAV8-scRS/IRBPhRS), in the retinoschisin knockout (Rs1-KO) mouse. The therapeutic vector at 1 × 10(6) to 2.5 × 10(9) (1E6-2.5E9) vector genomes (vg)/eye or vehicle was administered to one eye of 229 male Rs1-KO mice by intravitreal injection at 22 ± 3 days postnatal age (PN). Analysis of retinal function (dark-adapted electroretinogram, ERG), structure (cavities and outer nuclear layer thickness) by in vivo retinal imaging using optical coherence tomography, and retinal immunohistochemistry (IHC) for RS1 was done 3-4 months and/or 6-9 months postinjection (PI). RS1 IHC staining was dose dependent across doses ≥1E7 vg/eye, and the threshold for significant improvement in all measures of retinal structure and function was 1E8 vg/eye. Higher doses, however, did not produce additional improvement. At all doses showing efficacy, RS1 staining in Rs1-KO mouse was less than that in wild-type mice. Improvement in the ERG and RS1 staining was unchanged or greater at 6-9 months than at 3-4 months PI. This study demonstrates that vitreal administration of AAV8 scRS/IRBPhRS produces significant improvement in retinal structure and function in the mouse model of XLRS over a vector dose range that can be extended to a human trial. It indicates that a fully normal level of RS1 expression is not necessary for a therapeutic effect. PMID:27036983

  2. Serious Incident Management in Australia

    ERIC Educational Resources Information Center

    Ellis, Ike; Thorley-Smith, Sara

    2007-01-01

    As part of its efforts to ensure school safety, the government of New South Wales, Australia, has developed simulation exercises to better prepare principals to manage serious incidents, in collaboration with police. This article describes two initiatives implemented across NSW. The exercises provide principals in both secondary and primary…

  3. Benefit Incidence Analysis in Education

    ERIC Educational Resources Information Center

    Lassibille, Gerard; Tan, Jee-Peng

    2007-01-01

    The standard benefit incidence algebra generally produces biased estimates of the distribution of public spending on education when students from poor and rich families are enrolled in schools that receive different levels of public spending per student. Except in very rare instances, removing these biases entails combining several sources of…

  4. [Incidence of cancer in Navarre].

    PubMed

    Ardanaz, E; Moreno, C; Pérez de Rada Arístegui, M E; Ezponda, C; Navaridas, N

    2004-01-01

    Between 1998 and 2000 an annual average of 3,303 cases of invasive cancer were registered in Navarre, 58% of them in men. If we except non melanoma skin tumours, the annual number of cases was 2,495, with gross incidence rates of 559 and 372 per 100,000 in men and women, and rates adjusted to the world population of 312 and 203 per 100,000 respectively. Amongst men, the four most frequently diagnosed tumoural localisations were the prostate, lung, colorectal and bladder, accounting for 57% of all cases. The most notable due to their frequency amongst women were tumours of the breast, colorectal, uterus body and ovary, accounting for 54% of all cases. With respect to the five year period from 1993 to 1997, the global incidence of cancer in the three year period from 1998 to 2000 has increased 4.2% in men and 7.4% in women. The incidence of lung cancer and non-Hodgkin lymphomas in both sexes and of breast cancer in women and prostate cancer in men are notable. There continues to be a fall in the incidence rates of stomach cancer in both sexes, following the tendency begun in the 1970s. PMID:15644889

  5. Local Control With Reduced-Dose Radiotherapy for Low-Risk Rhabdomyosarcoma: A Report From the Children's Oncology Group D9602 Study

    SciTech Connect

    Breneman, John; Meza, Jane; Donaldson, Sarah S.; Raney, R. Beverly; Wolden, Suzanne; Michalski, Jeff; Laurie, Fran; Rodeberg, David A.; Meyer, William

    2012-06-01

    Purpose: To analyze the effect of reduced-dose radiotherapy on local control in children with low-risk rhabdomyosarcoma (RMS) treated in the Children's Oncology Group D9602 study. Methods and Materials: Patients with low-risk RMS were nonrandomly assigned to receive radiotherapy doses dependent on the completeness of surgical resection of the primary tumor (clinical group) and the presence of involved regional lymph nodes. After resection, most patients with microscopic residual and uninvolved nodes received 36 Gy, those with involved nodes received 41.4 to 50.4 Gy, and those with orbital primary tumors received 45 Gy. All patients received vincristine and dactinomycin, with cyclophosphamide added for patient subsets with a higher risk of relapse in Intergroup Rhabdomyosarcoma Study Group III and IV studies. Results: Three hundred forty-two patients were eligible for analysis; 172 received radiotherapy as part of their treatment. The cumulative incidence of local/regional failure was 15% in patients with microscopic involved margins when cyclophosphamide was not part of the treatment regimen and 0% when cyclophosphamide was included. The cumulative incidence of local/regional failure was 14% in patients with orbital tumors. Protocol-specified omission of radiotherapy in girls with Group IIA vaginal tumors (n = 5) resulted in three failures for this group. Conclusions: In comparison with Intergroup Rhabdomyosarcoma Study Group III and IV results, reduced-dose radiotherapy does not compromise local control for patients with microscopic tumor after surgical resection or with orbital primary tumors when cyclophosphamide is added to the treatment program. Girls with unresected nonbladder genitourinary tumors require radiotherapy for postsurgical residual tumor for optimal local control to be achieved.

  6. Modeling Wildfire Incident Complexity Dynamics

    PubMed Central

    Thompson, Matthew P.

    2013-01-01

    Wildfire management in the United States and elsewhere is challenged by substantial uncertainty regarding the location and timing of fire events, the socioeconomic and ecological consequences of these events, and the costs of suppression. Escalating U.S. Forest Service suppression expenditures is of particular concern at a time of fiscal austerity as swelling fire management budgets lead to decreases for non-fire programs, and as the likelihood of disruptive within-season borrowing potentially increases. Thus there is a strong interest in better understanding factors influencing suppression decisions and in turn their influence on suppression costs. As a step in that direction, this paper presents a probabilistic analysis of geographic and temporal variation in incident management team response to wildfires. The specific focus is incident complexity dynamics through time for fires managed by the U.S. Forest Service. The modeling framework is based on the recognition that large wildfire management entails recurrent decisions across time in response to changing conditions, which can be represented as a stochastic dynamic system. Daily incident complexity dynamics are modeled according to a first-order Markov chain, with containment represented as an absorbing state. A statistically significant difference in complexity dynamics between Forest Service Regions is demonstrated. Incident complexity probability transition matrices and expected times until containment are presented at national and regional levels. Results of this analysis can help improve understanding of geographic variation in incident management and associated cost structures, and can be incorporated into future analyses examining the economic efficiency of wildfire management. PMID:23691014

  7. Aberrations for Grazing Incidence Optics

    NASA Technical Reports Server (NTRS)

    Saha, Timo T.

    2008-01-01

    Large number of grazing incidence telescope configurations have been designed and studied. Wolte1 telescopes are commonly used in astronomical applications. Wolter telescopes consist of a paraboloidal primary mirror and a hyperboloidal or an ellipsoidal secondary mirror. There are 8 possible combinations of Wolter telescopes. Out of these possible designs only type 1 and type 2 telescopes are widely used. Type 1 telescope is typically used for x-ray applications and type 2 telescopes are used for EUV applications. Wolter-Schwarzshild (WS) telescopes offer improved image quality over a small field of view. The WS designs are stigmatic and free of third order coma and, therefore, the PSF is significantly better over a small field of view. Typically the image is more symmetric about its centroid. As for the Wolter telescopes there are 8 possible combinations of WS telescopes. These designs have not been widely used because the surface equations are complex parametric equations complicating the analysis and typically the resolution requirements are too low to take full advantage of the WS designs. There are several other design options. Most notable are wide field x-ray telescope designs. Polynomial designs were originally suggested by Burrows4 and hyperboloid-hyperboloid designs for solar physics applications were designed by Harvey5. No general aberration theory exists for grazing incidence telescopes that would cover all the design options. Several authors have studied the aberrations of grazing incidence telescopes. A comprehensive theory of Wolter type 1 and 2 telescopes has been developed. Later this theory was expanded to include all possible combinations of grazing incidence and also normal incidence paraboloid-hyperboloid and paraboloid-ellipsoid telescopes. In this article the aberration theory of Wolter type telescopes is briefly reviewed.

  8. Developing a departmental culture for reporting adverse incidents.

    PubMed

    Bhatia, R; Blackshaw, G; Rogers, A; Grant, A; Kulkarni, R

    2003-01-01

    A simple, reproducible model for reporting adverse events was developed in order to promote cultural awareness and acceptance of risk management within the authors' department. A departmental proforma was created and prospective reporting of adverse events was encouraged. In the six months prior to commencing this study only four adverse incidents were reported. Following the introduction of the proforma 64 critical incidents and near-misses were reported in the one-year period. In conclusion a simple model for reporting critical incidents and near-misses has been established. This has fostered a cultural change within the department and all members of staff feel more comfortable with reporting such incidents. The process is seen as educational and an important part of continuing professional and departmental development. Protocols and changes in organisational practice have been developed to reduce and prevent the occurrence of adverse events and offer patients continuous improvement in care. PMID:12870255

  9. Incidence of out-of-hospital cardiac arrest.

    PubMed

    Rea, Thomas D; Pearce, Rachel M; Raghunathan, Trivellore E; Lemaitre, Rozenn N; Sotoodehnia, Nona; Jouven, Xavier; Siscovick, David S

    2004-06-15

    Estimates of the incidence of out-of-hospital primary cardiac arrest (CA) have typically relied solely upon emergency medical service or death certificate records and have not investigated incidence in clinical subgroups. Overall and temporal patterns of CA incidence were investigated in clinically defined groups using systematic methods to ascertain CA. Estimates of incidence were derived from a population-based case-control study in a large health plan from 1986 to 1994. Subjects were enrollees aged 50 to 79 years who had had CA (n = 1,275). A stratified random sample of enrollees who had not had CA was used to estimate the population at risk with various clinical characteristics (n = 2,323). Poisson's regression was used to estimate incidence overall and for 3-year time periods (1986 to 1988, 1989 to 1991, and 1992 to 1994). The overall CA incidence was 1.89/1,000 subject-years and varied up to 30-fold across clinical subgroups. For example, incidence was 5.98/1,000 subject-years in subjects with any clinically recognized heart disease compared with 0.82/1,000 subject-years in subjects without heart disease. In subgroups with heart disease, incidence was 13.69/1,000 subject-years in subjects with prior myocardial infarction and 21.87/1,000 subject-years in subjects with heart failure. Risk decreased by 20% from the initial to the final time period, with a greater decrease observed in those with (25%) compared with those without (12%) clinical heart disease. Thus, CA incidence varied considerably across clinical groups. The results provide insights regarding absolute and population-attributable risk in clinically defined subgroups, information that may aid strategies aimed at reducing mortality from CA. PMID:15194012

  10. [Decreasing incidence of stent thrombosis].

    PubMed

    Lemesle, G; Delhaye, C

    2011-12-01

    Stent thrombosis (ST) remains a major pitfall of stent implantation in contemporary percutaneous coronary intervention (PCI) leading to high rates of death and non-fatal myocardial infarction. Many predictors of ST have been reported worldwide but the strongest have to be highlighted regarding the catastrophic prognosis of such an event. Because platelet aggregation has a pivotal role in ST pathogenesis, the new antiplatelet regimens combining aspirin and P2Y12 receptor inhibitors have led to a remarkable decrease in the ST incidence, especially in the setting of acute coronary syndrome (ACS). In this article, our purpose is to review the evolution of ST incidence since first stent use in PCI. We will also overview the main predictors of ST focusing on ACS and clopidogrel low response. PMID:22054519

  11. Influenza Vaccination Reduces Dementia Risk in Chronic Kidney Disease Patients: A Population-Based Cohort Study.

    PubMed

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

    2016-03-01

    disorder; and statin, metformin, ACEI, and aspirin use with the incidence of dementia in various models. A stronger protective effect against dementia risk was demonstrated during the noninfluenza season. Regardless of comorbidities or drug use, influenza vaccination was an independent protective factor and dose-dependently reduced the risk of dementia in CKD patients. Influenza vaccination exerts dose-response and synergistic protective effects against dementia in CKD patients with dementia risk factors by reducing the incidence of dementia. PMID:26945371

  12. Incidence of silicosis in flourmill workers

    PubMed Central

    Athavale, Amita; Iyer, Aparna; Sahoo, Debasis; Salgia, Kapil; Raut, Abhijit; Kanodra, Neeti

    2011-01-01

    Background: Silicosis is an ancient occupational illness reported in silica mill workers, agate stone workers, slate pen workers and mining industry. However its association in flour mill workers has not been established. Aims: To study the incidence of silicosis and respiratory morbidity in flour mill workers. Settings and Design: A prospective study of 56 flour mill workers working with open silica grinding stones was undertaken. Materials and Methods: 56 flour mill workers who volunteered following information regarding the study purpose were recruited from the community. Detailed clinical and occupational history, lung functions, chest x-ray, and high resolution computed tomography (HRCT) were done. Diagnosis was made on the basis of radiological findings. Statistical Analysis: Data analysis was done with the help of the statistical package for social sciences software. The Chi-square test was used for determining the relationship between qualitative data and descriptive statistics was used where required. Results: 93% had respiratory symptoms that included cough (66.1%), dyspnea (75%), chest pain (17.1%), and rhinorrhea (46.4%). Radiological abnormalities were noted in chest X-ray (60.7%) and HRCT (81.48%). A significant correlation was seen between duration of exposure and HRCT abnormalities. Lung functions revealed obstruction in 28.5% subjects, restriction in 19%, mixed ventilatory defects in 21.4%, while 18.9% had a reduced diffusion capacity. Conclusion: Incidence of silicosis in our study on flour mill workers working with silica containing grinding stones was 30.4%. They had high respiratory morbidity (93%) cough and dyspnea being predominant symptoms. Duration of exposure correlates with radiological findings and increased incidence of silicosis. PMID:22412287

  13. Perceived Discrimination and Incident Cardiovascular Events

    PubMed Central

    Everson-Rose, Susan A.; Lutsey, Pamela L.; Roetker, Nicholas S.; Lewis, Tené T.; Kershaw, Kiarri N.; Alonso, Alvaro; Diez Roux, Ana V.

    2015-01-01

    Perceived discrimination is positively related to cardiovascular disease (CVD) risk factors; its relationship with incident CVD is unknown. Using data from the Multi-Ethnic Study of Atherosclerosis, a population-based multiethnic cohort study of 6,508 adults aged 45–84 years who were initially free of clinical CVD, we examined lifetime discrimination (experiences of unfair treatment in 6 life domains) and everyday discrimination (frequency of day-to-day occurrences of perceived unfair treatment) in relation to incident CVD. During a median 10.1 years of follow-up (2000–2011), 604 incident events occurred. Persons reporting lifetime discrimination in ≥2 domains (versus none) had increased CVD risk, after adjustment for race/ethnicity and sociodemographic factors, behaviors, and traditional CVD risk factors (hazard ratio (HR) = 1.36, 95% confidence interval (CI): 1.09, 1.70) and after control for chronic stress and depressive symptoms (HR = 1.28, 95% CI: 1.01, 1.60). Reported discrimination in 1 domain was unrelated to CVD (HR = 1.05, 95% CI: 0.86, 1.30). There were no differences by race/ethnicity, age, or sex. In contrast, everyday discrimination interacted with sex (P = 0.03). Stratified models showed increased risk only among men (for each 1–standard deviation increase in score, adjusted HR = 1.14, 95% CI: 1.03, 1.27); controlling for chronic stress and depressive symptoms slightly reduced this association (HR = 1.11, 95% CI: 0.99, 1.25). This study suggests that perceived discrimination is adversely related to CVD risk in middle-aged and older adults. PMID:26085044

  14. Global Incidence of Preterm Birth.

    PubMed

    Tielsch, James M

    2015-01-01

    Estimating the incidence of preterm birth depends on accurate assessment of gestational age and pregnancy outcomes. In many countries, such data are not routinely collected, making global estimates difficult. A recent systematic approach to this problem has estimated a worldwide incidence of 11.1 per 100 live births in 2010. Significant variation in rates by country and region of the world was noted, but this variation is smaller than observed for a number of other important reproductive outcomes. Rates range from approximately 5% in some northern European countries to over 15% in some countries in sub-Saharan Africa and Asia. Time trends suggest that preterm birth incidence is increasing, but much of this change may reflect changes in medically induced early delivery practices as improvements in survival of preterm infants has improved. Whether there have been major changes in spontaneous preterm birth is unknown. New approaches to classifying etiologic heterogeneity have been proposed and offer the promise of developing specific interventions to address the range of underlying causes of this important health problem. PMID:26111559

  15. The incidence of diagnostic error in medicine.

    PubMed

    Graber, Mark L

    2013-10-01

    A wide variety of research studies suggest that breakdowns in the diagnostic process result in a staggering toll of harm and patient deaths. These include autopsy studies, case reviews, surveys of patient and physicians, voluntary reporting systems, using standardised patients, second reviews, diagnostic testing audits and closed claims reviews. Although these different approaches provide important information and unique insights regarding diagnostic errors, each has limitations and none is well suited to establishing the incidence of diagnostic error in actual practice, or the aggregate rate of error and harm. We argue that being able to measure the incidence of diagnostic error is essential to enable research studies on diagnostic error, and to initiate quality improvement projects aimed at reducing the risk of error and harm. Three approaches appear most promising in this regard: (1) using 'trigger tools' to identify from electronic health records cases at high risk for diagnostic error; (2) using standardised patients (secret shoppers) to study the rate of error in practice; (3) encouraging both patients and physicians to voluntarily report errors they encounter, and facilitating this process. PMID:23771902

  16. Tobacco use and incidence of tooth loss among US male health professionals.

    PubMed

    Dietrich, T; Maserejian, N N; Joshipura, K J; Krall, E A; Garcia, R I

    2007-04-01

    Data on the dose-dependent effects of smoking and smoking cessation on tooth loss are scarce. We hypothesized that smoking has both dose- and time-dependent effects on tooth loss incidence. We used longitudinal data on tobacco use and incident tooth loss in 43,112 male health professionals, between 1986 and 2002. In multivariate Cox models, current smokers of 5 to 14 and 45+ cigarettes daily had a two-fold (HR, 1.94; 95% CI, 1.72, 2.18) and three-fold (HR, 3.05; 95% CI, 2.38, 3.90) higher risk of tooth loss, respectively, compared with never-smokers. Risk decreased with increasing time since cessation, but remained elevated by 20% (95% CI, 16%, 25%) for men who had quit 10+ years before. Current pipe/cigar smokers had a 20% (95% CI, 1.11, 1.30) increased risk of tooth loss compared with never- and former smokers of pipes/cigars. PMID:17384035

  17. Tobacco use and incidence of tooth loss among US male health professionals

    PubMed Central

    Dietrich, T.; Maserejian, N. N.; Joshipura, K. J.; Krall, E.A.; Garcia, R. I.

    2008-01-01

    Data on the dose dependent effect of smoking and smoking cessation on tooth loss are scarce. We hypothesized that smoking has a dose and time dependent effect on tooth loss incidence. We used longitudinal data on tobacco use and incident tooth loss in 43,112 male health professionals between 1986 and 2002. In multivariate Cox models, current smokers of 5 to 14 and 45+ cigarettes daily had a two-fold (HR: 1.94; 95% CI: 1.72, 2.18) and three-fold (HR: 3.05; 95% CI: 2.38, 3.90) higher risk of tooth loss, respectively, compared to never-smokers. Risk decreased with increasing time since cessation, but remained elevated by 20% (95% CI: 16%, 25%) for men who had quit 10+ years before. Current pipe/cigar smokers had a 20% (95% CI: 1.11, 1.30) increased risk of tooth loss compared to never and former smokers of pipes/cigars. PMID:17384035

  18. Bias-Related Incidents, Hate Crimes, and Conflict Resolution.

    ERIC Educational Resources Information Center

    Prutzman, Priscilla

    1994-01-01

    Examines the role of conflict resolution in addressing bias-related incidents and hate crimes. The author discusses how one organization, Children's Creative Response to Conflict, is working to teach conflict-resolution skills to students and teachers to reduce bias-related violence. Recommendations for the creation of bigotry-free school…

  19. Vaccine Reduces HPV Infections in Young Men

    Cancer.gov

    An international randomized clinical trial has shown that the vaccine Gardasil can reduce the incidence of anogenital human papillomavirus (HPV) infections in young men 16 to 26 years of age at the time of vaccination.

  20. Recall compliance and incidence of dental caries among underserved children.

    PubMed

    Hsu, Ulysses; Hui, Brian K; Pourat, Nadereh

    2015-02-01

    Regular dental recall intervals are widely recommended by dentists in the U.S. to prevent caries and improve periodontal health. However, there is some debate on whether or not compliance with six-month or more frequent recall intervals results in reduced incidence of dental caries. This study examines whether compliance with regular recall and receipt of cleanings, exams and patient education reduces rates of new decay in underserved children and finds a positive impact. PMID:25868221

  1. Incidence and predicting factors of falls of older inpatients

    PubMed Central

    Abreu, Hellen Cristina de Almeida; Reiners, Annelita Almeida Oliveira; Azevedo, Rosemeiry Capriata de Souza; da Silva, Ageo Mário Cândido; Abreu, Débora Regina de Oliveira Moura; de Oliveira, Adriana Delmondes

    2015-01-01

    OBJECTIVE To estimate the incidence and predicting factors associated with falls among older inpatients. METHODS Prospective cohort study conducted in clinical units of three hospitals in Cuiaba, MT, Midwestern Brazil, from March to August 2013. In this study, 221 inpatients aged 60 or over were followed until hospital discharge, death, or fall. The method of incidence density was used to calculate incidence rates. Bivariate analysis was performed by Chi-square test, and multiple analysis was performed by Cox regression. RESULTS The incidence of falls was 12.6 per 1,000 patients/day. Predicting factors for falls during hospitalization were: low educational level (RR = 2.48; 95%CI 1.17;5.25), polypharmacy (RR = 4.42; 95%CI 1.77;11.05), visual impairment (RR = 2.06; 95%CI 1.01;4.23), gait and balance impairment (RR = 2.95; 95%CI 1.22;7.14), urinary incontinence (RR = 5.67; 95%CI 2.58;12.44) and use of laxatives (RR = 4.21; 95%CI 1.15;15.39) and antipsychotics (RR = 4.10; 95%CI 1.38;12.13). CONCLUSIONS The incidence of falls of older inpatients is high. Predicting factors found for falls were low education level, polypharmacy, visual impairment, gait and balance impairment, urinary incontinence and use of laxatives and antipsychotics. Measures to prevent falls in hospitals are needed to reduce the incidence of this event. PMID:26083943

  2. p38 mitogen-activated protein kinase inhibitor reduces neurocan production in cultured spinal cord astrocytes.

    PubMed

    Yamaoka, Gotaro; Morino, Tadao; Morizane, Kei; Horiuchi, Hideki; Miura, Hiromasa; Ogata, Tadanori

    2012-06-20

    Chondroitin sulfate proteoglycans are formed in scar tissue after a spinal cord injury and inhibit axon regrowth. The production of neurocan, one of these chondroitin sulfate proteoglycans, in cultured spinal cord astrocytes increased after the addition of epidermal growth factor (EGF) in a dose-dependent manner (2-200 ng/ml). In astrocytes stimulated by 20 ng/ml of EGF, neurocan production was inhibited after the addition of the p38 mitogen-activated protein kinase (MAPK) inhibitor (SB203580: 3-10 μM) in a dose-dependent manner. These results suggest that the activation of p38 MAPK is one of the mechanisms of neurocan production in EGF-stimulated astrocytes. The p38 MAPK inhibitor may reduce neurocan production and accelerate axonal regrowth after a spinal cord injury. PMID:22525836

  3. Effect of Emergency Argon on FCF Operational Incidents

    SciTech Connect

    Charles Solbrig

    2011-12-01

    The following report presents analyses of operational incidents which are considered in the safety analysis of the FCF argon cell and the effect that the operability of the emergency argon system has on the course of these incidents. The purpose of this study is to determine if the emergency argon system makes a significant difference in ameliorating the course of these incidents. Six incidents were considered. The following three incidents were analyzed. These are: 1. Cooling failing on 2. Vacuum Pump Failing on 3. Argon Supplies Failing on. In the remaining three incidents, the emergency argon supply would have no effect on the course of these transients since it would not come on during these incidents. The transients are 1. Loss of Cooling 2. Loss of power (Differs from above by startup delay till the Diesel Generators come on.) 3. Cell rupture due to an earthquake or other cause. The analyses of the first three incidents are reported on in the next three sections. This report is issued realizing the control parameters used may not be optimum, and additional modeling must be done to model the inertia of refrigeration system, but the major conclusion concerning the need for the emergency argon system is still valid. The timing of some events may change with a more accurate model but the differences between the transients with and without emergency argon will remain the same. Some of the parameters assumed in the analyses are Makeup argon supply, 18 cfm, initiates when pressure is = -6 iwg., shuts off when pressure is = -3.1 iwg. 170,000 ft3 supply. Min 1/7th always available, can be cross connected to HFEF argon supply dewar. Emergency argon supply, 900 cfm, initiates when pressure is = -8 iwg. shuts off when pressure is =-4 iwg. reservoir 220 ft3, refilled when tank farm pressure reduces to 1050 psi which is about 110 ft3.

  4. Concussion Incidence in Professional Football

    PubMed Central

    Nathanson, John T.; Connolly, James G.; Yuk, Frank; Gometz, Alex; Rasouli, Jonathan; Lovell, Mark; Choudhri, Tanvir

    2016-01-01

    Background: In the United States alone, millions of athletes participate in sports with potential for head injury each year. Although poorly understood, possible long-term neurological consequences of repetitive sports-related concussions have received increased recognition and attention in recent years. A better understanding of the risk factors for concussion remains a public health priority. Despite the attention focused on mild traumatic brain injury (mTBI) in football, gaps remain in the understanding of the optimal methodology to determine concussion incidence and position-specific risk factors. Purpose: To calculate the rates of concussion in professional football players using established and novel metrics on a group and position-specific basis. Study Design: Case-control study; Level of evidence, 3. Methods: Athletes from the 2012-2013 and 2013-2014 National Football League (NFL) seasons were included in this analysis of publicly available data. Concussion incidence rates were analyzed using established (athlete exposure [AE], game position [GP]) and novel (position play [PP]) metrics cumulatively, by game unit and position type (offensive skill players and linemen, defensive skill players and linemen), and by position. Results: In 480 games, there were 292 concussions, resulting in 0.61 concussions per game (95% CI, 0.54-0.68), 6.61 concussions per 1000 AEs (95% CI, 5.85-7.37), 1.38 concussions per 100 GPs (95% CI, 1.22-1.54), and 0.17 concussions per 1000 PPs (95% CI, 0.15-0.19). Depending on the method of calculation, the relative order of at-risk positions changed. In addition, using the PP metric, offensive skill players had a significantly greater rate of concussion than offensive linemen, defensive skill players, and defensive linemen (P < .05). Conclusion: For this study period, concussion incidence by position and unit varied depending on which metric was used. Compared with AE and GP, the PP metric found that the relative risk of concussion for

  5. 78 FR 38949 - Computer Security Incident Coordination (CSIC): Providing Timely Cyber Incident Response

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-28

    ... National Institute of Standards and Technology Computer Security Incident Coordination (CSIC): Providing... Technology (NIST) is seeking information relating to Computer Security Incident Coordination (CSIC). NIST is... Computer Security Incident Response Teams (CSIRTs) to coordinate effectively when responding to...

  6. Physical activity and incident diabetes mellitus in postmenopausal women.

    PubMed Central

    Folsom, A R; Kushi, L H; Hong, C P

    2000-01-01

    OBJECTIVES: This study determined whether the incidence of diabetes is reduced among physically active older women. METHODS: We assessed physical activity by mailed questionnaire and 12-year incidence of diabetes (ostensibly type 2 diabetes) in a cohort of 34257 women aged 55 to 69 years. RESULTS: After adjustment for age, education, smoking, alcohol intake, estrogen use, dietary variables, and family history of diabetes, women who reported any physical activity had a relative risk of diabetes of 0.69 (95% confidence interval = 0.63, 0.77) compared with sedentary women. CONCLUSIONS: These findings suggest that physical activity is important for type 2 diabetes prevention among older women. PMID:10630154

  7. Paradoxical effect of radiation on tumor incidence in the rat: implications for radiation therapy

    SciTech Connect

    Hellman, S.; Moloney, W.C.; Meissner, W.A.

    1982-02-01

    The high incidence of leukemia in the Fischer rat is reduced by radiation to an incidence below that seen spontaneously. Fractionating the radiation decreased this effect. In contrast, mammary tumors increased with dose until reaching a plateau at the highest doses. Fractionation had little effect. These results are consistent with a hypothesis suggesting that tumor incidence due to radiation is the result of competing processes of tumor induction and cell killing.

  8. The incidence of acute hospital-treated eye injuries.

    PubMed

    Karlson, T A; Klein, B E

    1986-10-01

    Little information is available on the incidence and severity of eye injuries despite the disfigurement and vision loss they cause. From a population-based study in Dane County, Wisconsin, the incidence of acute hospital-treated eye injuries was 423/100,000 residents in 1979. The most common causes of eye injuries were assaults, work-related events, sports and recreational activities, motor vehicle crashes, and falls. Consumer products were involved in almost 70% (9/13) of severe eye injuries classified as severe. Injuries from fireworks were not found at all in this population. Implementing known strategies for eye injury prevention would substantially reduce their incidence. These include requiring certified eye protectors at workplaces and in sports activities whenever possible rather than making their use voluntary. For the preponderance of eye injuries, however, modifying potentially hazardous consumer products, including the interior of passenger cars, will be necessary. PMID:3767676

  9. Reducing Dropouts.

    ERIC Educational Resources Information Center

    Timpane, Michael; And Others

    A group of three conference papers, all addressing the subject of effective programs to decrease the number of school dropouts, is presented in this document. The first paper, "Systemic Approaches to Reducing Dropouts" (Michael Timpane), asserts that dropping out is a symptom of failures in the social, economic, and educational systems. Dropping…

  10. Age, Race and Regional Disparities in Colorectal Cancer Incidence Rates in Georgia between 2000 and 2012

    PubMed Central

    Yoo, Wonsuk; De, Subhendu; Wilkins, Thad; Smith, Selina A.; Blumenthal, Daniel

    2016-01-01

    Colorectal cancer (CRC) incidence rates and mortality have been decreasing in the United States. Currently, states in the South have the smallest reduction in CRC mortality. The trends of CRC incidence rates in Georgia in comparison to the United States have not been investigated. We analyzed age-adjusted incidence rates of CRC in Georgia and the United States from 2000 to 2012 using data from SEER 18 registries. Age-adjusted incidence rates (95% CI) were calculated as cases per 100,000 to the 2000 US Standard population. CRC incidence rates were calculated for groupings based on age at time of diagnosis, race, sex, and geographic location within Georgia. Incidence rates were higher in males compared to females in Georgia. In Georgians age 50–64, incidence rates were higher compared to the US, while those ages 65+ displayed lower incidence rates. Black Georgians age 50–64 generally exhibited higher incidence rates of CRC and lower rates of decrease in incidence compared to other races in Georgia. Asian/Pacific Islander females age 50–64 in Georgia exhibited an increasing trend in incidence rate. Whites and blacks Georgians age 50–64 displayed higher incidence rates compared to the US, while Asian/Pacific Islanders displayed lower incidence rates. Greater incidence rates of CRC in rural and Greater Georgia were seen across all races when compared to overall rates in Georgia. Efforts should be made to address disparities in Georgia based on race and geographic location. Increased screening by colonoscopy or fecal occult blood testing, reduction of risk factors and promotion of healthy lifestyles can reduce CRC incidence rates. PMID:27042701

  11. Incidence of Pancreatitis in HIV-1–Infected Individuals Enrolled in 20 Adult AIDS Clinical Trials Group Studies

    PubMed Central

    Reisler, Ronald B.; Murphy, Robert L.; Redfield, Robert R.; Parker, Robert A.

    2005-01-01

    Objective To report on the incidence of clinical- and laboratory-defined pancreatitis in HIV-1–infected individuals treated with antiretrovirals (ARVs). Methods Pancreatitis incidence rates were calculated based on a Poisson distribution for subjects enrolled in 1 or more of 20 Adult AIDS Clinical Trials Group studies from October 1989 through July 1999. Results A total of 8451 subjects were enrolled. The overall pancreatitis rates were 0.61 per 100 person-years (PYs) clinical and 2.23 per 100 PYs clinical/laboratory. Pancreatitis rates for single, dual, and triple nucleoside reverse transcriptase inhibitors (NRTIs) were similar. Rates of pancreatitis in didanosine (ddI) arms seemed to be dose dependent. Pancreatitis rates in ddI/hydroxyurea (HU) arms were not significantly different from the rates for ddI alone. Overall pancreatitis rates for ddI/stavudine (d4T) trials were high at 4.16 per 100 PYs clinical and 6.25 per 100 PYs clinical/laboratory. The highest rates were seen with the combination of indinavir (IDV)/ddI/d4Twith or without HU. Conclusions The combination of NRTIs and definition has an impact on the incidence of pancreatitis. Standardization of definition and more comprehensive evaluations are needed to determine how much of this pancreatitis is directly caused by ARVs and how much is attributable to preexisting comorbidities and other known risk factors. PMID:15905731

  12. The Incidence of Abortion in Nigeria

    PubMed Central

    Bankole, Akinrinola; Adewole, Isaac F.; Hussain, Rubina; Awolude, Olutosin; Singh, Susheela; Akinyemi, Joshua O.

    2016-01-01

    CONTEXT Because of Nigeria’s low contraceptive prevalence, a substantial number of women have unintended pregnancies, many of which are resolved through clandestine abortion, despite the country’s restrictive abortion law. Up-to-date estimates of abortion incidence are needed. METHODS A widely used indirect methodology was used to estimate the incidence of abortion and unintended pregnancy in Nigeria in 2012. Data on provision of abortion and postabortion care were collected from a nationally representative sample of 772 health facilities, and estimates of the likelihood that women who have unsafe abortions experience complications and obtain treatment were collected from 194 health care professionals with a broad understanding of the abortion context in Nigeria. RESULTS An estimated 1.25 million induced abortions occurred in Nigeria in 2012, equivalent to a rate of 33 abortions per 1,000 women aged 15–49. The estimated unintended pregnancy rate was 59 per 1,000 women aged 15–49. Fifty-six percent of unintended pregnancies were resolved by abortion. About 212,000 women were treated for complications of unsafe abortion, representing a treatment rate of 5.6 per 1,000 women of reproductive age, and an additional 285,000 experienced serious health consequences but did not receive the treatment they needed. CONCLUSION Levels of unintended pregnancy and unsafe abortion continue to be high in Nigeria. Improvements in access to contraceptive services and in the provision of safe abortion and postabortion care services (as permitted by law) may help reduce maternal morbidity and mortality. PMID:26871725

  13. Sunlight and breast cancer incidence in the USSR.

    PubMed

    Gorham, E D; Garland, F C; Garland, C F

    1990-12-01

    Epidemiological and laboratory evidence suggest that vitamin D may play a role in reducing risk of breast cancer. Lack of exposure to ultraviolet sunlight can increase the prevalence of vitamin D deficiency, and may place some populations at higher risk of breast cancer. The association between total average annual sunlight energy striking the ground and age-adjusted breast cancer incidence rates in the USSR was evaluated. Breast cancer had a threefold range of incidence. Sunlight levels varied from 210 to 400 calories per cm2 per day. A statistically significant negative association was found between breast cancer incidence rates and total sunlight levels (R = -0.75, p = 0.001). The slope of the regression line corresponded to two additional cases per 100,000 per year for each reduction of 35 calories per cm2 of sunlight. The pattern of increased breast cancer incidence in regions of low solar radiation in the USSR is consistent with the geographical pattern seen for breast cancer mortality in the US and worldwide. A positive relationship between socioeconomic status and breast cancer incidence was also present in the Soviet Union, based on an approximate socioeconomic measure, the number of doctors per 1000 population (R = +0.89, p = 0.0001). The possibility that correlates of socioeconomic status, such as dietary, ethnic, or behavioural factors, could account for the association is discussed. PMID:2084008

  14. Why have ovarian cancer mortality rates declined? Part I. Incidence.

    PubMed

    Sopik, Victoria; Iqbal, Javaid; Rosen, Barry; Narod, Steven A

    2015-09-01

    The age-adjusted mortality rate from ovarian cancer in the United States has declined over the past several decades. The decline in mortality might be the consequence of a reduced number of cases (incidence) or a reduction in the proportion of patients who die from their cancer (case-fatality). In part I of this three-part series, we examine rates of ovarian cancer incidence and mortality from the Surveillance Epidemiology and End Results (SEER) registry database and we explore to what extent the observed decline in mortality can be explained by a downward shift in the stage distribution of ovarian cancer (i.e. due to early detection) or by fewer cases of ovarian cancer (i.e. due to a change in risk factors). The proportion of localized ovarian cancers did not increase, suggesting that a stage-shift did not contribute to the decline in mortality. The observed decline in mortality paralleled a decline in incidence. The trends in ovarian cancer incidence coincided with temporal changes in the exposure of women from different birth cohorts to various reproductive risk factors, in particular, to changes in the use of the oral contraceptive pill and to declining parity. Based on recent changes in risk factor propensity, we predict that the trend of the declining age-adjusted incidence rate of ovarian cancer in the United States will reverse and rates will increase in coming years. PMID:26080287

  15. Ground effects on aircraft noise. [near grazing incidence

    NASA Technical Reports Server (NTRS)

    Willshire, W. L., Jr.; Hilton, D. A.

    1979-01-01

    A flight experiment was conducted to investigate air-to-ground propagation of sound near grazing incidence. A turbojet-powered aircraft was flown at low altitudes over the ends of two microphone arrays. An eight-microphone array was positioned along a 1850 m concrete runway. The second array consisted of 12 microphones positioned parallel to the runway over grass. Twenty-eight flights were flown at altitudes ranging from 10 m to 160 m. The acoustic data recorded in the field reduced to one-third-octave band spectra and time correlated with the flight and weather information. A small portion of the data was further reduced to values of ground attenuation as a function of frequency and incidence angle by two different methods. In both methods, the acoustic signals compared originated from identical sources. Attenuation results obtained by using the two methods were in general agreement. The measured ground attenuation was largest in the frequency range of 200 to 400 Hz. A strong dependence was found between ground attenuation and incidence angle with little attenuation measured for angles of incidence greater than 10 to 15 degrees.

  16. Computer Simulation for Emergency Incident Management

    SciTech Connect

    Brown, D L

    2004-12-03

    This report describes the findings and recommendations resulting from the Department of Homeland Security (DHS) Incident Management Simulation Workshop held by the DHS Advanced Scientific Computing Program in May 2004. This workshop brought senior representatives of the emergency response and incident-management communities together with modeling and simulation technologists from Department of Energy laboratories. The workshop provided an opportunity for incident responders to describe the nature and substance of the primary personnel roles in an incident response, to identify current and anticipated roles of modeling and simulation in support of incident response, and to begin a dialog between the incident response and simulation technology communities that will guide and inform planned modeling and simulation development for incident response. This report provides a summary of the discussions at the workshop as well as a summary of simulation capabilities that are relevant to incident-management training, and recommendations for the use of simulation in both incident management and in incident management training, based on the discussions at the workshop. In addition, the report discusses areas where further research and development will be required to support future needs in this area.

  17. Dibutyryl cyclic AMP reduces the radiosensitivity of cultured endothelial cells

    SciTech Connect

    Ward, W.; Molteni, A.; Ts'ao, C.; Hinz, J. )

    1991-03-11

    The purpose of this study was to determine whether dibutyryl cyclic AMP modifies the radiosensitivity of confluent monolayers of bovine aortic endothelial cells (BAEC). Three indices of BAEC function were monitored from 4-24 hrs after exposure to 1-10 Gy of {sup 60}Co gamma rays: the release of {sup 51}Cr from prelabeled cells, and release of lactate dehydrogenase (LDH) and plasminogen activator (PLA) into the culture medium. There was a time- and radiation dose-dependent increase in {sup 51}Cr, LDH and PLA release from the BAEC, detectable within 12 hrs after 5 Gy or higher, and by 24 hrs after 1 Gy or higher. This increased release was accompanied by a radiation dose-dependent decrease in {sup 51}Cr and LDH, and an increase in PLA activity in the lysate of cells adherent to the monolayer at 24 hrs. The continuous presence of cAMP from 1 hr before to 24 hrs after irradiation reduced all of these radiation reactions, although mM concentrations of cAMP were required for significant sparing. The presence of cAMP from 1 hr before to 10 min after irradiation had no effect on BAEC sensitivity, whereas cAMP added 10 min after irradiation was fully as effective as continuously administered drug. Thus, cultured BAEC exhibit membrane dysfunction within 24 hrs after clinically relevant radiation doses, and this dysfunction is ameliorated by cAMP present after irradiation.

  18. Noribogaine reduces nicotine self-administration in rats

    PubMed Central

    Chang, Qing; Hanania, Taleen; Mash, Deborah C

    2015-01-01

    Noribogaine, a polypharmacological drug with activities at opioid receptors, ionotropic nicotinic receptors, and serotonin reuptake transporters, has been investigated for treatment of substance abuse-related disorders. Smoking cessation has major benefits for both individuals and society, therefore the aim of this study was to evaluate the potential of noribogaine for use as a treatment for nicotine dependence. Adult male Sprague-Dawley rats were trained to self-administer nicotine intravenous. After initial food pellet training, followed by 26 sessions of nicotine self-administration training, the rats were administered noribogaine (12.5, 25 or 50 mg/kg orally), noribogaine vehicle, varenicline or saline using a within-subject design with a Latin square test schedule. Noribogaine dose-dependently decreased nicotine self-administration by up to 64% of saline-treated rats’ levels and was equi-effective to 1.7 mg/kg intraperitoneal varenicline. Noribogaine was less efficient at reducing food pellets self-administration than at nicotine self-administration, inhibiting the nondrug reinforcing effects of palatable pellets by 23% at the highest dose. These results suggest that noribogaine dose-dependently attenuates drug-taking behavior for nicotine, attenuates the reinforcing effects of nicotine and is comparable to varenicline power in that regard. The findings from the present study hold promise for a new therapy to aid smoking cessation. PMID:25995321

  19. Noribogaine reduces nicotine self-administration in rats.

    PubMed

    Chang, Qing; Hanania, Taleen; Mash, Deborah C; Maillet, Emeline L

    2015-06-01

    Noribogaine, a polypharmacological drug with activities at opioid receptors, ionotropic nicotinic receptors, and serotonin reuptake transporters, has been investigated for treatment of substance abuse-related disorders. Smoking cessation has major benefits for both individuals and society, therefore the aim of this study was to evaluate the potential of noribogaine for use as a treatment for nicotine dependence. Adult male Sprague-Dawley rats were trained to self-administer nicotine intravenous. After initial food pellet training, followed by 26 sessions of nicotine self-administration training, the rats were administered noribogaine (12.5, 25 or 50 mg/kg orally), noribogaine vehicle, varenicline or saline using a within-subject design with a Latin square test schedule. Noribogaine dose-dependently decreased nicotine self-administration by up to 64% of saline-treated rats' levels and was equi-effective to 1.7 mg/kg intraperitoneal varenicline. Noribogaine was less efficient at reducing food pellets self-administration than at nicotine self-administration, inhibiting the nondrug reinforcing effects of palatable pellets by 23% at the highest dose. These results suggest that noribogaine dose-dependently attenuates drug-taking behavior for nicotine, attenuates the reinforcing effects of nicotine and is comparable to varenicline power in that regard. The findings from the present study hold promise for a new therapy to aid smoking cessation. PMID:25995321

  20. Behavioral Traits and Airport Type Affect Mammal Incidents with U.S. Civil Aircraft

    NASA Astrophysics Data System (ADS)

    Schwarz, Kristin B.; Belant, Jerrold L.; Martin, James A.; DeVault, Travis L.; Wang, Guiming

    2014-10-01

    Wildlife incidents with aircraft cost the United States (U.S.) civil aviation industry >US1.4 billion in estimated damages and loss of revenue from 1990 to 2009. Although terrestrial mammals represented only 2.3 % of wildlife incidents, damage to aircraft occurred in 59 % of mammal incidents. We examined mammal incidents (excluding bats) at all airports in the Federal Aviation Administration (FAA) National Wildlife Strike Database from 1990 to 2010 to characterize these incidents by airport type: Part-139 certified (certificated) and general aviation (GA). We also calculated relative hazard scores for species most frequently involved in incidents. We found certificated airports had more than twice as many incidents as GA airports. Incidents were most frequent in October ( n = 215 of 1,764 total) at certificated airports and November ( n = 111 of 741 total) at GA airports. Most (63.2 %) incidents at all airports ( n = 1,523) occurred at night but the greatest incident rate occurred at dusk (177.3 incidents/hr). More incidents with damage ( n = 1,594) occurred at GA airports (38.6 %) than certificated airports (19.0 %). Artiodactyla (even-toed ungulates) incidents incurred greatest (92.4 %) damage costs ( n = 326; US51.8 million) overall and mule deer ( Odocoileus hemionus) was the most hazardous species. Overall, relative hazard score increased with increasing log body mass. Frequency of incidents was influenced by species relative seasonal abundance and behavior. We recommend airport wildlife officials evaluate the risks mammal species pose to aircraft based on the hazard information we provide and consider prioritizing management strategies that emphasize reducing their occurrence on airport property.

  1. Behavioral traits and airport type affect mammal incidents with U.S. civil aircraft.

    PubMed

    Schwarz, Kristin B; Belant, Jerrold L; Martin, James A; DeVault, Travis L; Wang, Guiming

    2014-10-01

    Wildlife incidents with aircraft cost the United States (U.S.) civil aviation industry >US$1.4 billion in estimated damages and loss of revenue from 1990 to 2009. Although terrestrial mammals represented only 2.3 % of wildlife incidents, damage to aircraft occurred in 59 % of mammal incidents. We examined mammal incidents (excluding bats) at all airports in the Federal Aviation Administration (FAA) National Wildlife Strike Database from 1990 to 2010 to characterize these incidents by airport type: Part-139 certified (certificated) and general aviation (GA). We also calculated relative hazard scores for species most frequently involved in incidents. We found certificated airports had more than twice as many incidents as GA airports. Incidents were most frequent in October (n = 215 of 1,764 total) at certificated airports and November (n = 111 of 741 total) at GA airports. Most (63.2 %) incidents at all airports (n = 1,523) occurred at night but the greatest incident rate occurred at dusk (177.3 incidents/hr). More incidents with damage (n = 1,594) occurred at GA airports (38.6 %) than certificated airports (19.0 %). Artiodactyla (even-toed ungulates) incidents incurred greatest (92.4 %) damage costs (n = 326; US$51.8 million) overall and mule deer (Odocoileus hemionus) was the most hazardous species. Overall, relative hazard score increased with increasing log body mass. Frequency of incidents was influenced by species relative seasonal abundance and behavior. We recommend airport wildlife officials evaluate the risks mammal species pose to aircraft based on the hazard information we provide and consider prioritizing management strategies that emphasize reducing their occurrence on airport property. PMID:25082299

  2. Review of hydrogen accidents and incidents in NASA operations

    NASA Technical Reports Server (NTRS)

    Ordin, P. M.

    1974-01-01

    A number of the accidents/incidents with hydrogen in NASA operations are reviewed. The cause factors for the mishaps are reviewed and show that although few accidents occurred, the number could have been further reduced if the established NASA rules and regulations had been followed. Requirements for effective safety codes and areas of study for hydrogen safety information are included. The report concludes with a compilation of 96 hydrogen mishaps; a description of the accidents and their causes.

  3. Relationships between disease incidence at two levels in a spatial hierarchy.

    PubMed

    Hughes, G; McRoberts, N; Madden, L V; Gottwald, T R

    1997-05-01

    ABSTRACT Relationships between disease incidence measured at two levels in a spatial hierarchy are derived. These relationships are based on the properties of the binomial distribution, the beta-binomial distribution, and an empirical power-law relationship that relates observed variance to theoretical binomial variance of disease incidence. Data sets for demonstrating and testing these relationships are based on observations of the incidence of grape downy mildew, citrus tristeza, and citrus scab. Disease incidence at the higher of the two scales is shown to be an asymptotic function of incidence at the lower scale, the degree of aggregation at that scale, and the size of the sampling unit. For a random pattern, the relationship between incidence measured at two spatial scales does not depend on any unknown parameters. In that case, an equation for estimating an approximate variance of disease incidence at the lower of the two scales from incidence measurements made at the higher scale is derived for use in the context of sampling. It is further shown that the effect of aggregation of incidence at the lower of the two scales is to reduce the rate of increase of disease incidence at the higher scale. PMID:18945110

  4. Selection of broiler chickens for a high and low incidence of tibial dys