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Sample records for dose-dependently reduce incidence

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

    PubMed

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

    2015-03-13

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

  2. Dietary trans-10,cis-12 CLA reduces murine collagen-induced arthritis in a dose-dependent manner.

    PubMed

    Huebner, Shane M; Olson, Jake M; Campbell, James P; Bishop, Jeffrey W; Crump, Peter M; Cook, Mark E

    2014-02-01

    Dietary trans-10,cis-12 (t10c12) conjugated linoleic acid (CLA) has been shown to reduce inflammation in a murine collagen-induced arthritis (CA) model. To understand the anti-inflammatory potential of t10c12-CLA in the diet, the minimum dose of pure dietary t10c12-CLA capable of reducing CA was investigated. Because plasma inflammatory cytokines often do not reflect the progression of late-stage arthritis, inflamed tissue cytokine concentrations were also investigated in relation to increasing dietary t10c12-CLA amounts. Mice were randomly assigned to the following dietary treatments upon the establishment of arthritis: corn oil (CO) or 0.125%, 0.25%, 0.375%, or 0.5% t10c12-CLA (wt:wt) for 84 d. Sham mice (no arthritis) were fed CO and served as controls. Arthritic paw score, based on subjective assessment of arthritic severity, and paw thickness decreased linearly overall [16-65% (P < 0.001) and 0.5-12% (P < 0.001), respectively] as dietary t10c12-CLA increased (P < 0.001, R(2) < 0.81). Increasing dietary t10c12-CLA was associated with a decrease in plasma interleukin (IL)-1β at days 21 and 42 compared with CO-fed arthritic mice, such that mice fed ≥0.25% t10c12-CLA had IL-1β concentrations that were similar to sham mice. Plasma cytokines returned to sham mice concentrations by day 63 regardless of treatment; however, an arthritis-induced elevation in paw IL-1β decreased linearly as dietary t10c12-CLA concentrations increased at day 84 (P = 0.007, R(2) = 0.92). Similarly, increasing dietary t10c12-CLA linearly decreased paw tumor necrosis factor (TNF)-α (P = 0.05, R(2) = 0.70). In conclusion, ≥0.125% t10c12-CLA dose-dependently reduced inflammation in a murine CA model.

  3. Ventricular arrhythmia incidence in the rat is reduced by naloxone.

    PubMed

    Pugsley, M K; Hayes, E S; Wang, W Q; Walker, M J A

    2015-07-01

    This study characterized the antiarrhythmic effects of the opioid receptor antagonist naloxone in rats subject to electrically induced and ischemic arrhythmias. Naloxone (2, 8 and 32 μmol/kg/min) was examined on heart rate, blood pressure, and the electrocardiogram (EKG) as well as for effectiveness against arrhythmias produced by occlusion of the left anterior descending coronary artery or electrical stimulation of the left ventricle. Naloxone reduced blood pressure at the highest dose tested while heart rate was dose-dependently reduced. Naloxone dose-dependently prolonged the P-R and QRS intervals and increased the RSh amplitude indicative of effects on cardiac sodium (Na) channels. Naloxone prolonged the Q-T interval suggesting a delay in repolarization. Naloxone effects were comparable to the comparator quinidine. Naloxone (32 μmol/kg/min) reduced ventricular fibrillation (VF) incidence to 38% (from 100% in controls). This same dose significantly increased the threshold for induction of ventricular fibrillation (VFt), prolonged the effective refractory period (ERP) and reduced the maximal following frequency (MFF). The patterns of ECG changes, reduction in ischemic arrhythmia (VF) incidence and changes in electrically induced arrhythmia parameters at high doses of naloxone suggest that it directly blocks cardiac Na and potassium (K) ion channels.

  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.

  6. Reducing Incidents of Cheating in Adolescence.

    ERIC Educational Resources Information Center

    Bopp, Mary; Gleason, Patricia; Misicka, Stacey

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

  7. 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 ...

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

    PubMed

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

    2016-03-01

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

  9. Influenza vaccine oculorespiratory syndrome incidence is reduced in HIV.

    PubMed

    Cooper, Curtis; Thorne, Anona

    2011-10-19

    Clinical experience suggests Oculorespiratory Syndrome (ORS) following influenza vaccination is rare in HIV but this is not well evaluated. We assessed ORS incidence in a randomized influenza vaccine trial of HIV participants. The overall incidence was 0.8% suggesting that influenza vaccine ORS incidence is reduced in HIV.

  10. DNA vaccines expressing the duck hepatitis B virus surface proteins lead to reduced numbers of infected hepatocytes and protect ducks against the development of chronic infection in a virus dose-dependent manner.

    PubMed

    Miller, Darren S; Kotlarski, Ieva; Jilbert, Allison R

    2006-07-20

    We tested the efficacy of DNA vaccines expressing the duck hepatitis B virus (DHBV) pre-surface (pre-S/S) and surface (S) proteins in modifying the outcome of infection in 14-day-old ducks. In two experiments, Pekin Aylesbury ducks were vaccinated on days 4 and 14 of age with plasmid DNA vaccines expressing either the DHBV pre-S/S or S proteins, or the control plasmid vector, pcDNA1.1Amp. All ducks were then challenged intravenously on day 14 of age with 5 x 10(7) or 5 x 10(8) DHBV genomes. Levels of initial DHBV infection were assessed using liver biopsy tissue collected at day 4 post-challenge (p.c.) followed and immunostained for DHBV surface antigen to determine the percentage of infected hepatocytes. All vector vaccinated ducks challenged with 5 x 10(7) and 5 x 10(8) DHBV genomes had an average of 3.21% and 20.1% of DHBV-positive hepatocytes respectively at day 4 p.c. and 16 out of 16 ducks developed chronic DHBV infection. In contrast, pre-S/S and S vaccinated ducks challenged with 5 x 10(7) DHBV genomes had reduced levels of initial infection with an average of 1.38% and 1.93% of DHBV-positive hepatocytes at day 4 p.c. respectively and 10 of 18 ducks were protected against chronic infection. The pre-S/S and the S DNA vaccinated ducks challenged with 5 x 10(8) DHBV genomes had an average of 31.5% and 9.2% of DHBV-positive hepatocytes on day 4 p.c. respectively and only 4 of the 18 vaccinated ducks were protected against chronic infection. There was no statistically significant difference in the efficacy of the DHBV pre-S/S or S DNA vaccines. In conclusion, vaccination of young ducks with DNA vaccines expressing the DHBV pre-S/S and S proteins induced rapid immune responses that reduced the extent of initial DHBV infection in the liver and prevented the development of chronic infection in a virus dose-dependent manner.

  11. Verapamil reduces incidence of reentry during ventricular fibrillation in pigs.

    PubMed

    Jin, Qi; Dosdall, Derek J; Li, Li; Rogers, Jack M; Ideker, Raymond E; Huang, Jian

    2014-11-01

    The characteristics of reentrant circuits during short duration ventricular fibrillation (SDVF; 20 s in duration) and the role of Ca(++) and rapid-activating delayed rectifier potassium currents during long duration ventricular fibrillation (LDVF; up to 10 min in duration) were investigated using verapamil and sotalol. Activation mapping of the LV epicardium with a 21 × 24 electrode plaque was performed in 12 open-chest pigs. Pigs were given either verapamil (0.136 mg/kg) or sotalol (1.5 mg/kg) and verapamil. Reentry patterns were quantified for SDVF, and, for LDVF, activation patterns were compared with our previously reported control LDVF data. Verapamil significantly increased conduction velocity around the reentrant core by 10% and reduced the reentrant cycle length by 15%, with a net reduction in reentry incidence of 70%. Sotolol had an opposite effect of decreasing the conduction velocity around the core by 6% but increasing the reentrant cycle length by 13%, with a net reduction of reentry incidence of 50%. After 200 s of VF, verapamil significantly slowed wavefront conduction velocity and activation rate compared with control data. Verapamil decreased the incidence of reentry in SDVF by accelerating conduction velocity to increase the likelihood of conduction block, possibly through increased sympathetic tone. The drug slowed activation rate and conduction velocity after 200 s of VF, suggesting that L-type Ca(++) channels remain active and may be important in the maintenance of LDVF. Sotalol in addition to verapamil caused no additional antiarrhythmic effect.

  12. 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

  13. Colchicine Significantly Reduces Incident Cancer in Gout Male Patients

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

    Wu, Szu-Yuan

    2016-01-01

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

  15. 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. Dose-dependent protective effect of baicalin against testicular torsion-detorsion in rats.

    PubMed

    Fouad, A A; Qutub, H O; Jresat, I

    2017-02-01

    Testicular torsion/detorsion induces oxidative/nitrosative stress, inflammation and apoptosis of testicular tissues. Baicalin exerts antioxidant and anti-inflammatory properties. This study investigated the possible protective effect of baicalin against testicular torsion-detorsion injury in rats. Surgical testicular torsion was induced for 2 h, followed by detorsion which was continued for 24 h. Baicalin was administered in three different doses (25, 50 and 100 mg kg(-1) , by intraperitoneal injection). Each dose was given twice, the first 30 min before and the second 12 h after testicular detorsion. Baicalin, in a dose-dependent manner, decreased the torsion/detorsion-induced elevations of testicular malondialdehyde, nitric oxide, tumour necrosis factor-α, BCL2-associated X protein (Bax), cytosolic cytochrome c and caspase-3 and caspase-9 activities. Baicalin, dose dependently, attenuated the reductions of B-cell leucemia/lymphoma 2 (Bcl-2), and glutathione peroxidase and superoxide dismutase activities in testicular tissues resulted from torsion/detorsion. In addition, baicalin ameliorated the histopathological testicular tissue damage and reduced the expression of Fas ligand in rat testes exposed to torsion/detorsion in a dose-dependent manner. It was concluded that baicalin, dose dependently, ameliorated testicular injury induced by torsion/detorsion via its antioxidant, antinitrosative, anti-inflammatory and anti-apoptotic effects.

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

    PubMed

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

    2013-08-01

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

  18. Dose-dependent protective effect of breast-feeding against breast cancer among ever-lactated women in Korea.

    PubMed

    Kim, Yeonju; Choi, Ji-Yeob; Lee, Kyoung-Mu; Park, Sue Kyung; Ahn, Sei-Hyun; Noh, Dong-Young; Hong, Yun-Chul; Kang, Daehee; Yoo, Keun-Young

    2007-04-01

    Lactation might have a crucial role in an extraordinary increase in breast cancer incidence in Korea, as the proportion of mothers who practised breast-feeding fell dramatically. This hospital-based case-control analysis has been carried out since 1997 to evaluate whether lactation is associated with breast cancer risk in Korean women. Among the eligible study participants, a total of 753 histologically confirmed incident cases and an equal number of controls were included in the analysis. The risk was estimated using unconditional logistic regression models. Family history, older at menopause, more full-term pregnancies increased the risk of breast cancer. Breast cancer risk decreased according to the total months of breast-feeding (P for trend=0.03). Average duration of breast-feeding of 11-12 months reduced risk of breast cancer by 54% compared with the duration of 1-4 months (odds ratio, 0.46; 95% confidence interval, 0.30-0.70). The decreasing risk trend according to average months of breast-feeding was also statistically significant (P for trend=0.02). Moreover, a reduced risk of breast cancer was apparent when analysis was restricted to the first breast-fed child (P for trend=0.006). This study confirms that lactation has an apparent dose-dependent protective effect against breast cancer in Korean women.

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

    ERIC Educational Resources Information Center

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

    2015-01-01

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

  20. Evaluation of a patient education tool to reduce the incidence of incontinence post-prostate surgery.

    PubMed

    Ip, Virginia

    2004-10-01

    A pelvic floor muscle exercise program can reduce the incidence of incontinence post-prostate surgery. The purpose of this study was to validate a new education tool, a refrigerator magnet, in comparison to a paper copy with the same information, to determine if patient compliance with the exercises increased.

  1. 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.

  2. Exercise is associated with a reduced incidence of sleep-disordered breathing

    PubMed Central

    Awad, Karim M.; Malhotra, Atul; Barnet, Jodi H; Quan, Stuart F.; Peppard, Paul E

    2012-01-01

    Background The effect of exercise on sleep-disordered breathing is unknown. While diet and weight loss have been shown to reduce the severity of sleep-disordered breathing, it is unclear whether exercise has an independent effect. Methods A population-based longitudinal epidemiologic study of adults measured the association between exercise and incidence and severity of sleep-disordered breathing. Hours of weekly exercise were assessed by two mailed surveys (1988 and 2000). Sleep-disordered breathing was assessed by 18-channel in-laboratory polysomnography at baseline and at follow up. Results Associations were modeled using linear and logistic regression, adjusting for body mass index, age, sex, and other covariates. Hours of exercise were associated with reduced incidence of mild (Odds Ratio = 0.76, p= 0.011) and moderate (Odds Ratio = 0.67, p= 0.002) sleep-disordered breathing. Also a decrease in exercise duration was associated with worsening sleep-disordered breathing, as measured by the apnea-hypopnea index, AHI (ß = 2.368, p= 0.048). Adjustment for body mass index attenuated these effects. Conclusions Exercise is associated with a reduced incidence of mild and moderate sleep-disordered breathing and decreasing exercise is associated with worsening of sleep-disordered breathing. The effect of exercise on sleep-disordered breathing appears to be largely, but perhaps not entirely, mediated by changes in body habitus. PMID:22482846

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

    PubMed

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

    2014-09-01

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

  4. Antipsychotic drugs dose-dependently suppress the spontaneous hyperactivity of the chakragati mouse.

    PubMed

    Dawe, G S; Nagarajah, R; Albert, R; Casey, D E; Gross, K W; Ratty, A K

    2010-11-24

    The chakragati (ckr) mouse has been proposed as a model of aspects of schizophrenia. The mice, created serendipitously as a result of a transgenic insertional mutation, exhibit spontaneous circling, hyperactivity, hypertone of the dopamine system, reduced social interactions, enlarged lateral ventricles, deficits in pre-pulse inhibition of acoustic startle and deficits in latent inhibition of conditioned learning. In this study, the dose-dependent effects of antipsychotic drugs (haloperidol, pimozide, risperidone, clozapine, olanzapine, ziprasidone, quetiapine and aripiprazole) on the spontaneous hyperactivity of the mice were investigated. All the antipsychotic drugs tested dose-dependently suppressed spontaneous hyperactivity. Aripriprazole, which is known to be a dopamine D2 receptor partial agonist, exhibited a tri-phasic dose-response, initially suppressing hyperactivity at low doses, having little effect on hyperactivity at intermediate doses, and suppressing activity again at high doses. These data suggest that the spontaneous circling and hyperactivity of the ckr mouse may allow screening of candidate antipsychotic compounds, distinguishing compounds with aripriprazole-like profiles.

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

    PubMed

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

    2011-06-01

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

  6. History of allergy and reduced incidence of colorectal cancer, Iowa Women's Health Study.

    PubMed

    Prizment, Anna E; Folsom, Aaron R; Cerhan, James R; Flood, Andrew; Ross, Julie A; Anderson, Kristin E

    2007-11-01

    Previous epidemiologic studies have reported that a history of allergy is associated with reduced risk of colorectal cancer and other malignancies. We studied the association between allergy history and incident colorectal cancer (n=410) prospectively in 21,292 Iowa women followed for 8 years. Allergy was defined from four self-reported questions about physician-diagnosed asthma (a), hay fever (b), eczema or allergy of the skin (c), and other allergic conditions (d). A history of any allergy was inversely associated with incident colorectal cancer: after multivariate adjustment, the hazard ratio (HR) was 0.74 [95% confidence interval (95% CI), 0.59-0.94]. Compared with women with no allergy, women reporting only one of the four types of allergy and women reporting two or more types had HRs of 0.75 (95% CI, 0.56-1.01) and 0.58 (95% CI, 0.37-0.90), respectively (P trend=0.02). The inverse association persisted in analyses restricted to any type of nonasthmatic allergy (HR, 0.73; 95% CI, 0.56-0.95). HRs were similar for rectal and colon cancers as well as for colon subsites: proximal and distal (HRs for any allergy ranged from 0.63 to 0.78 across these end points). Allergy history, which may reflect enhanced immunosurveillance, is associated with a reduced risk of colorectal cancer.

  7. Manipulating dietary anions and cations for prepartum dairy cows to reduce incidence of milk fever.

    PubMed

    Block, E

    1984-12-01

    Twenty preparturient dairy cows were in a 2-yr switchover design to test effects of dietary ions on incidence of milk fever. In yr 1, cows were blocked and assigned randomly 45 days prepartum to one of two diets; one diet contained an excess of anions, and the second diet contained an excess of cations. In yr 2, cows were changed to the opposite diet. Both diets were equivalent for crude protein (11%), calcium (.65%), phosphorus (.25%), and energy on a dry basis but differed for quantities of chlorine, sulfur, and sodium. Both diets were chopped alfalfa hay, corn silage, high moisture corn, and vitamin-mineral mix. Diets were available ad libitum as complete rations. There were no differences in dry matter intake of the diets. Cows consuming the anionic diet had no milk fever, but cows consuming the canionic diet had 47.4% incidence. Samples of blood plasma showed that cows consuming the anionic diet maintained calcium and phosphorus through parturition, whereas cows consuming the cationic diet decreased in these minerals around calving. Hydroxyproline was higher for cows consuming the anionic diet during the peripartal period compared to cows consuming the cationic diet. Milk produced in the lactation subsequent to prepartum treatment was 6.8% less for cows offered the cationic diet. When milk production of paretic and nonparetic cows offered the cationic diet was compared, milk was reduced 14% with milk fever.

  8. 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.

  9. Incidence and Risk Factors for and the Effect of a Program To Reduce the Incidence of Surgical Site Infection after Cardiac Surgery

    PubMed Central

    Cohen, Bevin; Hyman, Sandra; Larson, Elaine; Fowler, Dennis L.

    2014-01-01

    Abstract Background: Surgical site infection (SSI) after cardiac surgery (CS) is a serious complication that increases hospital length of stay (LOS), has a substantial financial impact, and increases mortality. The study described here was done to evaluate the effect of a program to reduce SSI after CS. Methods: In January 2007, a multi-disciplinary CS infection-prevention team developed guidelines and implemented bundled tactics for reducing SSI. Data for all patients who underwent CS from 2006–2008 were used to determine whether there was: 1) A difference in the incidence of SSI in white patients and those belonging to minority groups; 2) a reduction in SSI after intervention; and 3) a statistically significant difference in the incidence of SSI in the third quarter of each year as compared with the other quarters of the year. Results: Of 3,418 patients who underwent CS; 1,125 (32.9%) were members of minority groups and 2,293 (67.1%) were white. Eighty (2.3%) patients developed SSI. There was no significant difference in the incidence of SSI in non-Hispanic white patients and all others (2.1% vs. 2.8%, p=0. 42). The incidence of SSI decreased significantly from 2006 (3.0%) to 2007 (2.5%) and 2008 (1.4%), (p=0.03). Surgical site infection occurred more often in the third quarter of each of the years of the study than in other quarters of each year (3.3 vs. 2.0%, p=0.038). Conclusions: Implementation of a program to reduce SSI after CS was associated with a lower incidence of SSI across all racial and ethnic groups and over time, but was not associated with a lower incidence of SSI in the third quarter of each year than in the other quarters. PMID:24800982

  10. Dose-dependent adverse effects of salinomycin on male reproductive organs and fertility in mice.

    PubMed

    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

  11. 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

  12. Use of aqueous foam to reduce radioactive material dispersal in sabotage incidents

    SciTech Connect

    Hartman, W.F.

    1986-01-01

    One potential type of sabotage incident in a nuclear facility involves the use of a large quantity of high explosive to disperse radioactive material into the atmosphere. This paper discusses the possible use of aqueous foam to reduce the consequences of such an event under the assumption that the location of the explosive is known and that some minimal time is available to emplace a mitigation system. Work conducted over the past several years has shown that low expansion ratio aqueous foams (e.g., 60 parts of air to one part water-soap concentrate solution by volume) exhibit exemplary properties in reducing the effects of a detonation. Not only does the foam significantly reduce the release of fine particulate which attempt to pass through it, but it also exhibits unusual pressure attentuation properties. Data demonstrating both the particle capture and pressure attenuation properties are presented along with information relative to generation of foam and some of the logistical constraints involved in its use.

  13. The use of aqueous foam to reduce radioactive material dispersal in sabotage incidents

    SciTech Connect

    Hartman, W.F.

    1986-01-01

    One potential type of sabotage incident in a nuclear facility involves the use of a large quantity of high explosive to disperse radioactive material into the atmosphere. This paper discusses the possible use of aqueous foam to reduce the consequences of such an event under the assumption that the location of the explosive is known and that some minimal time is available to emplace a mitigation system. Work conducted over the past several years has shown that low expansion ratio aqueous foams (e.g., 60 parts of air to one part water-soap concentrate solution by volume) exhibit exemplary properties in reducing the effects of a detonation. Not only does the foam significantly reduce the release of fine particulate which attempt to pass through it, but it also exhibits unusual pressure attenuation properties. Data demonstrating both the particle capture and pressure attenuation properties are presented along with information relative to generation of foam and some of the logistical constraints involved in its use.

  14. Dose-dependent protection by azelastine eye drops against pollen-induced allergic conjunctivitis. A double-blind, placebo-controlled study.

    PubMed

    Horak, F; Berger, U E; Menapace, R; Toth, J; Stübner, P U; Marks, B

    1998-04-01

    The efficacy and tolerability of azelastine (CAS 58581-89-8) eye drops at three different doses (0.025%, 0.05% and 0.1%) were investigated in a double-blind, randomized, placebo-controlled, crossover study in 24 subjects with a history of allergic conjunctivitis/rhinoconjunctivitis, who were challenged, out of season, by airbone allergen in the "Vienna Challenge Chamber" (VCC). Subjects received a single dose of azelastine eye drops 60 min before the start of a 4 h challenge in the VCC. Additional local challenge, mimicking a gust of wind, was administered 15 min before the end of the session. Each of the 4 study days was separated by a 2 week washout period. Azelastine eye drops showed a dose-dependent inhibition of the development of itching of the eyes. The effect was most pronounced 15 min after the additional local challenge. A maximal effect was achieved at a dose of 0.05%. Similar effects were observed on lacrimation. Azelastine eye drops also dose-dependently inhibited the degree of conjunctival redness, measured by digital imaging, and tended to reduce the low incidence of chemosis observed. Ranking of the results of all symptoms for each treatment group confirmed the optimal effect at a dose of 0.05%. Azelastine eye drops had no effect on nasal and bronchial symptoms or on measurements of airways function (FEV1). No adverse effects of the treatments were reported. The data support the use of 0.05% azelastine eye drops in the treatment of allergic conjunctivitis/rhinoconjunctivitis.

  15. 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

  16. 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

  17. Modifying Post-Operative Medical Care after EBV Implant May Reduce Pneumothorax Incidence

    PubMed Central

    Herzog, Dominik; Poellinger, Alexander; Doellinger, Felix; Schuermann, Dirk; Temmesfeld-Wollbrueck, Bettina; Froeling, Vera; Schreiter, Nils F.; Neumann, Konrad; Hippenstiel, Stefan; Suttorp, Norbert; Hubner, Ralf-Harto

    2015-01-01

    Objective Endoscopic lung volume reduction (ELVR) with valves has been shown to improve COPD patients with severe emphysema. However, a major complication is pneumothoraces, occurring typically soon after valve implantation, with severe consequences if not managed promptly. Based on the knowledge that strain activity is related to a higher risk of pneumothoraces, we asked whether modifying post-operative medical care with the inclusion of strict short-term limitation of strain activity is associated with a lower incidence of pneumothorax. Methods Seventy-two (72) emphysematous patients without collateral ventilation were treated with bronchial valves and included in the study. Thirty-two (32) patients received standard post-implantation medical management (Standard Medical Care (SMC)), and 40 patients received a modified medical care that included an additional bed rest for 48 hours and cough suppression, as needed (Modified Medical Care (MMC)). Results The baseline characteristics were similar for the two groups, except there were more males in the SMC cohort. Overall, ten pneumothoraces occurred up to four days after ELVR, eight pneumothoraces in the SMC, and only two in the MMC cohorts (p=0.02). Complicated pneumothoraces and pneumothoraces after upper lobe treatment were significantly lower in MMC (p=0.02). Major clinical outcomes showed no significant differences between the two cohorts. Conclusions In conclusion, modifying post-operative medical care to include bed rest for 48 hours after ELVR and cough suppression, if needed, might reduce the incidence of pneumothoraces. Prospective randomized studies with larger numbers of well-matched patients are needed to confirm the data. PMID:26010886

  18. Dose-dependent teratogenicity of the synthetic cannabinoid CP-55,940 in mice.

    PubMed

    Gilbert, Marcoita T; Sulik, Kathleen K; Fish, Eric W; Baker, Lorinda K; Dehart, Deborah B; Parnell, Scott E

    Potent synthetic cannabinoids (SCBs) are illegally distributed drugs of abuse that are frequently consumed in spite of their adverse consequences. This study was designed to determine if the toxicity observed in adults also extends to the prenatal period by examining the developmental toxicity/teratogenicity of one of these SCBs, CP-55,940, in a mammalian model. First, immunohistochemistry was employed for cannabinoid receptor 1 (CB1) localization within gestational day (GD) 8 mouse embryos; this receptor was identified in the cranial neural plate, suggesting that the endogenous cannabinoid system may be involved in normal development. Based on this information and on previous avian teratogenicity studies, the current investigation focused on cannabinoid exposure during neurulation. The treatment paradigm involved acute i.p. administration of vehicle, 0.0625, 0.125, 0.25, 0.5, 1.0, or 2.0mg/kg CP-55,940 to time-mated C57Bl/6J mice on their 8th day of pregnancy (n>10 litters per treatment group). On GD 17, litters were harvested and examined for numbers of live, dead, or resorbed fetuses, as well as for fetal weight, length, and gross morphological abnormalities. No effect on litter size, fetal weight, or crown rump length was seen at any of the CP-55,940 dosages tested. Major malformations involving the craniofacies and/or eyes were noted in all drug-treated groups. Selected fetuses with craniofacial malformations were histologically sectioned and stained, allowing investigation of brain anomalies. Observed craniofacial, ocular, and brain abnormalities in drug-treated fetuses included lateral and median facial clefts, cleft palate, microphthalmia, iridial coloboma, anophthalmia, exencephaly, holoprosencephaly, and cortical dysplasia. With the most commonly observed defects involving the eyes, the incidence and severity of readily identifiable ocular malformations were utilized as a basis for dose-response analyses. Ocular malformation ratings revealed dose-dependent

  19. Dose-dependent effects of D-methionine for rescuing noise-induced permanent threshold shift in guinea-pigs.

    PubMed

    Lo, W-C; Liao, L-J; Wang, C-T; Young, Y-H; Chang, Y-L; Cheng, P-W

    2013-12-19

    The purpose of this study was to examine the dose-response effectiveness of d-methionine (d-met) in rescuing a noise-induced permanent threshold shift (PTS) and cochlear biochemistry following noise exposure. One hour after being exposed to continuous broadband white noise at 105dB sound pressure level (SPL) for 6h, guinea-pigs were treated five times at 12-h intervals with 200, 400, or 600mg/kg d-met or sterile 0.9% saline (each group, N=6) by intraperitoneal injection. Six guinea-pigs with normal hearing that were not exposed to noise served as control animals. Although administration of d-met 200mg/kg did not significantly reduce the mean PTS, treatment with d-met 600mg/kg achieved a complete rescue response. The level of rescue from noise-induced PTS following treatment with 200, 400, or 600mg/kg d-met was dose dependent. The attenuation of the noise-induced decreases in the activities of the Na(+), K(+)-ATPase and Ca(2+)-ATPase following treatment with 200, 400, or 600mg/kg d-met was also dose dependent. Likewise, d-met-dose-dependent decreases in mean lipid peroxidation and nitric oxide levels were observed in the d-met treated groups. Significant attenuation of increased oxidative stress and decreased ATPase activities was concurrent with the d-met-mediated improvements in noise-induced auditory dysfunction.

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

    PubMed

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

    2006-01-01

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

  1. Use of indocyanine green videoangiography during intracranial aneurysm surgery reduces the incidence of postoperative ischaemic complications.

    PubMed

    Lai, Leon Tat; Morgan, Michael Kerin

    2014-01-01

    Microscope-integrated near-infrared indocyanine green videoangiography (ICGVA) has been shown to be a useful adjunct for intracranial aneurysm surgery. That the routine application of this technique reduces the risk of postoperative ischaemic complication, however, has not been reported. We present a retrospective matched-pair comparison of ICGVA guided aneurysm surgery versus historic control surgical cohort treated by the same author. Index patients and controls were matched for aneurysm size, location, patient demographics, risk factors, comorbidities, and surgical treatments. Ninety-one eligible patients with 100 intracranial aneurysms were treated using ICGVA assistance. There were no statistically significant differences between the two groups in terms of patient age, sex, risk factors, comorbidities and aneurysm characteristics. Of the 100 aneurysms in the ICGVA group, 107 investigations of ICGVA were performed. In 79 aneurysms (79.0%), ICGVA was considered useful but did not affect surgical management. In six patients (6.0%), ICGVA led to a crucial change of intraoperative strategies. In nine patients (9.0%), it was considered critical in assuring patency of small perforators. ICGVA was of no benefit in four patients (4.0%) and was misleading in two (2.0%). Postoperative ischaemic complications occurred in three patients (3.3%) in the ICGVA group compared with seven patients (7.7%) in the control group (p<0.001). Our study supports the use of ICGVA in aneurysm surgery as a safe and effective modality of intraoperative blood flow assessment. With all limitations of a retrospective matched-pair comparison, the use of ICGVA during routine aneurysm surgery reduces the incidence of postoperative ischaemic complications.

  2. 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

  3. Fatiguing exercise initiated later in life reduces incidence of fibrillation and improves sleep quality in Drosophila.

    PubMed

    Zheng, Lan; Feng, Yue; Wen, Deng Tai; Wang, Hui; Wu, Xiu Shan

    2015-08-01

    As the human body ages, the risk of heart disease and stroke greatly increases. While there is evidence that lifelong exercise is beneficial to the heart's health, the effects of beginning exercise later in life remain unclear. This study aimed to investigate whether exercise training started later in life is beneficial to cardiac aging in Drosophila. We examined 4-week-old wild-type virgin female flies that were exposed to exercise periods of either 1.5, 2.0, or 2.5 h per day, 5 days a week for 2 weeks. Using M-mode traces to analyze cardiac function by looking at parameters including heart rate, rhythmicity, systolic and diastolic diameter, and interval and fractional shortening, we found that cardiac function declined with age, shown by an increase in the number of fibrillation events and a decrease in fractional shortening. About 2.0 and 2.5 h of exercise per day displayed a reduced incidence of fibrillation events, and only physical exercise lasting 2.5-h period increased fractional shortening and total sleep time in Drosophila. These data suggested that training exercise needs to be performed for longer duration to exert physiological benefits for the aging heart. Additionally, climbing ability to assess the exercise-induced muscle fatigue was also measured. We found that 2.0 and 2.5 h of exercise caused exercise-induced fatigue, and fatiguing exercise is beneficial for cardiac and healthy aging overall. This study provides a basis for further study in humans on the impact of beginning an exercise regimen later in life on cardiac health.

  4. A common p73 polymorphism is associated with a reduced incidence of oesophageal carcinoma

    PubMed Central

    Ryan, B M; McManus, R; Daly, J S; Carton, E; Keeling, P W N; Reynolds, J V; Kelleher, D

    2001-01-01

    The incidence of oesophageal adenocarcinoma is rising; to date, no susceptibility genes have been identified. p73, a novel p53 homologue, maps to chromosome 1p36, a region commonly deleted in oesophageal cancers. p73 shares some p53-like activity, but in addition, may also play a role in gastrointestinal epithelial inflammatory responses. A non-coding p73 polymorphism (denoted AT or GC) may be functionally significant. We investigated whether this polymorphism might play a role in the aetiopathogenesis of oesophageal cancer. This was a case–control, retrospective study. 84 cases of oesophageal cancer (25 squamous and 59 adenocarcinoma) and 152 normal population controls were genotyped for this polymorphism. Informative cases were examined for p73 LOH within the tumour. AT/AT homozygotes were significantly less prevalent in the oesophageal cancer population (1/84 = 1.2%) compared to controls (15/152 = 9.9%) (P < 0.02), corresponding to an odds ratio of 0.11 (95% C.I. 0.02–0.6, P < 0.02), or 9-fold reduced risk. Moreover, AT/AT homozygotes were significantly less frequent in the cancer population than would be expected under the Hardy–Weinberg hypothesis (P = 0.0099). LOH at the p73 locus was observed in 37.8% (14/37) of the AT/GC heterozygotes studied; in all cases there was loss of the AT allele. Our findings indicate that p73 AT/AT homozygotes appear to be protected against the development of oesophageal cancer. Clinically, this observation could have implications in aiding identification of high-risk Barrett's oesophagus patients.© 2001 Cancer Research Campaign  http://www.bjcancer.com PMID:11720435

  5. 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.

  6. The impact of immigration and vaccination in reducing the incidence of hepatitis B in Catalonia (Spain)

    PubMed Central

    2012-01-01

    Background The Hepatitis B virus (HBV) infection is a major cause of liver disease and liver cancer worldwide according to the World Health Organization. Following acute HBV infection, 1-5% of infected healthy adults and up to 90% of infected infants become chronic carriers and have an increased risk of cirrhosis and primary hepatocellular carcinoma. The aim of this study was to investigate the relationship between the reduction in acute hepatitis B incidence and the universal vaccination programme in preadolescents in Catalonia (Spain), taking population changes into account, and to construct a model to forecast the future incidence of cases that permits the best preventive strategy to be adopted. Methods Reported acute hepatitis B incidence in Catalonia according to age, gender, vaccination coverage, percentage of immigrants and the year of report of cases was analysed. A statistical analysis was made using three models: generalized linear models (GLM) with Poisson or negative binomial distribution and a generalized additive model (GAM). Results The higher the vaccination coverage, the lower the reported incidence of hepatitis B (p <0.01). In groups with vaccination coverage > 70%, the reduction in incidence was 2-fold higher than in groups with a coverage <70% (p <0.01). The increase in incidence was significantly-higher in groups with a high percentage of immigrants and more than 15% (p <0.01) in immigrant males of working age (19-49 years). Conclusions The results of the adjusted models in this study confirm that the global incidence of hepatitis B has declined in Catalonia after the introduction of the universal preadolescent vaccination programme, but the incidence increased in male immigrants of working age. Given the potential severity of hepatitis B for the health of individuals and for the community, universal vaccination programmes should continue and programmes in risk groups, especially immigrants, should be strengthened. PMID:22867276

  7. Low-dose green tea intake reduces incidence of atrial fibrillation in a Chinese population.

    PubMed

    Liu, Dong-Chen; Yan, Jian-Jun; Wang, You-Nan; Wang, Ze-Mu; Xie, Zhi-Yong; Ma, Yao; Yang, Yang; Yang, Li; Wang, Lian-Sheng

    2016-12-20

    The aim of the present study was to assessthe association between green tea intake and incidence of atrial fibrillation (AF) in a Chinese population. A total of 801 (mean age: 62 years; 56% male) subjects were enrolled: 401 AF patients and 400 controls. All subjects completed a questionnaire and the associations between their green tea drinking habits and incidence of AF were assessed using the odds ratio (OR) and binary logistic regression. After multivariate adjustment, green tea intake presented as a protective factor against the incidence of AF (OR: 0.349, 95% CI: 0.253-0.483, P < 0.001). The green tea protection showed downward trend with increasing green tea intake (P for the trend= 0.001). Low frequency, low concentration, short-term tea consumption was classified as low-dose green tea intake. Green tea intake decreased the incidence of both paroxysmal AF (OR: 0.307, 95% CI: 0.216-0.436, P < 0.001) and persistent AF (OR: 0.355, 95% CI: 0.261-0.482, P < 0.001) and may be associated with a decreased incidence of AF. This study suggests that low-dose green tea intake strongly protects against AF.

  8. Cystathionine beta synthase gene dose dependent vascular remodeling in murine model of hyperhomocysteinemia.

    PubMed

    Tyagi, Neetu; Qipshidze, Natia; Sen, Utpal; Rodriguez, Walter; Ovechkin, Alexander; Tyagi, Suresh C

    2011-09-30

    Although children born with severe homocystinurea (i.e. cystathionine beta synthase homozygote knockout, CBS-/-) develop deleterious vascular complications with structural malformation and do not live past teenage, the heterozygote (CBS-/+) lives with apparently normal phenotype. Interestingly, this differential role of CBS expression in vascular remodeling is unclear. Peroxisome proliferator activated receptor gamma (PPARγ) is nuclear transcription factor that mitigates vascular complications. The hypothesis was that homocysteine (Hcy) decreased thioredoxin (Trx), peroxiredoxin (Prx), increased NADPH oxidase (NOX1), mitochondrial nitric oxide synthase (mtNOS) activity and reactive oxygen species (ROS) in mitochondria in a CBS gene dose-dependent manner. ROS transduced matrix metalloproteinase (MMP) activation causing thickening (fibrosis) of the basement membrane, rendering ineffective endothelial nitric oxide synthase (eNOS) and promoted endothelial-smooth muscle disconnection/uncoupling by antagonizing PPARγ. Wild type (WT-CBS+/+), CBS-/+ and CBS -/- mice were treated with or without ciglitazone (CZ, a PPARγ agonist) in food at birth. Aortic nuclear PPARγ expression was measured by EMSA. Aortic mtNOS activity and ROS production was measured using NO- and H(2)O(2)-electrodes, respectively. Aorta was analyzed for Trx, Prx, by Western blot, and PCR. MMP activity was by in situ zymography. Aortic function was measured in tissue myobath. The results suggested 90% morbidity in CBS-/- allele at 12 wks. However, treatment with the PPARγ agonist, CZ significantly reduced the morbidity to 20%. In addition, CZ restored the PPARγ activity in CBS-/+ and -/- mice to normal levels. The oxidative stress was alleviated by CZ treatment. In situ labeling with mito-tracker suggests co-localization of ROS with mitochondrial mitophagy. The mtNOS activity was increased in HHcy compared to WT. The data support the notion that Hcy decreases redoxins, increases mtNOS activity and

  9. 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.

  10. Dose-dependent effects of prostaglandin E2 in macrophage adhesion and migration.

    PubMed

    Osma-Garcia, Inés C; Punzón, Carmen; Fresno, Manuel; Díaz-Muñoz, Manuel D

    2016-03-01

    Macrophage migration to the focus of infection is a hallmark of the innate immune response. Macrophage spreading, adhesion, and migration through the extracellular matrix require dynamic remodeling of the actin cytoskeleton associated to integrin clustering in podosomes and focal adhesions. Here, we show that prostaglandin E2 (PGE2 ), the main prostaglandin produced by macrophages during inflammation, promote the distinctive dose-dependent formation of podosomes or focal adhesions in macrophages. Low concentrations of PGE2 increased p110γ PI3K expression, phosphorylation of actin-related protein 2, and formation of podosomes, which enhanced macrophage migration in response to chemokines. However, high doses of PGE2 increased phosphorylation of paxillin and focal adhesion kinase, the expression of serine/threonine protein kinase 1, and promoted focal adhesion formation and macrophage adhesion, reducing macrophage chemotaxis. In summary, we describe the dual role of PGE2 as a promoter of macrophage chemotaxis and adhesion, proposing a new model of macrophage migration to the inflammatory focus in the presence of a gradient of PGE2 .

  11. Daytime Alertness in Parkinson’s Disease: Potentially Dose-Dependent, Divergent Effects by Drug Class

    PubMed Central

    Bliwise, Donald L.; Trotti, Lynn Marie; Wilson, Anthony G.; Greer, Sophia A.; Wood-Siverio, Cathy; Juncos, Jorge J.; Factor, Stewart A.; Freeman, Alan; Rye, David B.

    2013-01-01

    Background Many patients with idiopathic Parkinson’s disease experience difficulties maintaining daytime alertness. Controversy exists regarding whether this reflects effects of anti-Parkinsonian medications, the disease itself or other factors such as nocturnal sleep disturbances. In this study we examined the phenomenon by evaluating medicated and unmedicated Parkinson’s patients with objective polysomnographic measurements of nocturnal sleep and daytime alertness. Methods Patients (n = 63) underwent a 48-hour laboratory-based study incorporating 2 consecutive nights of overnight polysomnography and 2 days of Maintenance of Wakefulness Testing. We examined correlates of individual differences in alertness, including demographics, clinical features, nocturnal sleep variables and class and dosage of anti-Parkinson’s medications. Results Results indicated that: 1) relative to unmediated patients, all classes of dopaminergic medications were associated with reduced daytime alertness and this effect was not mediated by disease duration or disease severity; 2) increasing dosages of dopamine agonists were associated with less daytime alertness, whereas higher levels of levodopa were associated with higher levels of alertness. Variables unrelated to Maintenance of Wakefulness Test defined daytime alertness included age, sex, years with diagnosis, motor impairment score and most nocturnal sleep variables. Conclusions Deficits in objectively assessed daytime alertness in Parkinson’s disease appear to be a function of both the disease and the medications and their doses utilized. The apparent divergent dose-dependent effects of drug class in Parkinson’s disease are anticipated by basic science studies of the sleep/wake cycle under different pharmacological agents. PMID:22753297

  12. Contrast media and glomerular filtration: dose dependence of clearance for three agents

    SciTech Connect

    Baeck, S.E.K.; Krutzen, E.; Nilsson-Ehle, P.

    1988-09-01

    Determination of plasma clearance of contrast agents has been advocated as a means to assess glomerular filtration rate. To evaluate the feasibility of different agents for this purpose, we have compared, in healthy volunteers, the dose dependence of plasma clearance for three contrast media (iohexol, a nonionic agent, and iothalamate and metrizoate, which are ionic substances), with special emphasis on the lower dose range (2-20 mL corresponding to 0.9-12.9 g, depending on dose and agent). Iohexol and iothalamate were cleared at constant rates, irrespective of given dose, whereas metrizoate clearance increased significantly at lower doses. In general, the clearances or iothalamate and metrizoate were, respectively, moderately and markedly higher than that of iohexol. The clearance of different doses of metrizoate (2 mL versus a radiographic dose of 40 mL or more) was also compared with the clearance of (/sup 51/Cr)EDTA in two groups of patients with reduced renal function. When compared with (/sup 51/Cr)EDTA in patients with renal dysfunction, metrizoate was cleared significantly faster after a 2-mL dose, whereas clearances were identical when the metrizoate dose was 40 mL or more. These findings indicate that tubular secretion plays an active role in the elimination of metrizoate. The pharmacokinetic properties of iohexol, in combination with its low toxicity, make it a suitable agent for determination of glomerular filtration rate in clinical practice.

  13. Dose-dependent effects of hydrocortisone infusion on autobiographical memory recall.

    PubMed

    Young, Kymberly; Drevets, Wayne C; Schulkin, Jay; Erickson, Kristine

    2011-10-01

    The glucocorticoid hormone cortisol has been shown to impair episodic memory performance. The present study examined the effect of two doses of hydrocortisone (synthetic cortisol) administration on autobiographical memory retrieval. Healthy volunteers (n = 66) were studied on two separate visits, during which they received placebo and either moderate-dose (0.15 mg/kg IV; n = 33) or high-dose (0.45 mg/kg IV; n = 33) hydrocortisone infusion. From 75 to 150 min post-infusion subjects performed an Autobiographical Memory Test and the California Verbal Learning Test (CVLT). The high-dose hydrocortisone administration reduced the percent of specific memories recalled (p = .04), increased the percent of categorical (nonspecific) memories recalled (p < .001), and slowed response times for categorical memories (p < .001), compared with placebo performance. Under moderate-dose hydrocortisone the autobiographical memory performance did not change significantly with respect to percent of specific or categorical memories recalled or reaction times. Performance on the CVLT was not affected by hydrocortisone. These findings suggest that cortisol affects accessibility of autobiographical memories in a dose-dependent manner. Specifically, administration of hydrocortisone at doses analogous to those achieved under severe psychosocial stress impaired the specificity and speed of retrieval of autobiographical memories.

  14. 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

  15. 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

  16. Breast Cancer Incidence After Risk-Reducing Salpingo-Oophorectomy in BRCA1 and BRCA2 Mutation Carriers.

    PubMed

    Fakkert, Ingrid E; Mourits, Marian J E; Jansen, Liesbeth; van der Kolk, Dorina M; Meijer, Kees; Oosterwijk, Jan C; van der Vegt, Bert; Greuter, Marcel J W; de Bock, Geertruida H

    2012-11-01

    Premenopausal risk-reducing salpingo-oophorectomy (RRSO) in BRCA1/2 mutation carriers effectively reduces ovarian cancer risk, but also reduces breast cancer risk. Breast cancer risk reductions up to 50% have been reported for both BRCA1 and BRCA2 mutation carriers, but recent prospective studies were not able to reproduce this finding for BRCA1 mutation carriers. Breast cancer incidence after RRSO was assessed in a consecutive series of 104 BRCA1 and 58 BRCA2 mutation carriers. On the basis of data from our own centre, and assuming a 50% risk reduction through RRSO at premenopausal age, we expected to find 8 breast cancers (range 6-10) in this population for the reported screening period (532 women-years). In 162 carriers with a median age of 41 years at RRSO, 13 incident breast cancers were diagnosed. In BRCA1 mutation carriers, 12 incident breast cancers were found compared with 5 (range 3-6) expected and in BRCA2 mutation carriers 1 breast cancer was found compared with 3 (range 2-5) expected. Breast cancer incidence after premenopausal RRSO is still high, especially in BRCA1 mutation carriers. Previously reported breast cancer risk reductions up to 50% were not confirmed. As a consequence, continued intensive screening for breast cancer is warranted in BRCA1 and BRCA2 mutation carriers after RRSO.

  17. A Comprehensive Evaluation for Aspiration After Esophagectomy Reduces the Incidence of Post-Operative Pneumonia

    PubMed Central

    Berry, Mark F.; Atkins, B. Zane; Tong, Betty C.; Harpole, David H.; D’Amico, Thomas A.; Onaitis, Mark W.

    2011-01-01

    OBJECTIVE This study assesses the impact of using a comprehensive swallowing evaluation before starting oral feedings on aspiration detection and pneumonia occurrence after esophagectomy. METHODS The records of all esophagectomy patients between January 1996 and June 2009 were reviewed. Multivariable logistic regression analysis assessed the effect of preoperative and operative variables on the incidence of aspiration and pneumonia. Separate analyses were performed on patients before (early era, 1996–2002) and after (later era, 2003–2009) a rigorous swallowing evaluation was used routinely before starting oral feedings. RESULTS During the study period, 799 patients (379 early era, 420 later era) underwent esophagectomy; 30-day mortality was 3.5% (28 patients). Cervical anastomoses were performed in 76% of patients in the later era compared with 40% of patients in the early era. Overall, 96 patients (12%) had evidence of aspiration postoperatively, and the pneumonia incidence was 14% (113 patients). Age (odds ratio 1.05 per year, p<0.0001) and later era (odds ratio 1.90, p=0.0001) predicted aspiration in all patients in a multivariable model. In the early era, cervical anastomosis and aspiration independently predicted pneumonia. With a comprehensive swallowing evaluation in the later era, the detected incidence of aspiration increased (16% vs 7%, p<0.0001) while the incidence of pneumonia declined (11% vs 18%, p=0.004) compared to the early era, such that neither anastomotic location nor aspiration predicted pneumonia in the later era. CONCLUSIONS Esophagectomy is often associated with occult aspiration. A comprehensive swallowing evaluation for aspiration prior to initiating oral feedings significantly decreases the occurrence of pneumonia. PMID:20884018

  18. 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.

  19. A maternal gluten-free diet reduces inflammation and diabetes incidence in the offspring of NOD mice.

    PubMed

    Hansen, Camilla Hartmann Friis; Krych, Lukasz; Buschard, Karsten; Metzdorff, Stine B; Nellemann, Christine; Hansen, Lars H; Nielsen, Dennis S; Frøkiær, Hanne; Skov, Søren; Hansen, Axel K

    2014-08-01

    Early-life interventions in the intestinal environment have previously been shown to influence diabetes incidence. We therefore hypothesized that a gluten-free (GF) diet, known to decrease the incidence of type 1 diabetes, would protect against the development of diabetes when fed only during the pregnancy and lactation period. Pregnant nonobese diabetic (NOD) mice were fed a GF or standard diet until all pups were weaned to a standard diet. The early-life GF environment dramatically decreased the incidence of diabetes and insulitis. Gut microbiota analysis by 16S rRNA gene sequencing revealed a pronounced difference between both mothers and their offspring on different diets, characterized by increased numbers of Akkermansia, Proteobacteria, and TM7 in the GF diet group. In addition, pancreatic forkhead box P3 regulatory T cells were increased in GF-fed offspring, as were M2 macrophage gene markers and tight junction-related genes in the gut, while intestinal gene expression of proinflammatory cytokines was reduced. An increased proportion of T cells in the pancreas expressing the mucosal integrin α4β7 suggests that the mechanism involves increased trafficking of gut-primed immune cells to the pancreas. In conclusion, a GF diet during fetal and early postnatal life reduces the incidence of diabetes. The mechanism may involve changes in gut microbiota and shifts to a less proinflammatory immunological milieu in the gut and pancreas.

  20. Dose-dependent modulation of myogenesis by HGF: implications for c-Met expression and downstream signalling pathways.

    PubMed

    Walker, Nicholas; Kahamba, Trish; Woudberg, Nicholas; Goetsch, Kyle; Niesler, Carola

    2015-01-01

    Hepatocyte growth factor (HGF) regulates satellite cell activation, proliferation, and differentiation. We analyzed the dose-dependent effects of HGF on myogenesis. Murine C2C12 and human donor-derived skeletal muscle myoblasts were treated with 0, 2, or 10 ng/ml HGF followed by assessment of proliferation and differentiation. HGF (2 ng/ml) significantly promoted cell division, but reduced myogenic commitment and fusion. Conversely, 10 ng/ml HGF reduced proliferative capability, but increased differentiation. c-Met expression analysis revealed significantly decreased expression in differentiating cells cultured with 2 ng/ml HGF, but increased expression in proliferating cells with 10 ng/ml HGF. Mitogen-activated protein kinase (MAPKs: ERK, JNK, or p38K) and phosphatidylinositol-3-kinase (PI3K) inhibition abrogated the HGF-stimulated increase in cell number. Interestingly, PI3K and p38 kinase facilitated the negative effect of HGF on proliferation, while ERK inhibition abrogated the HGF-mediated decrease in differentiation. Dose-dependent effects of HGF are mediated by changes in c-Met expression and downstream MAPK and PI3K signalling.

  1. 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.

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

    PubMed Central

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

    2014-01-01

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

  3. 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

  4. Chronic intermittent nicotine treatment dose-dependently alters serotonergic neurons response to citalopram in the rat.

    PubMed

    Touiki, Khalid; Rat, Pascal; Arib, Ouafa; Molimard, Robert; Chait, Abderrahman; de Beaurepaire, Renaud

    2008-05-01

    Acetylcholine nicotinic systems and serotonergic systems are known to interact. In rodents, acute and chronic nicotine treatments have consequences on several aspects of the activity of dorsal raphe serotonin (DRN 5-HT) neurons. One hypothesis is that states of functioning of DRN 5-HT neurons (firing rate and sensitivity) vary as a function of nicotine dose and mode of administration during chronic nicotine treatment. In the present study, the firing rate and sensitivity of DRN 5-HT neurons were investigated using single (0.5 and 1 mg/kg) or multiple (3 injections of 0.7 mg/kg) daily injections of nicotine over 10 days. The sensitivity of neurons was tested by the cumulative dose of the selective serotonin reuptake inhibitor citalopram necessary to inhibit their firing. The activity of neurons was tested during treatment, and then 24 and 48 h after nicotine withdrawal. The results show that, on day 10, DRN 5-HT neurons were desensitized (reduced response to citalopram) after chronic single daily injection treatments with the high dose of nicotine (1 mg/kg), while their sensitivity remained unaltered after single daily injections with the low dose (0.5 mg/kg), and after the multiple daily injection paradigm. None of the treatments altered the firing rate of DRN 5-HT neurons. The dose-dependent and time-dependent alterations of serotonergic neurons sensitivity after chronic nicotine treatments are likely the consequences of long-term adaptations of nicotinic receptors. The desensitization of DRN 5-HT neurons after chronic single daily injections of 1 mg/kg of nicotine suggests an antidepressant-like effect of chronic nicotine.

  5. Context- and dose-dependent modulatory effects of naringenin on survival and development of Drosophila melanogaster.

    PubMed

    Chattopadhyay, Debarati; Sen, Soumadeep; Chatterjee, Rishita; Roy, Debasish; James, Joel; Thirumurugan, Kavitha

    2016-04-01

    Naringenin, the predominant bioflavonoid found in grapefruit and tomato has diverse bioactive properties that encompass anti-carcinogenic, anti-inflammatory, anti-atherogenic, anti-estrogenic, anti-hyperlipidemic and anti-hyperglycemic characteristics. Naringenin has not been explored for its pro-longevity traits in fruit flies. Therefore, the current study explores its influence on longevity, fecundity, feeding rate, larval development, resistance to starvation stress and body weight in male and female wild-type Drosophila melanogaster Canton-S flies. Flies were fed with normal and high fat diets respectively. The results implied hormetic effects of naringenin on longevity and development in flies. In flies fed with standard and high fat diets, lower concentrations of naringenin (200 and 400 µM) augmented mean lifespan while higher concentrations (600 and 800 µM) were consistently lethal. However, enhanced longevity seen at 400 µM of naringenin was at the expense of reduced fecundity and food intake in flies. Larvae reared on standard diet having 200 µM of naringenin exhibited elevated pupation and emergence as flies. Eclosion time was hastened in larvae reared on standard diet having 200 µM of naringenin. Female flies fed with a standard diet having 200 and 400 µM of naringenin were more resistant to starvation stress. Reduction in body weight was observed in male and female flies fed with a high fat diet supplemented with 200 and 400 µM of naringenin respectively. Collectively, the results elucidated a context- and dose-dependent hormetic efficacy of naringenin that varied with gender, diet and stage of lifecycle in flies.

  6. Dose-Dependent Effects of Evening Primrose Oil in Children and Adolescents with Atopic Dermatitis

    PubMed Central

    Chung, Bo Young; Kim, Jin Hye; Cho, Soo Ick; Ahn, In Su; Kim, Hye One; Lee, Cheol Heon

    2013-01-01

    Background Previous clinical trials with evening primrose oil in atopic dermatitis (AD) treatment have shown different results. In addition, the optimal dose and duration of treatment with evening primrose oil have not yet been determined. Objective The aim of this study is to investigate the dose-response treatment effects of evening primrose oil on clinical symptoms of AD and serum concentrations of polyunsaturated fatty acids. Methods Forty AD patients were enrolled for the study and randomly divided into 2 groups: those who received evening primrose oil 160 mg daily for 8 weeks and those who received 320 mg of evening primrose oil twice daily for 8 weeks. We evaluated the Eczema Area Severity Index (EASI) scores of all AD patients at weeks 0, 2, 4 and 8. In addition, we measured the levels of serum fatty acids, including C16 : 0 (palmitic), C18 : 2n (linoleic), C18 : 3n (linolenic) and C20 : 4 (arachidonic acid) using gas chromatography. Results The serum fatty acid levels C18 : 3n and C20 : 4 were higher in the 320 mg group than in the 160 mg group, with statistical significance. After evening primrose oil treatment, EASI scores were reduced in the 2 groups. The improvement in EASI scores was greater in the 320 mg group than in the 160 mg group. There were no side effects seen in either group during the study in the 2 groups. Conclusion The results of this study suggest that the 320 mg and 160 mg groups may be equally effective in treating AD patients and show dose-dependent effects on serum fatty acid levels and EASI scores. PMID:24003269

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

    PubMed Central

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

    2016-01-01

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

  8. 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...

  9. Absorbed dose dependence of the correction factors for ionization chamber cable irradiation effects.

    PubMed

    Campos, L L; Caldas, L V

    1991-03-01

    A simple method was developed, for possible use by hospital physicists, to evaluate the irradiation effects on cables and connectors during large-radiation-field dosimetry with ionization chambers and to determine correction factors for the used system or geometry. This method was based on the absorbed dose dependence of the correction factor.

  10. A double blind randomized controlled trial comparing primary suture closure with mesh augmented closure to reduce incisional hernia incidence

    PubMed Central

    2013-01-01

    Background Incisional hernia is the most frequently seen long term complication after laparotomy causing much morbidity and even mortality. The overall incidence remains 11-20%, despite studies attempting to optimize closing techniques. Two patient groups, patients with abdominal aortic aneurysm and obese patients, have a risk for incisional hernia after laparotomy of more than 30%. These patients might benefit from mesh augmented midline closure as a means to reduce incisional hernia incidence. Methods/design The PRImary Mesh Closure of Abdominal Midline Wound (PRIMA) trial is a double-blinded international multicenter randomized controlled trial comparing running slowly absorbable suture closure with the same closure augmented with a sublay or onlay mesh. Primary endpoint will be incisional hernia incidence 2 years postoperatively. Secondary outcomes will be postoperative complications, pain, quality of life and cost effectiveness. A total of 460 patients will be included in three arms of the study and randomized between running suture closure, onlay mesh closure or sublay mesh closure. Follow-up will be at 1, 3, 12 and 24 months with ultrasound imaging performed at 6 and 24 months to objectify the presence of incisional hernia. Patients, investigators and radiologists will be blinded throughout the whole follow up. Disccusion The use of prosthetic mesh has proven effective and safe in incisional hernia surgery however its use in a prophylactic manner has yet to be properly investigated. The PRIMA trial will provide level 1b evidence whether mesh augmented midline abdominal closure reduces incisional hernia incidence in high risk groups. Trial registration Clinical trial.gov NCT00761475. PMID:24499111

  11. Use of the six sigma methodology to reduce incidence of breast milk administration errors in the NICU.

    PubMed

    Drenckpohl, Douglas; Bowers, Laura; Cooper, Hoa

    2007-01-01

    Breast milk is the optimal source of nutrition for infants. According to research, neonates fed breast milk have a reduced risk of sepsis, increased feeding tolerance, a decreased incidence of necrotizing enterocolitis, and better neurodevelopmental outcomes. Unfortunately, researchers have not identified practices to reduce or eliminate the risk for errors in breast milk administration. This article discusses the potential hazards of incorrect administration of breast milk. It then describes how the tertiary care center at Children's Hospital of Illinois implemented a policy utilizing six sigma quality improvement methodologies to improve breast milk administration. Since implementation of this policy, the NICU at our hospital has reduced the risk of breast milk administration errors to less than 3.4 mistakes per million opportunities.

  12. Use of a portable bladder scanner to reduce the incidence of bladder catheterisation prior to laparoscopy.

    PubMed

    Moselhi, M; Morgan, M

    2001-04-01

    The aim of this study was to evaluate the usefulness of estimating bladder volume with a dedicated portable ultrasound device immediately prior to gynaecological laparoscopy. Catheterisation was performed if the estimated volume was greater than 100 ml. Forty consecutive women were studied prospectively. Twenty-six women did not require catheterisation. The procedure was quick and effective in safely reducing the frequency of pre-operative catheterisation.

  13. Formula with long chain polyunsaturated fatty acids reduces incidence of allergy in early childhood

    PubMed Central

    Foiles, Amanda M.; Kerling, Elizabeth H.; Wick, Jo A.; Scalabrin, Deolinda M.F.; Colombo, John; Carlson, Susan E.

    2016-01-01

    Background Allergy has sharply increased in affluent Western countries in the last 30 years. N-3 long chain polyunsaturated fatty acids (n-3 LCPUFAs) may protect the immune system against development of allergy. Methods We prospectively categorized illnesses by body system in a subset of 91 children from the Kansas City cohort of the DIAMOND (DHA Intake and Measurement of Neural Development) study who had yearly medical records through 4 years of age. As infants, they were fed either a control formula without LCPUFA (n=19) or one of three formulas with LCPUFA from docosahexaenoic acid (DHA) and arachidonic acid (ARA) (n=72). Results Allergic illnesses in the first year were lower in the combined LCPUFA group compared to the control. LCPUFAs significantly delayed time to first allergic illness (p=0.04) and skin allergic illness (p=0.03); and resulted in a trend to reduced wheeze/asthma (p=0.1). If the mother had no allergies, LCPUFAs reduced the risk of any allergic diseases (HR = 0.24, 95% CI = 0.1, 0.56, p=0.0.001) and skin allergic diseases (HR = 0.35, 95% CI = 0.13, 0.93, p=0.04). In contrast, if the mother had allergies, LCPUFAs reduced wheezing/asthma (HR = 0.26, 95% CI = 0.07, 0.9, p = 0.02). Conclusions LCPUFA supplementation during infancy reduced the risk of skin and respiratory allergic diseases in childhood with effects influenced by maternal allergies. PMID:26613373

  14. Simulations of High-Intensity Short-Pulse Lasers Incident on Reduced Mass Targets

    NASA Astrophysics Data System (ADS)

    King, Frank W.

    This thesis presents the results of a series of fully kinetic particle-in-cell (PIC) simulations of reduced mass targets with pre-plasma subjected to high-intensity short-pulse lasers. The simulations are performed in one, two, and three dimensions. The results of these simulations show that the creation of an electrostatic collisionless ion shock in the preplasma controls the creation of an above solid density ion perturbation in the target bulk, and this determines the reduced mass target heating and deformation. The ion perturbation is initiated by a population of high-energy electrons that rapidly spread throughout the target and reflux. The perturbation spreads longitudinally and transversely through the target and results in compression followed by the destruction of the target. This deformation requires a kinetic treatment due to the generation of non-equilibrium particle distributions and the role of ballistic electrons and ions. Kinetic and fluid simulations are compared and both exhibit the basic features of the above solid density ion perturbation, but the magnitude of the effect and the speed of propagation vary significantly between the two methods. Kinetic simulations do not naturally include equation-of-state physics and other aspects of the problem. Both approaches are complementary. The requirements on spatial resolution, particle count, and other numerical parameters are addressed in this work. From these simulations, the behavior of the reduced mass targets is found to vary significantly depending on the laser focal spot size or the intensity of the laser pulse. This occurs even if the energy and power of the laser pulses are held constant. The number of dimensions used in the particle-in-cell simulations has been observed to have a significant effect on late-time heating of the target, but not during or shortly after laser excitation. This is due to the representation of the equilibration process as the initial population of laser heated

  15. Evidence from a large-scale meta-analysis indicates eczema reduces the incidence of glioma

    PubMed Central

    Cao, Chao; Dong, Jing; Chu, Yudong; He, Guijuan; Xu, Zhiwei

    2016-01-01

    We investigated the relationship between eczema and the risk of primary glioma. Relevant studies were selected through electronic searches of PubMed and EMBASE. A meta-analysis of 12 case-control studies and one cohort study was performed. A fixed effect model was applied to analyze 13 studies consisting of 10,897 glioma cases and 56,081 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the strength of the associations. The data demonstrate that eczema significantly reduces the risk of glioma (OR = 0.69, 95% CI = 0.61–0.78, P < 0.001). Additional studies with larger patient cohorts are required to validate our findings. PMID:27566584

  16. Radiation dose dependent change in physiochemical, mechanical and barrier properties of guar gum based films.

    PubMed

    Saurabh, Chaturbhuj K; Gupta, Sumit; Bahadur, Jitendra; Mazumder, S; Variyar, Prasad S; Sharma, Arun

    2013-11-06

    Mechanical and water vapor barrier properties of biodegradable films prepared from radiation processed guar gum were investigated. Films prepared from GG irradiated up to 500 Gy demonstrated significantly higher tensile strength as compared to non-irradiated control films. This improvement in tensile strength observed was demonstrated to be due to the ordering of polymer structures as confirmed by small angle X-ray scattering analysis. Exposure to doses higher than 500 Gy, however, resulted in a dose dependent decrease in tensile strength. A dose dependent decrease in puncture strength with no significant differences in the percent elongation was also observed at all the doses studied. Water vapor barrier properties of films improved up to 15% due to radiation processing. Radiation processing at lower doses for improving mechanical and barrier properties of guar based packaging films is demonstrated here for the first time.

  17. Statins dose-dependently exert a chemopreventive effect against lung cancer in COPD patients: a population-based cohort study

    PubMed Central

    Hsu, Yi-Ping; Hao, Wen-Rui; Kao, Pai-Feng; Sung, Li-Chin; Chen, Chun-Chao; Wu, Szu-Yuan

    2016-01-01

    Purpose Chronic obstructive pulmonary disease (COPD) is associated with increased lung cancer risk. We evaluated the association of statin use with lung cancer risk in COPD patients and identified which statins possess the highest chemopreventive potential. Results After adjustment for age, sex, CCI, diabetes, hypertension, dyslipidemia, urbanization level, and monthly income according to propensity scores, lung cancer risk in the statin users was lower than that in the statin nonusers (adjusted hazard ratio [aHR] = 0.37). Of the individual statins, lovastatin and fluvastatin did not reduce lung cancer risk significantly. By contrast, lung cancer risk in patients using rosuvastatin, simvastatin, atorvastatin, and pravastatin was significantly lower than that in statin nonusers (aHRs = 0.41, 0.44, 0.52, and 0.58, respectively). Statins dose-dependently reduced lung cancer risk in all subgroups and the main model with additional covariates (nonstatin drug use). MATERIALS AND METHODS The study cohort comprised all patients diagnosed with COPD at health care facilities in Taiwan (n = 116,017) between January 1, 2001 and December 31, 2012. Our final study cohort comprised 43,802 COPD patients: 10,086 used statins, whereas 33,716 did not. Patients were followed up to assess lung cancer risk or protective factors. In addition, we also considered demographic characteristics, namely age, sex, comorbidities (diabetes, hypertension, dyslipidemia, and Charlson comorbidity index [CCI]), urbanization level, monthly income, and nonstatin drug use. The index date of statin use was the COPD confirmation date. To examine the dose–response relationship, we categorized statin use into four groups in each cohort: < 28, 28–90, 91–365, and > 365 cumulative defined daily doses (cDDDs). Patients receiving < 28 cDDDs were defined as nonstatin users. Conclusions Statins dose-dependently exert a significant chemopreventive effect against lung cancer in COPD patients. Rosuvastatin

  18. Use of low doses of clenbuterol to reduce incidence of ascites syndrome in broilers.

    PubMed

    Ocampo, L; Cortez, U; Sumano, H; Avila, E

    1998-09-01

    Beta-adrenergic agonists have been shown to be capable of improving growth performance in poultry when added to the feed at 1.0 ppm. However, no reference has been made concerning the cardiovascular responses when one of these agents is added to the feed at a lower concentration during the whole production cycle. The aim of this paper was to assess the effects on the ascites syndrome of 0.25 ppm clenbuterol in the feed, throughout 52 d, in broiler chicks. Results showed a lack of difference in growth and feed conversion rate between the untreated control groups and the experimental group. There were differences in mortality due to the ascites syndrome, abdominal fat:body weight ratio, and ventricular index. A statistically significant positive correlation was also found between ventricular index and mortality rate (r = 0.98). If adequate withdrawal times are ensured, the use of clenbuterol at 0.25 ppm is suggested to reduce mortality due to the ascites syndrome in broilers.

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

    SciTech Connect

    Jacobsson, H.; Naeslund, I. )

    1991-06-01

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

  20. 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

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

    PubMed

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

    2014-10-07

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

  2. Novel Application of Stem Cell-Derived Neurons to Evaluate the Time- and Dose-Dependent Progression of Excitotoxic Injury

    PubMed Central

    Gut, Ian M.; Beske, Phillip H.; Hubbard, Kyle S.; Lyman, Megan E.; Hamilton, Tracey A.; McNutt, Patrick M.

    2013-01-01

    Glutamate receptor (GluR)-mediated neurotoxicity is implicated in a variety of disorders ranging from ischemia to neural degeneration. Under conditions of elevated glutamate, the excessive activation of GluRs causes internalization of pathologic levels of Ca2+, culminating in bioenergetic failure, organelle degradation, and cell death. Efforts to characterize cellular and molecular aspects of excitotoxicity and conduct therapeutic screening for pharmacologic inhibitors of excitogenic progression have been hindered by limitations associated with primary neuron culture. To address this, we evaluated glutamate-induced neurotoxicity in highly enriched glutamatergic neurons (ESNs) derived from murine embryonic stem cells. As of 18 days in vitro (DIV 18), ESNs were synaptically coupled, exhibited spontaneous network activity with neurotypic mEPSCs and expressed NMDARs and AMPARs with physiological current:voltage behaviors. Addition of 0.78–200 μM glutamate evoked reproducible time- and dose-dependent metabolic failure in 6 h, with a calculated EC50 value of 0.44 μM at 24 h. Using a combination of cell viability assays and electrophysiology, we determined that glutamate-induced toxicity was specifically mediated by NMDARs and could be inhibited by addition of NMDAR antagonists, increased extracellular Mg2+ or substitution of Ba2+ for Ca2+. Glutamate treatment evoked neurite fragmentation and focal swelling by both immunocytochemistry and scanning electron microscopy. Presentation of morphological markers of cell death was dose-dependent, with 0.78–200 μM glutamate resulting in apoptosis and 3000 μM glutamate generating a mixture of necrosis and apoptosis. Addition of neuroprotective small molecules reduced glutamate-induced neurotoxicity in a dose-dependent fashion. These data indicate that ESNs replicate many of the excitogenic mechanisms observed in primary neuron culture, offering a moderate-throughput model of excitotoxicity that combines the verisimilitude

  3. 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

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

    PubMed Central

    2014-01-01

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

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

    PubMed

    Becker, Talia; Ashkenazi, Malka

    2011-10-01

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

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

    PubMed

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

    2016-02-01

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

  7. A retrospective study on the use of a dental dressing to reduce dry socket incidence in smokers.

    PubMed

    Murph, James T; Jaques, Susan H; Knoell, Alexander N; Archibald, Geoffrey D; Yang, Stan

    2015-01-01

    This study assessed the effectiveness of using an oxidized cellulose dental dressing in order to reduce the rate of alveolar osteitis after posterior tooth extraction in smokers. Dry socket incidences of heavy smokers from 4 independent dental clinics, which routinely used oxidized cellulose dental dressings to mitigate dry socket formation between March 2011 and December 2012, were compiled and evaluated. All extraction sites healed uneventfully except for those cases that developed dry sockets. Overall, 1.7% of male patients and 2.2% of female patients developed dry sockets. No conclusive relationship was found between the number of cigarettes smoked and dry socket formation among patients in this study. The results of this study were consistent with the view that gender, age, postextraction regimen, and multiple extractions affect dry socket formation. The results indicate that an oxidized cellulose dental dressing postextraction is a safe and effective method for mitigating dry socket formation among smokers.

  8. Peripheral venous congestion causes time- and dose-dependent release of endothelin-1 in humans.

    PubMed

    Lin, Jeffrey; Chudasama, Neelesh; Hayashi, Yacki; Hawk, Christopher; Ramnauth, Sahadeo D; Wong, Ka Yuk; Harxhi, Ante; Onat, Duygu; Wakabayashi, Michiyori; Uriel, Nir; Jorde, Ulrich P; LeJemtel, Thierry H; Sabbah, Hani N; Demmer, Ryan T; Colombo, Paolo C

    2017-03-01

    Endothelin-1 (ET-1) is a pivotal mediator of vasoconstriction and inflammation in congestive states such as heart failure (HF) and chronic kidney disease (CKD). Whether peripheral venous congestion (VC) increases plasma ET-1 at pressures commonly seen in HF and CKD patients is unknown. We seek to characterize whether peripheral VC promotes time- and dose-dependent increases in plasma ET-1 and whether these changes are sustained after decongestion. We used a randomized, cross-over design in 20 healthy subjects (age 30 ± 7 years). To experimentally model VC, venous pressure was increased to either 15 or 30 mmHg (randomized at first visit) above baseline by inflating a cuff around the subject's dominant arm; the nondominant arm served as a noncongested control. We measured plasma ET-1 at baseline, after 20, 60 and 120 min of VC, and finally at 180 min (60 min after cuff release and decongestion). Plasma ET-1 progressively and significantly increased over 120 min in the congested arm relative to the control arm and to baseline values. This effect was dose-dependent: ET-1 increased by 45% and 100% at VC doses of 15 and 30 mmHg, respectively (P < 0.05), and declined after 60 min of decongestion though remaining significantly elevated compared to baseline. In summary, peripheral VC causes time- and dose-dependent increases in plasma ET-1. Of note, the lower dose of 15 mmHg (more clinically relevant to HF and CKD patients) was sufficient to raise ET-1. These findings support the potentially contributory, not merely consequential, role of VC in the pathophysiology of HF and CKD.

  9. Caffeine ingestion impairs insulin sensitivity in a dose-dependent manner in both men and women.

    PubMed

    Beaudoin, Marie-Soleil; Allen, Brian; Mazzetti, Gillian; Sullivan, Peter J; Graham, Terry E

    2013-02-01

    The effects of alkaloid caffeine on insulin sensitivity have been investigated primarily in men, and with a single caffeine dose most commonly of 5-6 mg·kg(-1) of body weight (BW). It is unknown if the effects of caffeine on glucose homeostasis are sex-specific and (or) dose-dependent. This study examined whether caffeine ingestion would disrupt glucose homeostasis in a dose-dependent or threshold manner. It also examined whether sex-specific responses to caffeine exist. It was hypothesized that women would have an exaggerated response to caffeine, and that caffeine would only impair glucose metabolism once a threshold was reached. Twenty-four healthy volunteers (12 males, 12 females) participated in 4 trials, in a crossover, randomized, and double-blind fashion. They ingested caffeine (1, 3, or 5 mg·kg(-1) of BW) or placebo followed, 1 h later, by a 2-h oral glucose tolerance test. Glucose, insulin, C-peptide area under the curve (AUC), and insulin sensitivity index data were fitted to a segmented linear model to determine dose-responses. There were no differences between sexes for any endpoints. Regression slopes were significantly different from zero (p < 0.05) for glucose, insulin, and C-peptide AUCs, with thresholds being no different from zero. Increasing caffeine consumption by 1 mg·kg(-1) of BW increased insulin and C-peptide AUCs by 5.8% and 8.7%, respectively. Despite this exaggerated insulin response, glucose AUC increased by 11.2 mmol per 120 min·L(-1) for each mg·kg(-1) BW consumed. These results showed that caffeine ingestion disrupted insulin sensitivity in a dose-dependent fashion beginning at very low doses (0-1 mg·kg(-1) BW) in both healthy men and women.

  10. Intracellular magnesium blocks sodium outward currents in a voltage- and dose-dependent manner.

    PubMed Central

    Pusch, M; Conti, F; Stühmer, W

    1989-01-01

    Tail currents through Na+ channels have been measured in inside-out patches from Xenopus laevis oocytes injected with cDNA-derived mRNA coding for the rat brain type II Na+ channel. It is shown that intracellular Mg2+ blocks outward currents in a voltage- and dose-dependent manner with a half blocking concentration between 3 and 4 mM at 0 mV and a voltage dependence of e-fold per 49 mV. PMID:2548634

  11. 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

  12. 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.

  13. Association between Hypophosphatemia and Cardiac Arrhythmias in the Early Stage of Sepsis: Could Phosphorus Replacement Treatment Reduce the Incidence of Arrhythmias?

    PubMed

    Schwartz, Andrei; Brotfain, Evgeni; Koyfman, Leonid; Kutz, Ruslan; Gruenbaum, Shaun E; Klein, Moti; Zlotnik, Alexander

    2014-06-01

    It is well known that new-onset arrhythmias are common in septic patients. It is thought that hypophosphatemia in the early stages of sepsis may contribute to the development of new arrhythmias. In this study, we hypothesized that intravenous (IV) phosphorus replacement may reduce the incidence of arrhythmias in critically ill patients. 34 adult septic patients with hypophosphatemia admitted to the general intensive care unit were treated with IV phosphorus replacement per ICU protocol, and the incidence of new arrhythmias were compared with 16 patients from previously published data. IV phosphorus replacement was associated with a significantly reduced incidence of arrhythmias (38% vs. 63%, p=0.04). There were no differences in observed mortality between subgroups, which may be due to the small sample size. This study demonstrated that IV phosphorus replacement might be effective in reducing the incidence of new arrhythmias in septic patients.

  14. 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.

  15. An easy method to account for light scattering dose dependence in radiochromic films

    SciTech Connect

    Miras, Hector; Arrans, Rafael

    2009-09-15

    Purpose: To date no detector can offer the unbeatable characteristics of film dosimetry in terms of spatial resolution and this is why it has been chosen by many institutions for treatment verification and, in that respect, radiochromic films are becoming increasingly popular due to their advantageous properties. It is the aim of this work to suggest an easy method to overcome one of the drawbacks in radiochromic film dosimetry associated with the scanning device, namely, the non-uniform dose dependent response, mainly due to the light scattering effect. Methods: The suggested procedure consists of building four correction matrices by sequentially scanning one, two, three, and four unexposed blank films. The color level of these four matrices is compatible with four points in the calibration curve dose range. Therefore, the dose dependent correction to the scanned irradiated film will be obtained by interpolating between the four correction matrices. Results: The validity of the suggested method is checked against an ion chamber 2D array. The use of the proposed flattening correction improves considerably the dose agreement when compared with the cases in which no correction is applied. Conclusions: The method showed to be fast and easy and practically overcomes the dependence on the dose of light scattering of flatbed scanners.

  16. 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.

  17. Pharmacokinetics of Amoxicillin: Dose Dependence After Intravenous, Oral, and Intramuscular Administration

    PubMed Central

    Spyker, Daniel A.; Rugloski, Raymond J.; Vann, Robert L.; O'Brien, William M.

    1977-01-01

    Amoxicillin was studied in normal subjects after intravenous, oral, and intramuscular administration of 250-, 500-, and 1,000-mg doses. Serum drug levels were analyzed using a two-compartment open model, as well as area under the curve (AUC) and urinary recovery. The variations of these pharmacokinetic parameters were then examined using the three-way analysis of variance and linear regression equations. These results confirmed nearly complete oral absorption: AUC was 93% of intravenous absorption, and urinary recovery was 86%. The intramuscular administration of amoxicillin results in complete and reliable absorption with peak drug levels, AUCs, and urinary recovery equivalent to oral dosage. The absorption of lyophilized amoxicillin after intramuscular injection resulted in an AUC that was 92% of intravenous absorption and urinary recovery of 91%. The peak serum levels, time to peak, and other pharmacokinetic parameters for intramuscular injection were nearly identical to those for oral administration. Kinetics of both intramuscular and oral administration exhibited dose-dependent absorption (absorption rate constant, 1.3/h for 250 mg and 0.7/h for 1,000 mg). This resulted in relatively later and lower peak serum levels for increasing dose. Total absorption, however, showed no dose dependence, as indicated by urinary recovery and AUC, which changed by less than 10%. PMID:836010

  18. Type I interferon causes thrombotic microangiopathy by a dose-dependent toxic effect on the microvasculature

    PubMed Central

    Kavanagh, David; Jury, Alexa; Williams, Jac; Scolding, Neil; Bellamy, Chris; Gunther, Claudia; Ritchie, Diane; Gale, Daniel P.; Kanwar, Yashpal S.; Challis, Rachel; Buist, Holly; Overell, James; Weller, Belinda; Flossmann, Oliver; Blunden, Mark; Meyer, Eric P.; Krucker, Thomas; Evans, Stephen J. W.; Campbell, Iain L.; Jackson, Andrew P.; Chandran, Siddharthan

    2016-01-01

    Many drugs have been reported to cause thrombotic microangiopathy (TMA), yet evidence supporting a direct association is often weak. In particular, TMA has been reported in association with recombinant type I interferon (IFN) therapies, with recent concern regarding the use of IFN in multiple sclerosis patients. However, a causal association has yet to be demonstrated. Here, we adopt a combined clinical and experimental approach to provide evidence of such an association between type I IFN and TMA. We show that the clinical phenotype of cases referred to a national center is uniformly consistent with a direct dose-dependent drug-induced TMA. We then show that dose-dependent microvascular disease is seen in a transgenic mouse model of IFN toxicity. This includes specific microvascular pathological changes seen in patient biopsies and is dependent on transcriptional activation of the IFN response through the type I interferon α/β receptor (IFNAR). Together our clinical and experimental findings provide evidence of a causal link between type I IFN and TMA. As such, recombinant type I IFN therapies should be stopped at the earliest stage in patients who develop this complication, with implications for risk mitigation. PMID:27663672

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

    PubMed

    Vidyashankar, Satyakumar; Sambaiah, Kari; Srinivasan, Krishnapura

    2009-06-01

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

  20. 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.

  1. Chito-oligosaccharide reduces diarrhea incidence and attenuates the immune response of weaned pigs challenged with Escherichia coli K88.

    PubMed

    Liu, P; Piao, X S; Thacker, P A; Zeng, Z K; Li, P F; Wang, D; Kim, S W

    2010-12-01

    Seventy-two barrows (Landrace × Large White, initial BW of 4.9 ± 0.3 kg and 17 ± 3 d old) were used to determine if dietary chito-oligosaccharides can replace antibiotics as a means to reduce signs associated with infection in weaned pigs challenged with Escherichia coli. Pigs were assigned to 1 of 4 treatments in a randomized complete block design using 6 pens per treatment with 3 pigs per pen. The treatments consisted of pigs fed the unsupplemented corn-soybean meal diet challenged or unchallenged with E. coli K88 and pigs fed the same diet supplemented with 160 mg of chito-oligosaccharides or 100 mg of cyadox/kg and challenged with E. coli K88. On d 7, 1 group of pigs fed the unsupplemented diet, as well as all pigs fed diets containing chito-oligosaccharides or cyadox, were orally dosed with 30 mL of an alkaline broth containing E. coli K88. Another group of pigs fed the unsupplemented diet was orally dosed with 30 mL of sterilized alkaline broth. Fecal consistency was visually assessed each morning from d 7 to 14. Blood samples were collected at 0, 24, 48, and 168 h postinfection. On d 14 postchallenge, all pigs were killed to evaluate intestinal morphology and determine E. coli concentrations in the intestine. During the postchallenge period (wk 2), unsupplemented pigs challenged with E. coli had decreased (P < 0.05) BW gain, feed intake, fecal consistency, villus height, villus height:crypt depth ratio, and plasma IGF-1, and increased (P < 0.05) diarrhea incidence, E. coli counts in the intestine, plasma interleukin-1β, plasma IL-10, and IGA-positive cells in the jejunal and ileal lamina propria, compared with unchallenged pigs. Supplementation with cyadox largely mitigated these effects. Although chito-oligosaccharide reduced the incidence of diarrhea, the growth performance of E. coli-challenged pigs supplemented with chito-oligosaccharide was not better than that of unsupplemented pigs challenged with E. coli. Therefore, chito-oligosaccharide, at the

  2. 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.

  3. Dose-dependent effects of allopurinol on human foreskin fibroblast cells and human umbilical vein endothelial cells under hypoxia.

    PubMed

    Sun, Yu; George, Jacob; Rocha, Sonia

    2015-01-01

    Allopurinol, an inhibitor of xanthine oxidase, has been used in clinical trials of patients with cardiovascular and chronic kidney disease. These are two pathologies with extensive links to hypoxia and activation of the transcription factor hypoxia inducible factor (HIF) family. Here we analysed the effects of allopurinol treatment in two different cellular models, and their response to hypoxia. We explored the dose-dependent effect of allopurinol on Human Foreskin Fibroblasts (HFF) and Human Umbilical Vein Endothelial Cells (HUVEC) under hypoxia and normoxia. Under normoxia and hypoxia, high dose allopurinol reduced the accumulation of HIF-1α protein in HFF and HUVEC cells. Allopurinol had only marginal effects on HIF-1α mRNA level in both cellular systems. Interestingly, allopurinol effects over the HIF system were independent of prolyl-hydroxylase activity. Finally, allopurinol treatment reduced angiogenesis traits in HUVEC cells in an in vitro model. Taken together these results indicate that high doses of allopurinol inhibits the HIF system and pro-angiogenic traits in cells.

  4. 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

  5. The Problem of using Quartz as a radiation dosimeter: fundamentals of dose dependence

    NASA Astrophysics Data System (ADS)

    King, G. E.; Finch, A. A.; Robinson, R. A. J.; Hole, D. E.

    2009-04-01

    Quartz is widely used as a radiation dosimeter in Quaternary geomorphological and archaeological dating applications through Optically Stimulated Luminescence (over 1,200 journal publications since 2000). However, obtaining an accurate equivalent radiation dose (DE) can be challenging, especially where the luminescence intensity of the quartz is dim. The causes of variation in luminescence intensity between quartz grains of different provenances, transport and thermal histories is unknown, however it has been suggested that it relates to either the dosimetric history of the grain, or mechanical processes which occur in transit. Investigation of the fundamental properties of the luminescence of quartz, enables investigation of dose dependent changes in luminescence intensity. A series of dose dependence experiments were conducted using spectroscopic ionoluminescence, which comprises the excitation of quartz with protons accelerated at 0.95 MeV. The energy delivered to the sample throughout ion implantation is similar to that received during gamma irradiation, and thus approximates sample radiation dosing. A natural macro-crystal of α-quartz was investigated parallel and perpendicular to c, to observe any orientation dependent effects, as well as a calibration quartz from the Risø National Laboratory, Denmark, and a Scottish geomorphological sample, prepared using standard laboratory procedures. The calibration quartz sample has excellent luminescence intensity and is suited to analysis using the single-aliquot regenerative dose (SAR) standard OSL protocol, the Scottish sample alternatively has very dim luminescence and exhibits variable behaviour when analysed with SAR. Despite the differences between the luminescence behaviour of the samples, all three responded to the dose dependence experiments in a similar manner. The UV/blue emission was observed to deplete with increasing dose, whereas the red emission, not normally analysed within OSL, exhibited increased

  6. Reduced incidence of interstitial pneumonitis after allogeneic hematopoietic stem cell transplantation using a modified technique of total body irradiation

    PubMed Central

    Chiang, Yun; Tsai, Cheng-Hong; Kuo, Sung-Hsin; Liu, Chieh-Yu; Yao, Ming; Li, Chi-Cheng; Huang, Shang-Yi; Ko, Bor-Sheng; Lin, Chien-Ting; Hou, Hsin-An; Chou, Wen-Chien; Liu, Jia-Hau; Lin, Chien-Chin; Wu, Shang-Ju; Hsu, Szu-Chun; Chen, Yao-Chang; Lin, Kai-Hsin; Lin, Dong-Tsamn; Chou, Hsien-Tang; Lu, Meng-Yu; Yang, Yung-Li; Chang, Hsiu-Hao; Liu, Ming-Chih; Liao, Xiu-Wen; Wu, Jian-Kuen; Chou, Sheng-Chieh; Cheng, Chieh-Lung; Chen, Chien-Yuan; Tsay, Woei; Tien, Hwei-Fang; Tang, Jih-Luh; Chen, Yu-Hsuan

    2016-01-01

    Allogeneic hematopoietic stem cell transplantation is a curative-intent treatment for patients with high-risk hematologic diseases. However, interstitial pneumonitis (IP) and other toxicities remain major concerns after total body irradiation (TBI). We have proposed using linear accelerators with rice-bag compensators for intensity modulation (IM-TBI), as an alternative to the traditional cobalt-60 teletherapy with lung-shielding technique (Co-TBI). Patients who received a TBI-based myeloablative conditioning regimen between 1995 and 2014 were recruited consecutively. Before March 2007, TBI was delivered using Co-TBI (n = 181); afterward, TBI was administered using IM-TBI (n = 126). Forty-four patients developed IP; of these cases, 19 were idiopathic. The IP-related mortality rate was 50% in the total IP cohort and 63% in the idiopathic subgroup. The 1-year cumulative incidences of IP and idiopathic IP were 16.5% and 7.4%, respectively; both rates were significantly higher in the Co-TBI group than in the IM-TBI group. Multivariate analysis revealed that Co-TBI was an independent prognostic factor for both total and idiopathic IP. In the acute myeloid leukemia subgroup, patients with different TBI techniques had similar outcomes for both overall and relapse-free survival. In conclusion, IM-TBI is an easy and effective TBI technique that could substantially reduce the complication rate of IP without compromising treatment efficacy. PMID:27830767

  7. Fludarabine-based reduced intensity conditioning transplants have a higher incidence of cytomegalovirus reactivation compared with myeloablative transplants.

    PubMed

    George, B; Kerridge, I; Gilroy, N; Huang, G; Hertzberg, M; Gottlieb, D; Bradstock, K

    2010-05-01

    Two hundred and ten adult CMV seropositive patients undergoing myeloablative conditioning (MAC) [n=127] or reduced intensity conditioning (RIC) [n=83] transplants (HCT) were serially monitored for CMV reactivation and disease, using a qualitative polymerase chain reaction (PCR) followed by quantitation with pp65 antigen or quantitative PCR. CMV reactivation occurred in 53 RIC (63.9%) and 61 MAC (48%; P=0.03) transplants at a median of 47 days (range: 24-1977). Risk factors identified included acute GVHD (P=0.001), RIC regimen (P=0.03), unrelated donor (P=0.02), use of anti-thymocyte globulin/alemtuzumb (P=0.02) and use of bone marrow in MAC transplants (P=0.011). On multivariate analysis, RIC transplants and acute GVHD remained independent predictors. Treatment with antiviral drugs resulted in CMV negativity rates of 86.8% in MAC and 88.6% in RIC transplants. CMV disease occurred in 10.8% of RIC and 4.7% of MAC transplants (P=0.15). At a median follow-up of 26 months (range: 3-88), 48.1% of RIC and 50.3% of MAC transplants are alive. The higher incidence of CMV reactivation among RIC transplants suggests the need for novel prophylactic or pre-emptive strategies in this high-risk group of patients.

  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.

  9. Drug and light dose dependence of PDT on pancreatic cancer cells in vitro

    NASA Astrophysics Data System (ADS)

    Halkiotis, Konstantinos N.; Manolopoulos, L. D.; Uzunoglou, Nikolaos K.; Yova, Dido M.

    1998-07-01

    Photodynamic therapy (PDT) is a promising new treatment for a variety of malignant tumors. Recently, PDT has been investigated as an alternative treatment for pancreatic carcinoma. The selection of photosensitizer and laser light are equally important for the treatment efficacy. The purpose of this study is to evaluate drug and light dose dependence of photodynamic effect in pancreatic cancer cells. Zinc tetrasulfonated phthalocyanines used as photosensitizer and a novel diode laser system terminated at alight shaping diffuser was used as light source. Viability was measured 24 and 72 hours after treatment and almost 100 percent lethality levels were achieved, by using low light doses independently of drug concentration. The results are discussed in correlation with light and drug doses.

  10. Dose-dependent effect of experimental Schmallenberg virus infection in sheep.

    PubMed

    Poskin, A; Martinelle, L; Mostin, L; Van Campe, W; Dal Pozzo, F; Saegerman, C; Cay, A B; De Regge, N

    2014-09-01

    Schmallenberg virus (SBV) is an orthobunyavirus affecting European domestic ruminants. In this study, the dose-dependent effect of experimental infection of sheep with SBV was evaluated. Four groups of three ewes were each inoculated subcutaneously with 1 mL of successive 10-fold dilutions of an SBV infectious serum. The ewes were monitored for 10 days, but no clinical signs were observed. The number of productively infected animals within each group, as evidenced by viraemia, seroconversion and viral RNA in the organs, depended on the inoculated dose, indicating that a critical dose has to be administered to obtain a homogeneous response in infected animals under experimental conditions. In the productively infected animals, no statistical differences between the different inoculation doses were found in the duration or quantity of viral RNA circulating in blood, nor in the amount of viral RNA present in virus positive lymphoid organs.

  11. 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.

  12. Resuscitation with Lipid Emulsion: Dose-dependent Recovery from Cardiac Pharmacotoxicity Requires a Cardiotonic Effect

    PubMed Central

    Fettiplace, Michael R.; Akpa, Belinda S.; Ripper, Richard; Zider, Brian; Lang, Jason; Rubinstein, Israel; Weinberg, Guy

    2014-01-01

    Background Recent publications have questioned the validity of the “lipid sink” theory of lipid resuscitation while others have identified sink-independent effects and posed alternative mechanisms like hemodilution. To address these issues, we tested the dose-dependent response to intravenous lipid emulsion during reversal of bupivacaine-induced cardiovascular toxicity in vivo. Subsequently, we modeled the relative contribution of volume resuscitation, drug sequestration, inotropy and combined drug sequestration and inotropy to this response using an in silico model. Methods Rats were surgically prepared to monitor cardiovascular metrics and deliver drugs. Following catheterization and instrumentation, animals received a nonlethal dose of bupivacaine to produce transient cardiovascular toxicity, then were randomized to receive one of four treatments: 30% or 20% intravenous lipid emulsion, intravenous saline or no treatment (n = 7 per condition; 28 total animals). Recovery responses were compared to the predictions of a pharmacokinetic-pharmacodynamic model parameterized using previously published laboratory data. Results Rats treated with lipid emulsions recovered faster than did rats treated with saline or no treatment. Intravenous lipid emulsion of 30% elicited the fastest hemodynamic recovery followed in order by 20% intravenous lipid emulsion, saline, and no-treatment. An increase in arterial blood pressure underlay the recovery in both lipid-emulsion treated groups. Heart rates remained depressed in all four groups throughout the observation period. Model predictions mirrored the experimental recovery and the model that combined volume, sequestration and inotropy predicted in vivo results most accurately. Conclusion Intravenous lipid emulsion accelerates cardiovascular recovery from bupivacaine toxicity in a dose-dependent manner, driven by a cardiotonic response that complements the previously reported sequestration effect. PMID:24496123

  13. Memory impairment in rats after desflurane anesthesia is age and dose dependent.

    PubMed

    Callaway, Jennifer K; Jones, Nigel C; Royse, Alistair G; Royse, Colin F

    2015-01-01

    Post-operative cognitive dysfunction (POCD) predominantly affects the elderly who suffer memory and concentration deficits after anesthesia and surgery. Animal studies have demonstrated anesthetic alone may contribute to POCD but results are variable and little is known about common anesthetics other than isoflurane. The present study investigated dose-dependence of desflurane anesthesia in young adult and aged rats. We hypothesize higher concentrations of desflurane will result in memory impairment in the water maze and that impairment will be worse in aged rats. Effects of anesthesia (1 or 1.5 MAC, 4 h) desflurane, or sham exposure on cognition were investigated in young adult (3 months) and aged (20-24 months) rats at 1, 4, and 12 weeks post-exposure. The Morris water maze was used to assess acquisition and retention of spatial reference memory. Latency to find the hidden platform and swimming speed were compared between treatments. Aged rats showed significant impairment in task acquisition after exposure to 1.5 MAC, but not 1.0 MAC desflurane anesthetic when tested 1 week following exposure. Latency to find the platform and distance travelled were significantly longer in aged rats given 1.5 MAC desflurane (latency: F(1,108) = 19.71, p < 0.0001; distance: F(1,108) = 5.79, p = 0.018). Deficits were not long-lasting and were no longer present at 4 or 12 weeks. In contrast, young adult rats performed equally as well as sham-exposed control rats irrespective of desflurane dose. This study showed the effects of desflurane on learning and memory in the water maze are age and dose dependent and are brief in duration.

  14. Dose-Dependent Effect of Deltamethrin in Testis, Liver, and Kidney of Wistar Rats

    PubMed Central

    Sharma, Poonam; Singh, Rambir; Jan, Mysra

    2014-01-01

    Objectives: Deltamethrin is a synthetic pyrethroid insecticide used worldwide in agriculture, household pest control, protection of foodstuff, and disease vector control. Although initially thought to be least toxic, a number of recent reports showed its toxic effects in mammalian and non-mammalian animal species. The current study was performed to assess the dose-dependent deltamethrin toxicity on testes, liver, and kidney of male Wistar rats. Materials and Methods: Twenty-four rats were divided in four groups of 6 each. Group A served as normal control. Group B, C, and D were administered with different doses (2 or 3 or 6 mg/kg corresponding to 1/30th or 1/20th or 1/10th of LD50, respectively) of deltamethrin for 28 days. Results: Deltamethrin exposure caused a significant reduction in weight of reproductive organs, decrease in sperm count, sperm motility, serum testosterone (T), follicle stimulating hormones (FSH), and luteinizing hormones (LH) in testis. Glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione S transferase (GST), glutathione reductase (GR), glutathione peroxidase (GPx) were decreased in testis, liver and kidney of exposed rats. Deltamethrin exposure significantly increased sperm abnormalities in testis. Significant increase in lipid peroxidation (LPO) level was observed in testis, liver and kidney. Deltamethrin also caused histological alterations in testes, liver, and kidney. Conclusions: The results indicated that deltamethrin at a dose of 6 mg/kg exerts significant harmful effects on testes, liver and kidney as compare to 2 mg and 3 mg/kg. The study concluded that the system toxicity induced by deltamethrin was dose dependent. PMID:25253921

  15. 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

  16. Overexpressed heat shock protein 70 protects cells against DNA damage caused by ultraviolet C in a dose-dependent manner

    PubMed Central

    Niu, Piye; Liu, Lin; Gong, Zhiyong; Tan, Hao; Wang, Feng; Yuan, Jing; Feng, Youmei; Wei, Qingyi; Tanguay, Robert M; Wu, Tangchun

    2006-01-01

    Heat shock protein 70 (Hsp70) comprises proteins that have been reported to protect cells, tissues, and organisms against damage from a wide variety of stressful stimuli; however, little is known about whether Hsp70 protects against DNA damage. In this study, we investigated the relationship between Hsp70 expression and the levels of ultraviolet C (UVC)–induced DNA damage in A549 cells with normal, inhibited, and overexpressed Hsp70 levels. Hsp70 expression was inhibited by treatment with quercetin or overexpressed by transfection of plasmids harboring the hsp70 gene. The level of DNA damage was assessed by the comet assay. The results showed that the levels of DNA damage (shown as the percentage of comet cells) in A549 cells increased in all cells after exposure to an incident dose of 0, 10, 20, 40, and 80 J/m2 whether Hsp70 was inhibited or overexpressed. This response was dose dependent: a protection against UVC-induced DNA damage in cells with overexpressed Hsp70 was observed at UVC dose 20 J/ m2 with a maximum at 40 J/m2 when compared with cells with normal Hsp70 levels and in quercetin-treated cells. This differential protection disappeared at 80 J/m2. These results suggest that overexpressed Hsp70 might play a role in protecting A549 cells from DNA damage caused by UVC irradiation, with a threshold of protection from at UVC irradiation-induced DNA damage by Hsp70. The detailed mechanism how Hsp70 is involved in DNA damage and possible DNA repair warrants further investigation. PMID:16817322

  17. Dose-dependent effects of docosahexaenoic acid supplementation on blood lipids in statin-treated hyperlipidaemic subjects.

    PubMed

    Meyer, Barbara J; Hammervold, Tone; Rustan, Arild Chr; Howe, Peter R C

    2007-03-01

    The objective of the study was to evaluate potential benefits of docosahexaenoic acid (DHA) rich fish oil supplementation as an adjunct to statin therapy for hyperlipidaemia. A total of 45 hyperlipidaemic patients on stable statin therapy with persistent elevation of plasma triglycerides (averaging 2.2 mmol/L) were randomised to take 4 g/day (n = 15) or 8 g/day (n = 15) of tuna oil or olive oil (placebo, n = 15) for 6 months. Plasma lipids, blood pressure and arterial compliance were assessed initially and after 3 and 6 months in 40 subjects who completed the trial. Plasma triglycerides were reduced 27% by 8 g/day DHA-rich fish oil (P < 0.05) but not by 4 g/day when compared with the placebo and this reduction was achieved by 3 months and was sustained at 6 months. Even though total cholesterol was already well controlled by the statin treatment (mean initial level 4.5 mmol/L), there was a further dose-dependent reduction with fish oil supplementation (r = -0.344, P < 0.05). The extent of total cholesterol reduction correlated (r = -0.44) with the initial total cholesterol levels (P < 0.005). In the subset with initial plasma cholesterol above 3.8 mmol/L, plasma very low density lipoprotein (VLDL), intermediate-density lipoprotein (IDL) and low-density lipoprotein (LDL) were isolated and assayed for cholesterol and apolipoprotein B (apoB) at the commencement of the trial and at 3 months of intervention. Fish oil tended to lower cholesterol and apoB in VLDL and raise both in LDL. There were no changes in IDL cholesterol, IDL apoB and high-density lipoprotein cholesterol. The results demonstrate that DHA-rich fish oil supplementation (2.16 g DHA/day) can improve plasma lipids in a dose-dependent manner in patients taking statins and these changes were achieved by 3 months. Fish oil in addition to statin therapy may be preferable to drug combinations for the treatment of combined hyperlipidaemia.

  18. 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

  19. Dose-dependent effect of galangin on fructose-mediated insulin resistance and oxidative events in rat kidney.

    PubMed

    Sivakumar, Allur S; Viswanathan, P; Anuradha, Carani V

    2010-01-01

    Galangin is an antioxidant flavonol present in high concentrations in the rhizome of Alpinia galanga. We investigated the effect of galangin on whole-body insulin resistance and kidney oxidative stress in a fructose-induced rat model of metabolic syndrome. Male albino Wistar rats were divided into 6 groups containing six animals each. Groups I and VI received a starch-based control diet, while groups II, III, IV and V were fed a high fructose diet (60 g/100 g). Groups III, IV and V additionally received galangin (50, 100 and 200 μg/kg body weight, respectively) while group VI received 200 μg galangin/kg body weight. At the end of 60 days, fructose-fed rats exhibited insulin resistance, increased levels of peroxidation end products and diminished antioxidant status. galangin, dose-dependently normalized blood glucose and insulin levels. The minimum effective dose was 100 μg galangin/kg body weight. At this dose, galangin also prevented the development of insulin resistance and the exaggerated the response to oral glucose challenge. The oxidant-antioxidant balance was maintained by galangin. Micro-albuminuria and tubular and glomerular changes observed in fructose-treated rats were significantly prevented by galangin (100 μg/kg body weight). These findings imply that galangin potentiates insulin sensitivity and antioxidant capacity and reduces renal damage in this dietary model of metabolic syndrome.

  20. A systematic review to evaluate exercise for anterior cruciate ligament injuries: does this approach reduce the incidence of knee osteoarthritis?

    PubMed Central

    Duncan, Koji J; Chopp-Hurley, Jaclyn N; Maly, Monica R

    2016-01-01

    Purpose Among a variety of conservative and surgical options to treat anterior cruciate ligament (ACL) injuries, we do not understand which options could potentially prevent knee osteoarthritis (OA). The aim of this systematic review was to examine the evidence pertaining to exercise treatment of ACL injuries in the context of knee OA. Methods Medline, Embase, CINAHL, PubMed, and PEDro (Physiotherapy Evidence Database) databases were systematically searched using keywords encompassed within four primary key terms: knee, osteoarthritis, anterior cruciate ligament, and exercise. Clinical studies evaluating the effect of an exercise treatment for ACL injuries on the development of knee OA in adult humans were included. The PEDro scale was used to critically assess the studies included in the review. Results Eighteen studies were included in this review, with a median PEDro score of 6/11 (range, 2/11–9/11). Three studies provided statistical evidence that exercise following ACL injury lowered the risk for knee OA development. Nine studies demonstrated no benefit of exercise in preventing knee OA incidence relative to either operative treatment or the contralateral, unaffected knee. However, exercise resulted in higher knee instability. Nonetheless, there were no significant differences in subjective or objective knee outcomes for early versus late ACL reconstruction. Limitations This review was not registered through PROSPERO. Conclusion The relationship between a rehabilitative exercise for ACL injuries and long-term knee OA prevalence is inconclusive. However, research suggests initial conservative treatment with optional late ACL reconstruction because this treatment strategy may reduce the risk of knee OA. More research, ideally randomized controlled trials or comparable designs, is required prior to establishing clinical guidelines for ACL injury management. PMID:27843365

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

    PubMed Central

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

    2016-01-01

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

  2. Incidence and risk factors for moderate-to-severe veno-occlusive disease of the liver after allogeneic stem cell transplantation using a reduced intensity conditioning regimen.

    PubMed

    Tsirigotis, P D; Resnick, I B; Avni, B; Grisariu, S; Stepensky, P; Or, R; Shapira, M Y

    2014-11-01

    The incidence and outcome of moderate-to-severe veno-occlusive (VOD) disease was analyzed in 271 consecutive patients with hematological malignancies who underwent allogeneic SCT (allo-SCT) using the same reduced intensity regimen (RIC). RIC consisted of fludarabine, BU and antithymocyte globulin (ATG). Twenty-four out of 271 patients (8.8%) developed VOD, which was severe in only 4 (1.4%) out of 24 cases. All four patients with severe VOD finally succumbed to their disease. In multivariate analysis, i.v. administration of BU was associated with significant reduced incidence of VOD as compared with per os administration. In conclusion, VOD remains a serious complication of allo-SCT using RIC regimens containing BU. Although the incidence of severe VOD is very low, the overall mortality rate in the group of patients with severe VOD remains extremely high and therefore novel treatment approaches are needed.

  3. Metformin Use Is Associated with Reduced Incidence and Improved Survival of Endometrial Cancer: A Meta-Analysis

    PubMed Central

    Zhu, Ling-Yan; Li, Yu; Yu, Jiao; Wang, Jiao; Zeng, Xiang-Xia; Hu, Kai-Xiang; Liu, Jian-Ying

    2017-01-01

    Studies have suggested that metformin can potentially decrease the incidence of cancer and improve survival outcomes. However, the association between metformin use and the incidence and survival of endometrial cancer (EC) remains controversial. So, a meta-analysis was performed. An electronic search was conducted using PubMed, EMBASE, and Web of Science. The outcome measures were relative risks (RRs) or hazard ratios (HRs) with 95% confidence intervals (CIs) comparing the EC incidence and survival in patients treated with and without metformin. Eleven studies involving 766,926 participants were included in this study. In the pooled analysis of five studies which evaluated the association of metformin use with the incidence of EC, we found that metformin use was associated with a 13% reduction in EC risk among patients with diabetes (RR = 0.87, 95% CI: 0.80–0.95; p = 0.006). In the pooled analysis of six retrospective cohort studies evaluating the effect of metformin on the survival of EC patients, we found that, relative to nonuse, metformin use significantly improved the survival of EC patients (HR = 0.63, 95% CI: 0.45–0.87; p = 0.006). This study showed that metformin use was significantly associated with a decreased incidence of EC in diabetes and a favorable survival outcome of EC patients.

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

    PubMed

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

    2015-01-01

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

  5. 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

  6. RAD001 (everolimus) induces dose-dependent changes to cell cycle regulation and modifies the cell cycle response to vincristine.

    PubMed

    Saunders, P O; Weiss, J; Welschinger, R; Baraz, R; Bradstock, K F; Bendall, L J

    2013-10-01

    More than 50% of adults and ~20% of children with pre-B acute lymphoblastic leukemia (ALL) relapse following treatment. Dismal outcomes for patients with relapsed or refractory disease mandate novel approaches to therapy. We have previously shown that the combination of the mTOR inhibitor RAD001 (everolimus) and the chemotherapeutic agent vincristine increases the survival of non-obese diabetic/severe combined immuno-deficient (NOD/SCID) mice bearing human ALL xenografts. We have also shown that 16 μM RAD001 synergized with agents that cause DNA damage or microtubule disruption in pre-B ALL cells in vitro. Here, we demonstrate that RAD001 has dose-dependent effects on the cell cycle in ALL cells, with 1.5 μM RAD001 inhibiting pRb, Ki67 and PCNA expression and increasing G0/1 cell cycle arrest, whereas 16 μM RAD001 increases pRb, cyclin D1, Ki67 and PCNA, with no evidence of an accumulation of cells in G0/1. Transition from G2 into mitosis was promoted by 16 μM RAD001 with reduced phosphorylation of cdc2 in cells with 4 N DNA content. However, 16 μM RAD001 preferentially induced cell death in cells undergoing mitosis. When combined with vincristine, 16 μM RAD001 reduced the vincristine-induced accumulation of cells in mitosis, probably as a result of increased death in this population. Although 16 μM RAD001 weakly activated Chk1 and Chk2, it suppressed strong vincristine-induced activation of these cell cycle checkpoint regulators. We conclude that RAD001 enhances chemosensitivity at least in part through suppression of cell cycle checkpoint regulation in response to vincristine and increased progression from G2 into mitosis.

  7. 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.

  8. Dose dependence of surface damage profiles for Ge(111) irradiated with 3 keV Ar +

    NASA Astrophysics Data System (ADS)

    Kido, Yoshiaki; Nakano, Hirohiko

    1990-12-01

    The damage profiles of 3 keV Ar + -irradiated Ge(111) were measured by medium energy ion scattering (MEIS) with 220 keV H + beams. A depth resolution of 0.5 nm has been achieved using an electrostatic toroidal analyzer. With doses over 1 × 10 14Ar+/ cm2 at room temperature, an amorphous layer is formed and the amorphous layer thickness is saturated by a dose of 1 × 10 15Ar+/ cm2. The saturated amorphous layer thickness of 12-13 nm obtained is in good agreement with that observed by a cross section transmission electron microscope. The dose dependence of the induced defects derived from MEIS is consistent with that determined by electron channeling pattern analysis. The amorphized damage profiles determined directly by MEIS agree well with those obtained by solving the rate equation using the unsaturated initial defect profile for a dose of 2 × 10 13Ar+/ cm2 and assuming a sputtering rate of 2.4-3.0.

  9. 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.

  10. Mechanisms of estrogens' dose-dependent neuroprotective and neurodamaging effects in experimental models of cerebral ischemia.

    PubMed

    Strom, Jakob O; Theodorsson, Annette; Theodorsson, Elvar

    2011-01-01

    Ever since the hypothesis was put forward that estrogens could protect against cerebral ischemia, numerous studies have investigated the mechanisms of their effects. Despite initial studies showing ameliorating effects, later trials in both humans and animals have yielded contrasting results regarding the fundamental issue of whether estrogens are neuroprotective or neurodamaging. Therefore, investigations of the possible mechanisms of estrogen actions in brain ischemia have been difficult to assess. A recently published systematic review from our laboratory indicates that the dichotomy in experimental rat studies may be caused by the use of insufficiently validated estrogen administration methods resulting in serum hormone concentrations far from those intended, and that physiological estrogen concentrations are neuroprotective while supraphysiological concentrations augment the damage from cerebral ischemia. This evidence offers a new perspective on the mechanisms of estrogens' actions in cerebral ischemia, and also has a direct bearing on the hormone replacement therapy debate. Estrogens affect their target organs by several different pathways and receptors, and the mechanisms proposed for their effects on stroke probably prevail in different concentration ranges. In the current article, previously suggested neuroprotective and neurodamaging mechanisms are reviewed in a hormone concentration perspective in an effort to provide a mechanistic framework for the dose-dependent paradoxical effects of estrogens in stroke. It is concluded that five protective mechanisms, namely decreased apoptosis, growth factor regulation, vascular modulation, indirect antioxidant properties and decreased inflammation, and the proposed damaging mechanism of increased inflammation, are currently supported by experiments performed in optimal biological settings.

  11. Dose-dependent clinical and immunological efficacy of sublingual immunotherapy with mite monomeric allergoid.

    PubMed

    Di Gioacchino, M; Cavallucci, E; Ballone, E; Cervone, M; Di Rocco, P; Piunti, E; Filardo, G S; Turi, M C; Mangifesta, R; Quecchia, C; Mistrello, G; Braga, M; Petrarca, C

    2012-01-01

    Sublingual immunotherapy with monomeric carbamylated allergoid (LAIS) is an effective and well tolerated treatment of respiratory allergy. The aim of the present study was to correlate the efficacy of two maintenance doses (1000 AU vs 3000 AU) of LAIS with the immunological modulation of allergen-driven Th1, Th2 and T regulatory cytokines produced in vitro by PBMCs, in patients suffering from mite allergic rhinitis. Forty-eight consecutive patients with mite allergic rhinitis were recruited. Patients were randomly assigned to group A (n=24) or group B (n=24), respectively receiving 1000 AU or 3000 AU weekly during one-year maintenance phase. Each patient was evaluated for rhinitis severity (ARIA protocol), and for drug consumption at the time of the inclusion and after 6 and 12 months of treatment. Patients were also asked to report the perceived severity of the disease and the tolerability of the treatment in a visual analogical scale (VAS). Before and at the end of the treatment allergen-driven release of cytokines by PBMCs in vitro was measured. After 1-year treatment, a statistically significant reduction of all clinical parameters was observed in all patients, associated with reduction of IL-4 and increase of INF-γ secreted in vitro by mite-challenged PBMCs. Notably, the group treated with the higher dose showed significantly better clinical and immunological results. The efficacy of LAIS is correlated to the immune modulation in a clear dose-dependent effect.

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

    PubMed

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

    2010-10-01

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

  13. 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.

  14. 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.

  15. 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

  16. Hydrogen Peroxide Modifies Human Sperm Peroxiredoxins in a Dose-Dependent Manner1

    PubMed Central

    O'Flaherty, Cristian; Rico de Souza, Angela

    2010-01-01

    Low levels of reactive oxygen species (ROS) modulate signaling pathways required for human sperm activation, but high levels impair sperm function, leading to infertility. Peroxiredoxins (PRDXs) are enzymes with a dual role as ROS scavengers and modulators of ROS-dependent signaling. The present study aimed to characterize PRDXs in human spermatozoa and possible modifications resulting from hydrogen peroxide (H2O2). We found PRDX1, PRDX4, PRDX5, and PRDX6 in both seminal plasma and spermatozoa. Using immunocytochemistry, we demonstrated that these PRDXs are differentially localized in the head, acrosome, mitochondrial sheath, and flagellum. These observations were confirmed by immunoblotting using cytosolic, Triton-soluble and -insoluble, and head and flagella sperm fractions. PRDXs are dose-dependently modified by H2O2, as seen by the formation of disulfide bridges and high-molecular-mass complexes. This first study, to our knowledge, on PRDXs in human spermatozoa indicates that PRDX1, PRDX4, PRDX5, and PRDX6 are modified when spermatozoa are challenged with H2O2. This suggests that PRDXs may protect these cells at high levels of H2O2 but could also control H2O2 levels within different cell compartments so that normal sperm activation can occur. PMID:20864641

  17. Dose-dependent induction of IL-6 by plant-derived proteases in vitro

    PubMed Central

    Rose, B; Herder, C; Löffler, H; Meierhoff, G; Schloot, N C; Walz, M; Martin, S

    2006-01-01

    Oral administration of proteases such as bromelain and papain is commonly used in patients with a wide range of inflammatory conditions, but their molecular and cellular mechanisms of action are still poorly understood. The aim of our study was to investigate the impact of these proteases on the release of interleukin-6 (IL-6) and other cytokines in the recently described modified mixed lymphocyte culture (MMLC) test system which is based on the mutual interaction of cells of the innate and adaptive immunity. Bromelain and papain enhanced IL-6 production dose-dependently up to 400-fold in MMLC before and up to 30-fold after neutralization of LPS content of proteases using polymyxin B, indicating that IL-6 induction by protease treatment was attributable to both protease action and LPS content of enzyme preparations. The production of IFNγ and IL-10 was not altered by bromelain or papain, indicating a selective and differential immune activation. Both proteases impaired cytokine stability, cell proliferation and expression of cell surface molecules like CD14 only marginally, suggesting no impact of these mechanisms on protease-mediated cytokine release. These findings might provide the mechanistic rationale for the current use of proteases in wound healing and tissue regeneration since these processes depend on IL-6 induction. PMID:16367938

  18. In silico models for the prediction of dose-dependent human hepatotoxicity

    NASA Astrophysics Data System (ADS)

    Cheng, Ailan; Dixon, Steven L.

    2003-12-01

    The liver is extremely vulnerable to the effects of xenobiotics due to its critical role in metabolism. Drug-induced hepatotoxicity may involve any number of different liver injuries, some of which lead to organ failure and, ultimately, patient death. Understandably, liver toxicity is one of the most important dose-limiting considerations in the drug development cycle, yet there remains a serious shortage of methods to predict hepatotoxicity from chemical structure. We discuss our latest findings in this area and present a new, fully general in silico model which is able to predict the occurrence of dose-dependent human hepatotoxicity with greater than 80% accuracy. Utilizing an ensemble recursive partitioning approach, the model classifies compounds as toxic or non-toxic and provides a confidence level to indicate which predictions are most likely to be correct. Only 2D structural information is required and predictions can be made quite rapidly, so this approach is entirely appropriate for data mining applications and for profiling large synthetic and/or virtual libraries.

  19. 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

  20. Dose-dependent cytotoxicity of clinically relevant cobalt nanoparticles and ions on macrophages in vitro.

    PubMed

    Kwon, Young-Min; Xia, Zhidao; Glyn-Jones, Sion; Beard, David; Gill, Harinderjit S; Murray, David W

    2009-04-01

    Despite the satisfactory short-term implant survivorship of metal-on-metal hip resurfacing arthroplasty, periprosthetic soft-tissue masses such as pseudotumours are being increasingly reported. Cytotoxic effects of cobalt or chromium have been suggested to play a role in its aetiology. The aim of this study was to investigate the effects of clinically relevant metal nanoparticles and ions on the viability of macrophages in vitro. A RAW 264.7 murine macrophage cell line was cultured in the presence of either: (1) cobalt, chromium and titanium nanoparticles sized 30-35 nm; or (2) cobalt sulphate and chromium chloride. Two methods were used to quantify cell viability: Alamar Blue assay and Live/Dead assay. The cytotoxicity was observed only with cobalt. Cobalt nanoparticles and ions demonstrated dose-dependent cytotoxic effects on macrophages in vitro: the cytotoxic concentrations of nanoparticles and ions were 1 x 10(12) particles ml(-1) and 1000 microM, respectively. The high concentration of cobalt nanoparticles required for cytotoxicity of macrophages in vitro suggests that increased production of cobalt nanoparticles in vivo, due to excessive MoM implant wear, may lead to local adverse biological effects. Therefore, cytotoxicity of high concentrations of metal nanoparticles phagocytosed by macrophages located in the periprosthetic tissues may be an important factor in pathogenesis of pseudotumours.

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

    PubMed Central

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

    2016-01-01

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

  2. Verapamil Parameter- and Dose-Dependently Impairs Memory Consolidation in Open Field Habituation Task in Rats

    PubMed Central

    Popović, Natalija; Giménez de Béjar, Verónica; Caballero-Bleda, María; Popović, Miroljub

    2017-01-01

    The purpose of the present study was to examine the effects of the phenylalkylamine class of the L-type voltage-dependent calcium channel antagonist, verapamil (1.0, 2.5, 5.0, or 10 mg/kg i.p.), administered immediately after the acquisition task, on memory consolidation of the open field habituation task, in male Wistar rats. On the 48 h retested trial, all tested parameters (ambulation in the side wall and in the central areas, number of rearing, time spent grooming and defecation rate) significantly decreased in the saline treated animals. A significant decrease of rearing was observed in all verapamil treated groups. On the retention day, the ambulation in the side wall and central areas significantly decreased in the animals treated with 1 mg/kg and 10 mg/kg of verapamil, while the time spent grooming and the defecation rate significantly decreased only in the group treated with 1 mg/kg of verapamil. According to the change ratio scores that correct the individual behavioral baseline differences during initial and final sessions, habituation deficit was found in animals treated with verapamil as follows: ambulation along the side wall area (1, 2.5, and 5 mg/kg), number of rearing (all used dose) and time spent grooming (2.5, 5, and 10 mg/kg). In conclusion, the present data suggest that the post-training administration of verapamil, parameter- and dose-dependently, impairs the habituation to a novel environment. PMID:28119614

  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.

  4. 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.

  5. 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

  6. Reducing the incidence of Obstetric Sphincter Injuries using a hands-on technique: an interventional quality improvement project

    PubMed Central

    Rasmussen, Ole Bredahl; Yding, Annika; Anh Ø, Jacob; Sander Andersen, Charlotte; Boris, Jane

    2016-01-01

    A main concern for women giving birth is the risk of obstetric anal sphincter injuries. In our department the incidence of sphincter injuries was around 8 % among vaginally delivering first time mothers. We aimed to halve the incidence to 4 % or less. A prospective interventional program was instituted. We implemented a hands-on technique with four elements in a bundle of care together with a certification process for all staff on the delivery ward. The incidence of episiotomies served as a balancing indicator. The adherence to three of the four elements of the care bundle rose significantly while the all-or-nothing indicator leveled around 80 %. The median number of deliveries between cases with a sphincter injury increased from 9.5 in the baseline period to 20 during the intervention period. This corresponded with a reduction in the incidence from 7.0 % to 3.4 %. The rate of episiotomy remained low at 8.4 % in this group. By implementing the hands-on technique, we halved the risk of obstetric anal sphincter injuries. Our data suggest that further improvement may be anticipated. The study has demonstrated how implementation of a hands-on technique can be carried out within a quality improvement framework with rapid and sustainable results. PMID:28074131

  7. 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

    2014-05-07

    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.

  8. [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.

  9. Nanosecond pulsed electric field induced dose dependent phosphatidylinositol-4,5-bisphosphate signaling and intracellular electro-sensitization.

    PubMed

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

    2017-03-01

    Previously, it was demonstrated that nanometer-sized pores (nanopores) are formed in outer cellular membranes after exposure to nanosecond electric pulses (nsEPs). We reported that plasma membrane nanoporation affects phospholipids of the cell membrane, culminating in cascading phosphoinositide phosphatidylinositol-4,5-bisphosphate (PIP2) intracellular signaling. In the current study, we show that nsEPs initiated electric field (EF) dose-dependent PIP2 hydrolysis and/or depletion from the plasma membrane. This process was confirmed using fluorescent optical probes of PIP2 hydrolysis: PLCδ-PH-EGFP and GFP-C1-PKCγ-C1a. The 50% maximum response occurs with a single 600ns pulse achieving an effective dose (ED50) of EF~8kV/cm within our model cell system. At 16.2kV/cm, the ED50 for the pulse width was 484ns. Reduction of the pulse width or EF amplitude gradually reduced the observed effect, but twenty 60ns 16.2kV/cm pulses produced an effect similar to a single 600ns pulse of the same amplitude. Propidium iodide (PI) uptake after the nsEP exposure confirmed a strong relationship between EF-induced plasma membrane impact and PIP2 depletion. These results have expanded our current knowledge of nsEPs dependent cell physiological effects, and serve as a basis for model development of new exposure standards, providing novel tools for drug independent stimulation and approaches to differential modulation of key cellular functions.

  10. 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

  11. 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

  12. Induced Terpene Accumulation in Norway Spruce Inhibits Bark Beetle Colonization in a Dose-Dependent Manner

    PubMed Central

    Zhao, Tao; Krokene, Paal; Hu, Jiang; Christiansen, Erik; Björklund, Niklas; Långström, Bo; Solheim, Halvor; Borg-Karlson, Anna-Karin

    2011-01-01

    Background Tree-killing bark beetles (Coleoptera, Scolytinae) are among the most economically and ecologically important forest pests in the northern hemisphere. Induction of terpenoid-based oleoresin has long been considered important in conifer defense against bark beetles, but it has been difficult to demonstrate a direct correlation between terpene levels and resistance to bark beetle colonization. Methods To test for inhibitory effects of induced terpenes on colonization by the spruce bark beetle Ips typographus (L.) we inoculated 20 mature Norway spruce Picea abies (L.) Karsten trees with a virulent fungus associated with the beetle, Ceratocystis polonica (Siem.) C. Moreau, and investigated induced terpene levels and beetle colonization in the bark. Results Fungal inoculation induced very strong and highly variable terpene accumulation 35 days after inoculation. Trees with high induced terpene levels (n = 7) had only 4.9% as many beetle attacks (5.1 vs. 103.5 attacks m−2) and 2.6% as much gallery length (0.029 m m−2 vs. 1.11 m m−2) as trees with low terpene levels (n = 6). There was a highly significant rank correlation between terpene levels at day 35 and beetle colonization in individual trees. The relationship between induced terpene levels and beetle colonization was not linear but thresholded: above a low threshold concentration of ∼100 mg terpene g−1 dry phloem trees suffered only moderate beetle colonization, and above a high threshold of ∼200 mg terpene g−1 dry phloem trees were virtually unattacked. Conclusion/Significance This is the first study demonstrating a dose-dependent relationship between induced terpenes and tree resistance to bark beetle colonization under field conditions, indicating that terpene induction may be instrumental in tree resistance. This knowledge could be useful for developing management strategies that decrease the impact of tree-killing bark beetles. PMID:22028932

  13. 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

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

    PubMed

    Murakami, Akira

    2014-09-01

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

  15. 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.

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

    PubMed

    Aboul-Soud, Mourad A M; Aboul-Enein, Ahmed M; Loake, Gary J

    2009-03-01

    Calcium (Ca(2+)) 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 ([Ca(2+)](cyt)) was investigated. For this purpose, transgenic Arabidopsis seedlings constitutively expressing the luminescent Ca(2+)-sensitive protein apoaequorin (35S::APOAEQUORIN) was employed. In chemiluminescence and in vivo Ca(2+) imaging assays, the NO-donor sodium nitroprusside (SNP) triggered a strong, instantaneous, reproducible, and dose-dependent rise in [Ca(2+)](cyt). Moreover, the observed rise in [Ca(2+)](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 [Ca(2+)](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 Ca(2+) transient. This observation indicates that, in addition to the mobilization of [Ca(2+)](cyt), as an external source in response to NO treatment, there also exists an appreciable contribution of an as yet unidentified internal pool.

  17. 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.

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

    PubMed Central

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

    2016-01-01

    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

  19. Nonlinear dose-dependent impact of D1 receptor activation on motor cortex plasticity in humans.

    PubMed

    Fresnoza, Shane; Paulus, Walter; Nitsche, Michael A; Kuo, Min-Fang

    2014-02-12

    The neuromodulator dopamine plays an important role in synaptic plasticity. The effects are determined by receptor subtype specificity, concentration level, and the kind of neuroplasticity induced. D1-like receptors have been proposed to be involved in cognitive processes via their impact on plasticity. Cognitive studies in humans and animals revealed a dosage-dependent effect of D1-like receptor activation on task performance. In humans, D1-like receptor activation re-establishes plasticity under D2 receptor block. However, a dosage-dependent effect has not been explored so far. To determine the impact of the amount of D1-like receptor activation on neuroplasticity in humans, we combined sulpiride, a selective D2 receptor antagonist, with the dopamine precursor l-DOPA (25, 100, and 200 mg) or applied placebo medication. The impact on plasticity induced by anodal and cathodal transcranial direct current stimulation (tDCS) was compared with the impact on plasticity induced by excitatory and inhibitory paired associative stimulation (PAS) at the primary motor cortex of healthy humans. Stimulation-generated cortical excitability alterations were monitored by transcranial magnetic stimulation-induced motor-evoked potential amplitudes. D1-like receptor activation produced an inverted U-shaped dose-response curve on plasticity induced by both facilitatory tDCS and PAS. For excitability-diminishing tDCS and PAS, aftereffects were abolished or converted trendwise into facilitation. These data extend findings of dose-dependent inverted U-shaped effects of D1 receptor activation on neuroplasticity of the motor cortex.

  20. Corticotropin releasing factor dose-dependently modulates excitatory synaptic transmission in the noradrenergic nucleus locus coeruleus.

    PubMed

    Prouty, Eric W; Waterhouse, Barry D; Chandler, Daniel J

    2017-03-01

    The noradrenergic nucleus locus coeruleus (LC) is critically involved in the stress response and receives afferent input from a number of corticotropin releasing factor (CRF) containing structures. Several in vivo and in vitro studies in rat have shown that CRF robustly increases the firing rate of LC neurons in a dose-dependent manner. While it is known that these increases are dependent on CRF receptor subtype 1 and mediated by effects of cAMP intracellular signaling cascades on potassium conductance, the impact of CRF on synaptic transmission within LC has not been clarified. In the present study, we used whole-cell patch clamp electrophysiology to assess how varying concentrations of bath-applied CRF affect AMPA-receptor dependent spontaneous excitatory post-synaptic currents (sEPSCs). Compared to vehicle, 10, 25, and 100 nm CRF had no significant effects on any sEPSC parameters. Fifty nanomolar CRF, however, significantly increased sEPSC amplitude, half-width, and charge transfer, while these measures were significantly decreased by 200 nm CRF. These observations suggest that stress may differentially affect ongoing excitatory synaptic transmission in LC depending on how much CRF is released from presynaptic terminals. Combined with the well-documented effects of CRF on membrane properties and spontaneous LC discharge, these observations may help explain how stress and CRF release are able to modulate the signal to noise ratio of LC neurons. These findings have implications for how stress affects the fidelity of signal transmission and information flow through LC and how it might impact norepinephrine release in the CNS.

  1. 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

  2. Neuroprotective effect of interleukin-6 regulation of voltage-gated Na(+) channels of cortical neurons is time- and dose-dependent.

    PubMed

    Xia, Wei; Peng, Guo-Yi; Sheng, Jiang-Tao; Zhu, Fang-Fang; Guo, Jing-Fang; Chen, Wei-Qiang

    2015-04-01

    Interleukin-6 has been shown to be involved in nerve injury and nerve regeneration, but the effects of long-term administration of high concentrations of interleukin-6 on neurons in the central nervous system is poorly understood. This study investigated the effects of 24 hour exposure of interleukin-6 on cortical neurons at various concentrations (0.1, 1, 5 and 10 ng/mL) and the effects of 10 ng/mL interleukin-6 exposure to cortical neurons for various durations (2, 4, 8, 24 and 48 hours) by studying voltage-gated Na(+) channels using a patch-clamp technique. Voltage-clamp recording results demonstrated that interleukin-6 suppressed Na(+) currents through its receptor in a time- and dose-dependent manner, but did not alter voltage-dependent activation and inactivation. Current-clamp recording results were consistent with voltage-clamp recording results. Interleukin-6 reduced the action potential amplitude of cortical neurons, but did not change the action potential threshold. The regulation of voltage-gated Na(+) channels in rat cortical neurons by interleukin-6 is time- and dose-dependent.

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

    PubMed

    Winters, Jackson; DeMont, Richard

    2014-01-01

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

  4. 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...

  5. A dose-dependent perturbation in cardiac energy metabolism is linked to radiation-induced ischemic heart disease in Mayak nuclear workers.

    PubMed

    Azimzadeh, Omid; Azizova, Tamara; Merl-Pham, Juliane; Subramanian, Vikram; Bakshi, Mayur V; Moseeva, Maria; Zubkova, Olga; Hauck, Stefanie M; Anastasov, Nataša; Atkinson, Michael J; Tapio, Soile

    2017-02-07

    Epidemiological studies show a significant increase in ischemic heart disease (IHD) incidence associated with total external gamma-ray dose among Mayak plutonium enrichment plant workers. Our previous studies using mouse models suggest that persistent alteration of heart metabolism due to the inhibition of peroxisome proliferator-activated receptor (PPAR) alpha accompanies cardiac damage after high doses of ionising radiation. The aim of the present study was to elucidate the mechanism of radiation-induced IHD in humans. The cardiac proteome response to irradiation was analysed in Mayak workers who were exposed only to external doses of gamma rays. All participants were diagnosed during their lifetime with IHD that also was the cause of death. Label-free quantitative proteomics analysis was performed on tissue samples from the cardiac left ventricles of individuals stratified into four radiation dose groups (0 Gy, < 100 mGy, 100-500 mGy, and > 500 mGy). The groups could be separated using principal component analysis based on all proteomics features. Proteome profiling showed a dose-dependent increase in the number of downregulated mitochondrial and structural proteins. Both proteomics and immunoblotting showed decreased expression of several oxidative stress responsive proteins in the irradiated hearts. The phosphorylation of transcription factor PPAR alpha was increased in a dose-dependent manner, which is indicative of a reduction in transcriptional activity with increased radiation dose. These data suggest that chronic external radiation enhances the risk for IHD by inhibiting PPAR alpha and altering the expression of mitochondrial, structural, and antioxidant components of the heart.

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

    PubMed

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

    2007-07-01

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

  7. The use of angiotensin-converting enzyme inhibitors and diuretics is associated with a reduced incidence of impairment on cognition in elderly women.

    PubMed

    Yasar, S; Zhou, J; Varadhan, R; Carlson, M C

    2008-07-01

    The effects of angiotensin-converting enzyme inhibitors (ACE-Is) and diuretics (used as antihypertensive agents) on global and domain-specific cognitive decline were evaluated in 326 non-demented community-dwelling participants over the age of 70 years in the Women's Health and Aging Study II. Time-dependent Cox proportional hazards regression analysis was used for evaluating the association between parameters. The use of ACE-I for more than 3 years was associated with reduced incidence of impairment on Mini-Mental State Examination (MMSE), Trail Making Test-Part A and Part B (TMT, Parts A and B), Hopkins Verbal Learning Test-Immediate Recall (HVLT-I), and Hopkins Verbal Learning Test-Delayed Recall (HVLT-D). The use of diuretics for more than 3 years was associated with reduced incidence of impairment on MMSE, TMT, Parts A and B, HVLT-I, and (HVLT-D). The presence of vascular disease did not make any difference to these effects. Therefore, the use of ACE-Is or diuretics was associated with reduced incidence of impairment of both global and domain-specific cognition in elderly women, and may help delay progression to dementia.

  8. Failure of cromolyn sodium to reduce the incidence of bronchopulmonary dysplasia: a pilot study. The Neonatal Cromolyn Study Group.

    PubMed

    Watterberg, K L; Murphy, S

    1993-04-01

    This prospective, randomized, blinded clinical trial was conducted to test whether therapy with cromolyn sodium might decrease the incidence or severity of bronchopulmonary dysplasia when given to newborns with respiratory distress syndrome. Cromolyn (20 mg) or placebo was aerosolized to intubated newborns with respiratory distress syndrome every 6 hours, beginning on the first day of intubation. Patients were stratified by birth weight less than 1000 g and 1000 to 2000 g; primary outcome success was defined as survival to 30 days without oxygen dependence. Of 10 patients enrolled who were less than 1000 g birth weight, there were no treatment successes, preventing outcome analysis. The study was discontinued after 28 patients of 1000 to 2000 g birth weight had been studied, at which time it had been found with 95% confidence, with a power of .80, that cromolyn sodium did not decrease by 50% the incidence of bronchopulmonary dysplasia. Severity of bronchopulmonary dysplasia was also similar, with 4 patients in the treatment group and 3 in the placebo group receiving mechanical ventilation at 30 days. Possible reasons for this study outcome include (1) a delivered dose too small to produce a clinical effect; (2) the start of therapy too late to prevent the onset of inflammation; (3) inadequate effect of cromolyn on polymorphonuclear cells in vivo; or (4) development of bronchopulmonary dysplasia through factors unaffected by the actions of cromolyn.

  9. Dietary vitamin D supplementation does not reduce the incidence or severity of asbestos-induced mesothelioma in a mouse model.

    PubMed

    Robinson, Cleo; Woo, Samantha; Nowak, Anna K; Lake, Richard A

    2014-01-01

    Epidemiological studies suggest that vitamin and mineral intake is associated with cancer incidence. A prevention strategy based on diet or dietary supplementation could have enormous benefit, both directly, by preventing disease, and indirectly by alleviating fear in millions of people worldwide who have been exposed to asbestos. We have previously shown that dietary supplementation with the antioxidants vitamins A, E, and selenium does not affect overall survival nor the time to progression of asbestos-induced mesothelioma in MexTAg mice. Here we have extended our analysis to vitamin D. We compared survival of asbestos-exposed MexTAg mice provided with diets that were deficient or supplemented with 4500 IU/kg vitamin D (cholecalciferol). Survival of supplemented mice was significantly shorter than mice given a standard AIN93 diet containing 1000 IU/kg cholecalciferol (median survival was 29 and 32.5 weeks respectively). However, mice deficient in vitamin D had the same rate of mesothelioma development as control mice. Neither the latency time from asbestos exposure to diagnosis nor disease progression after diagnosis were significantly different between mice on these diets. We conclude that vitamin D is unlikely to moderate the incidence of disease in asbestos-exposed populations or to ameliorate the pathology in patients with established mesothelioma.

  10. A transcription activator-like effector from Xanthomonas oryzae pv. oryzicola elicits dose-dependent resistance in rice.

    PubMed

    Hummel, Aaron W; Wilkins, Katherine E; Wang, Li; Cernadas, R Andres; Bogdanove, Adam J

    2017-01-01

    Xanthomonas spp. reduce crop yields and quality worldwide. During infection of their plant hosts, many strains secrete transcription activator-like (TAL) effectors, which enter the host cell nucleus and activate specific corresponding host genes at effector binding elements (EBEs) in the promoter. TAL effectors may contribute to disease by activating the expression of susceptibility genes or trigger resistance associated with the hypersensitive reaction (HR) by activating an executor resistance (R) gene. The rice bacterial leaf streak pathogen X. oryzae pv. oryzicola (Xoc) is known to suppress host resistance, and no host R gene has been identified against it, despite considerable effort. To further investigate Xoc suppression of host resistance, we conducted a screen of effectors from BLS256 and identified Tal2a as an HR elicitor in rice when delivered heterologously by a strain of the closely related rice bacterial blight pathogen X. oryzae pv. oryzae (Xoo) or by the soybean pathogen X. axonopodis pv. glycines. The HR required the Tal2a activation domain, suggesting an executor R gene. Tal2a activity was differentially distributed among geographically diverse Xoc isolates, being largely conserved among Asian isolates. We identified four genes induced by Tal2a in next-generation RNA sequencing experiments and confirmed them using quantitative real-time reverse transcription-polymerase chain reaction (qPCR). However, neither individual nor collective activation of these genes by designer TAL effectors resulted in HR. A tal2a knockout mutant of BLS256 showed virulence comparable with the wild-type, but plasmid-based overexpression of tal2a at different levels in the wild-type reduced virulence in a directly corresponding way. Overall, the results reveal that host resistance suppression by Xoc plays a critical role in pathogenesis. Further, the dose-dependent avirulence activity of Tal2a and the apparent lack of a single canonical target that accounts for HR point to

  11. Dose-Dependent ATP Depletion and Cancer Cell Death following Calcium Electroporation, Relative Effect of Calcium Concentration and Electric Field Strength

    PubMed Central

    Hansen, Emilie Louise; Sozer, Esin Bengisu; Romeo, Stefania; Frandsen, Stine Krog; Vernier, P. Thomas; Gehl, Julie

    2015-01-01

    Background Electroporation, a method for increasing the permeability of membranes to ions and small molecules, is used in the clinic with chemotherapeutic drugs for cancer treatment (electrochemotherapy). Electroporation with calcium causes ATP (adenosine triphosphate) depletion and cancer cell death and could be a novel cancer treatment. This study aims at understanding the relationship between applied electric field, calcium concentration, ATP depletion and efficacy. Methods In three human cell lines — H69 (small-cell lung cancer), SW780 (bladder cancer), and U937 (leukaemia), viability was determined after treatment with 1, 3, or 5 mM calcium and eight 99 μs pulses with 0.8, 1.0, 1.2, 1.4 or 1.6 kV/cm. Fitting analysis was applied to quantify the cell-killing efficacy in presence of calcium. Post-treatment intracellular ATP was measured in H69 and SW780 cells. Post-treatment intracellular ATP was observed with fluorescence confocal microscopy of quinacrine-labelled U937 cells. Results Both H69 and SW780 cells showed dose-dependent (calcium concentration and electric field) decrease in intracellular ATP (p<0.05) and reduced viability. The 50% effective cell kill was found at 3.71 kV/cm (H69) and 3.28 kV/cm (SW780), reduced to 1.40 and 1.15 kV/cm (respectively) with 1 mM calcium (lower EC50 for higher calcium concentrations). Quinacrine fluorescence intensity of calcium-electroporated U937 cells was one third lower than in controls (p<0.0001). Conclusions Calcium electroporation dose-dependently reduced cell survival and intracellular ATP. Increasing extracellular calcium allows the use of a lower electric field. General Significance This study supports the use of calcium electroporation for treatment of cancer and possibly lowering the applied electric field in future trials. PMID:25853661

  12. High salt diets dose-dependently promote gastric chemical carcinogenesis in Helicobacter pylori-infected Mongolian gerbils associated with a shift in mucin production from glandular to surface mucous cells.

    PubMed

    Kato, Sosuke; Tsukamoto, Tetsuya; Mizoshita, Tsutomu; Tanaka, Harunari; Kumagai, Toshiko; Ota, Hiroyoshi; Katsuyama, Tsutomu; Asaka, Masahiro; Tatematsu, Masae

    2006-10-01

    Intake of salt and salty food is known as a risk factor for gastric carcinogenesis. To examine the dose-dependence and the mechanisms underlying enhancing effects, Mongolian gerbils were treated with N-methyl-N-nitrosourea (MNU), Helicobacter pylori and food containing various concentrations of salt, and were sacrificed after 50 weeks. Among gerbils treated with MNU and H. pylori, the incidences of glandular stomach cancers were 15% in the normal diet group and 33%, 36% and 63% in the 2.5%, 5% and 10% NaCl diet groups, showing dose-dependent increase (p < 0.01). Intermittent intragastric injection of saturated NaCl solution, in contrast, did not promote gastric carcinogenesis. In gerbils infected with H. pylori, a high salt diet was associated with elevation of anti-H. pylori antibody titers, serum gastrin levels and inflammatory cell infiltration in a dose-dependent fashion. Ten percent NaCl diet upregulated the amount of surface mucous cell mucin (p < 0.05), suitable for H. pylori colonization, despite no increment of MUC5AC mRNA, while H. pylori infection itself had an opposing effect, stimulating transcription of MUC6 and increasing the amount of gland mucous cell mucin (GMCM). High salt diet, in turn, decreased the amount of GMCM, which acts against H. pylori infection. In conclusion, the present study demonstrated dose-dependent enhancing effects of salt in gastric chemical carcinogenesis in H. pylori-infected Mongolian gerbils associated with alteration of the mucous microenvironment. Reduction of salt intake could thus be one of the most important chemopreventive methods for human gastric carcinogenesis.

  13. Dose-dependent benefits of quercetin on tumorigenesis in the C3(1)/SV40Tag transgenic mouse model of breast cancer

    PubMed Central

    Steiner, JL; Davis, JM; McClellan, JL; Enos, RT; Carson, JA; Fayad, R; Nagarkatti, M; Nagarkatti, PS; Altomare, D; Creek, KE; Murphy, EA

    2014-01-01

    Breast cancer is the leading cause of cancer related death in women. Quercetin is a flavonol shown to have anti-carcinogenic actions. However, few studies have investigated the dose-dependent effects of quercetin on tumorigenesis and none have used the C3(1)/SV40 Tag breast cancer mouse model. At 4 weeks of age female C3(1)/SV40 Tag mice were randomized to one of four dietary treatments (n = 15–16/group): control (no quercetin), low-dose quercetin (0.02% diet), moderate-dose quercetin (0.2% diet), or high-dose quercetin (2% diet). Tumor number and volume was assessed twice a week and at sacrifice (20 wks). Results showed an inverted ‘U’ dose-dependent effect of dietary quercetin on tumor number and volume; at sacrifice the moderate dose was most efficacious and reduced tumor number 20% and tumor volume 78% compared to control mice (C3-Con: 9.0 ± 0.9; C3-0.2%: 7.3 ± 0.9) and (C3-Con: 2061.8 ± 977.0 mm3; and C3-0.2%: 462.9 ± 75.9 mm3). Tumor volume at sacrifice was also reduced by the moderate dose compared to the high and low doses (C3-2%: 1163.2 ± 305.9 mm3; C3-0.02%: 1401.5 ± 555.6 mm3), as was tumor number (C3-2%: 10.7 ± 1.3 mm3; C3-0.02%: 8.1 ± 1.1 mm3). Gene expression microarray analysis performed on mammary glands from C3-Con and C3-0.2% mice determined that 31 genes were down-regulated and 9 genes were up-regulated more than 2-fold (P < 0.05) by quercetin treatment. We report the novel finding that there is a distinct dose-dependent effect of quercetin on tumor number and volume in a transgenic mouse model of human breast cancer, which is associated with a specific gene expression signature related to quercetin treatment. PMID:25482952

  14. 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.

  15. 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.

  16. Statins dose-dependently exert a significant chemopreventive effect on colon cancer in patients with chronic obstructive pulmonary disease: A population-based cohort study

    PubMed Central

    Hsu, Yi-Ping; Sung, Li-Chin; Kao, Pai-Feng; Lin, Chao-Feng; Wu, Alexander T.H.; Yuan, Kevin Sheng-Po; Wu, Szu-Yuan

    2016-01-01

    Purpose We evaluated the chemopreventive effect of statins on colon cancer in patients with chronic obstructive pulmonary disease (COPD) and identified the statin exerting the strongest chemopreventive effect. Methods Using the National Health Insurance Research Database, we identified patients who received a COPD diagnosis in Taiwan between January 1, 2001, and December 31, 2012, and included them in the study cohort. Each patient was followed to assess the colon cancer risk and protective factors. A propensity score was derived using a logistic regression model to estimate the effect of statins by accounting for covariates predicted during the intervention (statins). To examine the dose–response relationship, we categorized statin doses into four groups in each cohort [<28, 28–90, 91–365, and >365 cumulative defined daily dose]. Results Compared with the statin nonusers, the adjusted hazard ratio (aHR) for colon cancer decreased in the statin users (aHR = 0.52, 95% confidence interval = 0.44, 0.62). Hydrophilic statins exerted a stronger preventive effect against colon cancer. Regarding the statin type, lovastatin, pravastatin, and fluvastatin nonsignificantly reduced the colon cancer risk in the patients with COPD. Compared with the statin nonusers, the aHRs for colon cancer decreased in the individual statin users (rosuvastatin, simvastatin, and atorvastatin: aHRs = 0.28, 0.64, and 0.65, respectively). In the sensitivity analysis, statins dose-dependently reduced the colon cancer risk. Conclusions Statins dose-dependently exert significant chemopreventive effects on colon cancer in patients with COPD, with rosuvastatin exerting the largest chemopreventive effect. PMID:27542242

  17. The dose dependence of glucocorticoid-inducible gene expression results from changes in the number of transcriptionally active templates.

    PubMed Central

    Ko, M S; Nakauchi, H; Takahashi, N

    1990-01-01

    Glucocorticoid hormones induce the transcription of genes having glucocorticoid response elements in a dose dependent manner. To determine whether this dose dependence represents a response of individual templates or of the mass of templates, we introduced a bacterial beta-galactosidase gene linked to the glucocorticoid-inducible enhancer/promoter of the mouse mammary tumor virus (MTV) into Ltk- cells and obtained stable transformants containing a single or a few templates per cell. Visual inspection and flow cytometry analysis by enzyme histochemistry assay for beta-galactosidase revealed that individual cells showed very heterogeneous beta-galactosidase activity after 48 h induction with dexamethasone. When the glucocorticoid concentration was increased, an increasing cell population producing beta-galactosidase was observed. These phenomena were probably not due to heterogeneity of template copy number or to a predetermined cellular state among individual cells, since cells forming a single small colony gave similar results. This was also supported by data showing that recloned cells retained both their responsiveness to the glucocorticoid hormone and their digestion pattern in Southern blotting analyses. These results indicate that the dose dependent increase of glucocorticoid-inducible gene expression is caused by an increase in the number of transcriptionally active templates. Images Fig. 1. Fig. 3. Fig. 4. Fig. 5. Fig. 8. PMID:2167833

  18. 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

  19. Dose-dependent biodistribution of prenatal exposure to rutile-type titanium dioxide nanoparticles on mouse testis

    NASA Astrophysics Data System (ADS)

    Kubo-Irie, Miyoko; Uchida, Hiroki; Mastuzawa, Shotaro; Yoshida, Yasuko; Shinkai, Yusuke; Suzuki, Kenichiro; Yokota, Satoshi; Oshio, Shigeru; Takeda, Ken

    2014-02-01

    Titanium dioxide nanoparticles (nano-TiO2), believed to be inert and safe, are used in many products especially rutile-type in cosmetics. Detection, localization, and count of nanoparticles in tissue sections are of considerable current interest. Here, we evaluate the dose-dependent biodistribution of rutile-type nano-TiO2 exposure during pregnancy on offspring testes. Pregnant mice were subcutaneously injected five times with 0.1 ml of sequentially diluted of nano-TiO2 powder, 35 nm with primary diameter, suspensions (1, 10, 100, or 1,000 μg/ml), and received total doses of 0.5, 5, 50, and 500 μg, respectively. Prior to injection, the size distribution of nano-TiO2 was analyzed by dynamic light scattering measurement. The average diameter was increased in a dose-dependent manner. The most diluted concentration, 1 μg/ml suspension, contained small agglomerates averaging 193.3 ± 5.4 nm in diameter. The offspring testes were examined at 12 weeks postpartum. Individual particle analysis in testicular sections under scanning and transmission electron microscopy enabled us to understand the biodistribution. The correlation between nano-TiO2 doses injected to pregnant mice, and the number of agglomerates in the offspring testes was demonstrated to be dose-dependent by semiquantitative evaluation. However, the agglomerate size was below 200 nm in the testicular sections of all recipient groups, independent from the injected dose during pregnancy.

  20. An inactivated gE-negative marker vaccine and an experimental gD-subunit vaccine reduce the incidence of bovine herpesvirus 1 infections in the field.

    PubMed

    Bosch, J C; De Jong, M C; Franken, P; Frankena, K; Hage, J J; Kaashoek, M J; Maris-Veldhuis, M A; Noordhuizen, J P; Van der Poel, W H; Verhoeff, J; Weerdmeester, K; Zimmer, G M; Van Oirschot, J T

    1998-01-01

    An inactivated glycoprotein E-negative vaccine and an experimental glycoprotein D-subunit vaccine against bovine herpesvirus 1 (V1) were examined for their effectiveness in a randomized, double-bline, placebo-controlled field trial comprising 130 dairy farms. The use of these marker vaccines enabled us to monitor the incidence of infections in vaccinated populations. The aims of this trial were to evaluate whether these vaccines: (1) reduce the proportion of outbreaks in dairy herds; and (2) reduced virus transmission within dairy herds and to what extent. Vaccination with either of the two vaccines significantly reduced the proportion of herds wherein an outbreak occurred as well as the virus transmission within herds, as compared to placebo-treated herds. The estimated number of secondary cases caused by one infectious animal, expressed as the reproduction ratio R, was for both vaccines significantly > 1. This indicates that when BHV1 is introduced into vaccinated herds, major outbreaks may still occur.

  1. Matching for the nonconventional MHC-I MICA gene significantly reduces the incidence of acute and chronic GVHD

    PubMed Central

    Carapito, Raphael; Jung, Nicolas; Kwemou, Marius; Untrau, Meiggie; Michel, Sandra; Pichot, Angélique; Giacometti, Gaëlle; Macquin, Cécile; Ilias, Wassila; Morlon, Aurore; Kotova, Irina; Apostolova, Petya; Schmitt-Graeff, Annette; Cesbron, Anne; Gagne, Katia; Oudshoorn, Machteld; van der Holt, Bronno; Labalette, Myriam; Spierings, Eric; Picard, Christophe; Loiseau, Pascale; Tamouza, Ryad; Toubert, Antoine; Parissiadis, Anne; Dubois, Valérie; Lafarge, Xavier; Maumy-Bertrand, Myriam; Bertrand, Frédéric; Vago, Luca; Ciceri, Fabio; Paillard, Catherine; Querol, Sergi; Sierra, Jorge; Fleischhauer, Katharina; Nagler, Arnon; Labopin, Myriam; Inoko, Hidetoshi; von dem Borne, Peter A.; Kuball, Jürgen; Ota, Masao; Katsuyama, Yoshihiko; Michallet, Mauricette; Lioure, Bruno; Peffault de Latour, Régis; Blaise, Didier; Cornelissen, Jan J.; Yakoub-Agha, Ibrahim; Claas, Frans; Moreau, Philippe; Milpied, Noël; Charron, Dominique; Mohty, Mohamad; Zeiser, Robert; Socié, Gérard

    2016-01-01

    Graft-versus-host disease (GVHD) is among the most challenging complications in unrelated donor hematopoietic cell transplantation (HCT). The highly polymorphic MHC class I chain–related gene A, MICA, encodes a stress-induced glycoprotein expressed primarily on epithelia. MICA interacts with the invariant activating receptor NKG2D, expressed by cytotoxic lymphocytes, and is located in the MHC, next to HLA-B. Hence, MICA has the requisite attributes of a bona fide transplantation antigen. Using high-resolution sequence-based genotyping of MICA, we retrospectively analyzed the clinical effect of MICA mismatches in a multicenter cohort of 922 unrelated donor HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 10/10 allele-matched HCT pairs. Among the 922 pairs, 113 (12.3%) were mismatched in MICA. MICA mismatches were significantly associated with an increased incidence of grade III-IV acute GVHD (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.50-2.23; P < .001), chronic GVHD (HR, 1.50; 95% CI, 1.45-1.55; P < .001), and nonelapse mortality (HR, 1.35; 95% CI, 1.24-1.46; P < .001). The increased risk for GVHD was mirrored by a lower risk for relapse (HR, 0.50; 95% CI, 0.43-0.59; P < .001), indicating a possible graft-versus-leukemia effect. In conclusion, when possible, selecting a MICA-matched donor significantly influences key clinical outcomes of HCT in which a marked reduction of GVHD is paramount. The tight linkage disequilibrium between MICA and HLA-B renders identifying a MICA-matched donor readily feasible in clinical practice. PMID:27549307

  2. Matching for the nonconventional MHC-I MICA gene significantly reduces the incidence of acute and chronic GVHD.

    PubMed

    Carapito, Raphael; Jung, Nicolas; Kwemou, Marius; Untrau, Meiggie; Michel, Sandra; Pichot, Angélique; Giacometti, Gaëlle; Macquin, Cécile; Ilias, Wassila; Morlon, Aurore; Kotova, Irina; Apostolova, Petya; Schmitt-Graeff, Annette; Cesbron, Anne; Gagne, Katia; Oudshoorn, Machteld; van der Holt, Bronno; Labalette, Myriam; Spierings, Eric; Picard, Christophe; Loiseau, Pascale; Tamouza, Ryad; Toubert, Antoine; Parissiadis, Anne; Dubois, Valérie; Lafarge, Xavier; Maumy-Bertrand, Myriam; Bertrand, Frédéric; Vago, Luca; Ciceri, Fabio; Paillard, Catherine; Querol, Sergi; Sierra, Jorge; Fleischhauer, Katharina; Nagler, Arnon; Labopin, Myriam; Inoko, Hidetoshi; von dem Borne, Peter A; Kuball, Jürgen; Ota, Masao; Katsuyama, Yoshihiko; Michallet, Mauricette; Lioure, Bruno; Peffault de Latour, Régis; Blaise, Didier; Cornelissen, Jan J; Yakoub-Agha, Ibrahim; Claas, Frans; Moreau, Philippe; Milpied, Noël; Charron, Dominique; Mohty, Mohamad; Zeiser, Robert; Socié, Gérard; Bahram, Seiamak

    2016-10-13

    Graft-versus-host disease (GVHD) is among the most challenging complications in unrelated donor hematopoietic cell transplantation (HCT). The highly polymorphic MHC class I chain-related gene A, MICA, encodes a stress-induced glycoprotein expressed primarily on epithelia. MICA interacts with the invariant activating receptor NKG2D, expressed by cytotoxic lymphocytes, and is located in the MHC, next to HLA-B Hence, MICA has the requisite attributes of a bona fide transplantation antigen. Using high-resolution sequence-based genotyping of MICA, we retrospectively analyzed the clinical effect of MICA mismatches in a multicenter cohort of 922 unrelated donor HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 10/10 allele-matched HCT pairs. Among the 922 pairs, 113 (12.3%) were mismatched in MICA MICA mismatches were significantly associated with an increased incidence of grade III-IV acute GVHD (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.50-2.23; P < .001), chronic GVHD (HR, 1.50; 95% CI, 1.45-1.55; P < .001), and nonelapse mortality (HR, 1.35; 95% CI, 1.24-1.46; P < .001). The increased risk for GVHD was mirrored by a lower risk for relapse (HR, 0.50; 95% CI, 0.43-0.59; P < .001), indicating a possible graft-versus-leukemia effect. In conclusion, when possible, selecting a MICA-matched donor significantly influences key clinical outcomes of HCT in which a marked reduction of GVHD is paramount. The tight linkage disequilibrium between MICA and HLA-B renders identifying a MICA-matched donor readily feasible in clinical practice.

  3. A PERMISSION SYSTEM FOR CARBAPENEM USE REDUCED INCIDENCE OF DRUG-RESISTANT BACTERIA AND COST OF ANTIMICROBIALS AT A GENERAL HOSPITAL IN JAPAN

    PubMed Central

    IKEDA, YOSHIAKI; MAMIYA, TAKAYOSHI; NISHIYAMA, HIDEKI; NARUSAWA, SHIHO; KOSEKI, TAKENAO; MOURI, AKIHIRO; NABESHIMA, TOSHITAKA

    2012-01-01

    ABSTRACT Some drug management systems have been established in Japanese hospitals to reduce medical costs and regulate drug usage. Among the many available prescription drugs, antimicrobials should be given special attention because their inappropriate use often leads to sudden outbreaks of resistant bacteria. As drug specialists, pharmacists should monitor the use of all drugs, particularly antimicrobials. Carbapenems are a class of broad-spectrum antimicrobials that are widely used to treat infections worldwide. However, their inappropriate use has led to an increase in the incidence of drug-resistant bacteria and consequently, medical costs, at hospitals. To reduce inappropriate use and drug resistance, we have established a permission system to control the use of carbapenems at the Japanese Red Cross Nagoya Daiichi Hospital. In this study, we retrospectively evaluated the applicability of the new permission system compared to that of the notification system and the non control system for 14 months each. The two management systems were able to maintain total antibiotic use density and control the outbreak of drug-resistant bacteria (P. aeruginosa, E. coli, and K. pneumoniae). The number of carbapenem prescriptions was decreased dramatically when this permission system was enforced. Compared to the non control system, the cost of antimicrobials was reduced by $757,470 for the 14-month study period using the permission system. These results suggest that our system to control the use of antimicrobials can efficiently suppress the incidence of drug-resistant bacteria and medical costs at hospitals. PMID:22515115

  4. 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.

  5. Effects of reduced deer density on the abundance of Ixodes scapularis (Acari: Ixodidae) and Lyme disease incidence in a northern New Jersey endemic area.

    PubMed

    Jordan, Robert A; Schulze, Terry L; Jahn, Margaret B

    2007-09-01

    We monitored the abundance of Ixodes scapularis Say (Acari: Ixodidae) and the Lyme disease incidence rate after the incremental removal of white-tailed deer, Odocoileus virginianus Zimmermann, within a suburban residential area to determine whether there was a measurable decrease in the abundance of ticks due to deer removal and whether the reduction in ticks resulted in a reduction in the incidence rate within the human population. After three seasons, the estimated deer population was reduced by 46.7%, from the 2002 postfawning estimate of 2,899 deer (45.6 deer per km2) to a 2005 estimate of 1,540 deer (24.3 deer per km2). There was no apparent effect of the deer culling program on numbers of questing I. scapularis subadults in the culling areas, and the overall numbers of host-seeking ticks in the culling areas seemed to increase in the second year of the program. The Lyme disease incidence rate generated by both passive and active surveillance systems showed no clear trend among years, and it did not seem to vary with declining deer density. Given the resources required to mount and maintain a community-based program of sufficient magnitude to effectively reduce vector tick density in ecologically open situations where there are few impediments to deer movement, it may be that deer reduction, although serving other community goals, is unlikely to be a primary means of tick control by itself. However, in concert with other tick control interventions, such programs may provide one aspect of a successful community effort to reduce the abundance of vector ticks.

  6. Shoulder Stretching Intervention Reduces the Incidence of Shoulder and Elbow Injuries in High School Baseball Players: a Time-to-Event Analysis

    PubMed Central

    Shitara, Hitoshi; Yamamoto, Atsushi; Shimoyama, Daisuke; Ichinose, Tsuyoshi; Sasaki, Tsuyoshi; Hamano, Noritaka; Ueno, Akira; Endo, Fumitaka; Oshima, Atsufumi; Sakane, Hideo; Tachibana, Masahiro; Tomomatsu, Yusuke; Tajika, Tsuyoshi; Kobayashi, Tsutomu; Osawa, Toshihisa; Iizuka, Haku; Takagishi, Kenji

    2017-01-01

    We prospectively evaluated the effects of a prevention program on the incidence of shoulder and elbow injuries in high school baseball pitchers. Ninety-two pitchers participated in this study and were taught to perform stretching and strength exercises aimed at improving shoulder external rotation strength in the preseason. The pitchers freely chose to participate in one of four groups [SM-group: performed both exercises, S-group: performed stretching exercise only, M-group: performed strength training only, and N-group: performed neither intervention]. Injury was defined as inability to play for ≥8 days because of shoulder/elbow symptoms. Kaplan-Meier survival curves were generated and hazard ratios (HRs) for injury occurrence were calculated using multivariate Cox regression. Log-rank test was used for between-group comparisons of survival distributions. The injuries occurred in 25, 35, and 57% of participants and median times to injury were 89, 92, and 29.5 days in the S- (n = 32), SM- (n = 46), and N- (n = 14) group, respectively. Nobody chose M-group. HRs were 0.36 and 0.47 for the S- and SM-group, respectively, based on the N-group. The incidence of injury was significantly lower in the S-group than in the N-group (p = 0.04). Daily posterior shoulder stretching may reduce the incidence of the injuries in high school baseball pitchers. PMID:28345616

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

    PubMed

    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.

  8. WE-EF-BRA-10: Prophylactic Cranial Irradiation Reduces the Incidence of Brain Metastasis in a Mouse Model of Metastatic Breast Cancerr

    SciTech Connect

    Smith, D; Debeb, B; Larson, R; Diagaradjane, P; Woodward, W

    2015-06-15

    Purpose: Prophylactic cranial irradiation (PCI) is a clinical technique used to reduce the incidence of brain metastasis and improve overall survival in select patients with acute lymphoblastic leukemia and small-cell lung cancer. We examined whether PCI could benefit breast cancer patients at high risk of developing brain metastases. Methods: We utilized our mouse model in which 500k green fluorescent protein (GFP)-labeled breast cancer cells injected into the tail vein of SCID/Beige mice resulted in brain metastases in approximately two-thirds of untreated mice. To test the efficacy of PCI, one set of mice was irradiated five days after cell injection with a single fraction of 4-Gy (two 2-Gy opposing fields) whole-brain irradiation on the XRAD 225Cx small-animal irradiator. Four controls were included: a non-irradiated group, a group irradiated two days prior to cell injection, and two groups irradiated 3 or 6 weeks after cell injection. Mice were sacrificed four and eight weeks post-injection and were evaluated for the presence of brain metastases on a fluorescent stereomicroscope. Results: The incidence of brain metastasis in the non-irradiated group was 77% and 90% at four and eight weeks, respectively. The PCI group had a significantly lower incidence, 20% and 30%, whereas the other three control groups had incidence rates similar to the non-treated control (70% to 100%). Further, the number of metastases and the metastatic burden were also significantly lower in the PCI group compared to all other groups. Conclusion: The timing of irradiation to treat subclinical disease is critical, as a small dose of whole-brain irradiation given five days after cell injection abrogated tumor burden by greater than 90%, but had no effect when administered twenty-one days after cell injection. PCI is likely to benefit breast cancer patients at high risk of developing brain metastases and should be strongly considered in the clinic.

  9. The efficiency of O-(beta-hydroxyethyl)-rutosides in reducing the incidence of superficial venous insufficiency in patients with calf muscle pump dysfunction.

    PubMed

    Yildiz, Cenk Eray; Conkbayir, Cenk; Huseynov, Eldeniz; Sayin, Omer Ali; Tok, Okan; Kaynak, Gokhan; Cebi, Deniz; Ugurlucan, Murat; Kantarci, Fatih; Inan, Muharrem

    2017-04-01

    Objective We aimed to evaluate the efficiency of O-(beta-Hydroxyethyl)-rutosides (Oxerutin) in reducing the incidence of venous system disease among patients with calf muscle pump dysfunction secondary to immobilization due to lower-limb fractures. Methods A total of 60 patients with lower-limb fractures and immobilized in plaster casts were included in this study randomized into control (n = 30; mean: 30.37 ± 6.03 years; 73.3% males; no treatment) and experiment (n = 30; mean: 31.67 ± 4.76 years; 66.6% males; Oxerutin, 500 mg po q12hr) treatment groups. Doppler ultrasound was performed to evaluate the effect of oxerutin on the alterations in the venous circulation. Results Patients in the control group were determined to be more commonly affected from the below-knee immobilization in terms of venous dysfunction in the great saphenous vein in the below-knee region when compared with the patients in the oxerutin treatment group (46.7 vs. 13.3%, respectively; p = 0.011). Incidence of reflux in the small saphenous vein was more common in the control group during the healing period when compared with the experiment group (40.0 vs. 10.0%, respectively; p = 0.017). None of the patients developed venous thrombosis. Conclusions In conclusion, the impairment of the lower extremity muscle pump should be considered as an important risk factor for venous disease, and should be evaluated. O-(beta-Hydroxyethyl)-rutosides during 6-8 week cast immobilization for a lower limb fracture may be an effective prophylactic regimen in reducing the incidence of reflux in the below-knee superficial veins.

  10. Age- and dose-dependent transplacental carcinogenesis by N-nitrosoethylurea in Syrian golden hamsters.

    PubMed

    Diwan, B A; Rehm, S; Rice, J M

    1996-01-01

    Syrian golden hamsters have a very short period (15 days) of gestation. The implantation of the blastocyst occurs on day 5, embryogenesis proceeds very rapidly thereafter and neural tube closure is completed by day 9. In the present study the effects of two different doses of N-nitrosoethylurea (NEU) administered at various stages of gestation were quantitatively evaluated in Syrian golden hamsters. NEU at either 0.2 or 0.5 mmol/kg was administered transplacentally as a single i.p. injection to pregnant hamsters on gestation days 7, 8, 9, 10, 11, 12, 13, or 14. The incidence, latency period and multiplicity of tumors varied with the dose of NEU and the stage of development at the time of NEU administration. Although tumors of the peripheral nervous system predominated, a variety of other tumors, including melanomas and visceral tumors of epithelial and mesenchymal origin, were also observed in hamster offspring exposed transplacentally to NEU. Sensitivity to transplacental carcinogenesis was maximal during late gestation and very low before day 9.

  11. 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.

  12. Dose-dependent effect of estrogen suppresses the osteo-adipogenic transdifferentiation of osteoblasts via canonical Wnt signaling pathway.

    PubMed

    Gao, Bo; Huang, Qiang; Lin, Yan-Shui; Wei, Bo-Yuan; Guo, Yun-Shan; Sun, Zhen; Wang, Long; Fan, Jing; Zhang, Hong-Yang; Han, Yue-Hu; Li, Xiao-Jie; Shi, Jun; Liu, Jian; Yang, Liu; Luo, Zhuo-Jing

    2014-01-01

    Fat infiltration within marrow cavity is one of multitudinous features of estrogen deficiency, which leads to a decline in bone formation functionality. The origin of this fat is unclear, but one possibility is that it is derived from osteoblasts, which transdifferentiate into adipocytes that produce bone marrow fat. We examined the dose-dependent effect of 17β-estradiol on the ability of MC3T3-E1 cells and murine bone marrow-derived mesenchymal stem cell (BMMSC)-derived osteoblasts to undergo osteo-adipogenic transdifferentiation. We found that 17β-estradiol significantly increased alkaline phosphatase activity (P<0.05); calcium deposition; and Alp, Col1a1, Runx2, and Ocn expression levels dose-dependently. By contrast, 17β-estradiol significantly decreased the number and size of lipid droplets, and Fabp4 and PPARγ expression levels during osteo-adipogenic transdifferentiation (P<0.05). Moreover, the expression levels of brown adipocyte markers (Myf5, Elovl3, and Cidea) and undifferentiated adipocyte markers (Dlk1, Gata2, and Wnt10b) were also affected by 17β-estradiol during osteo-adipogenic transdifferentiation. Western blotting and immunostaining further showed that canonical Wnt signaling can be activated by estrogen to exert its inhibitory effect of osteo-adipogenesis. This is the first study to demonstrate the dose-dependent effect of 17β-estradiol on the osteo-adipogenic transdifferentiation of MC3T3-E1 cells and BMMSCs likely via canonical Wnt signaling. In summary, our results indicate that osteo-adipogenic transdifferentiation modulated by canonical Wnt signaling pathway in bone metabolism may be a new explanation for the gradually increased bone marrow fat in estrogen-inefficient condition.

  13. One is enough: in vivo effective population size is dose-dependent for a plant RNA virus.

    PubMed

    Zwart, Mark P; Daròs, José-Antonio; Elena, Santiago F

    2011-07-01

    Effective population size (N(e)) determines the strength of genetic drift and the frequency of co-infection by multiple genotypes, making it a key factor in viral evolution. Experimental estimates of N(e) for different plant viruses have, however, rendered diverging results. The independent action hypothesis (IAH) states that each virion has a probability of infection, and that virions act independent of one another during the infection process. A corollary of IAH is that N(e) must be dose dependent. A test of IAH for a plant virus has not been reported yet. Here we perform a test of an IAH infection model using a plant RNA virus, Tobacco etch virus (TEV) variants carrying GFP or mCherry fluorescent markers, in Nicotiana tabacum and Capsicum annuum plants. The number of primary infection foci increased linearly with dose, and was similar to a Poisson distribution. At high doses, primary infection foci containing both genotypes were found at a low frequency (<2%). The probability that a genotype that infected the inoculated leaf would systemically infect that plant was near 1, although in a few rare cases genotypes could be trapped in the inoculated leaf by being physically surrounded by the other genotype. The frequency of mixed-genotype infection could be predicted from the mean number of primary infection foci using the independent-action model. Independent action appears to hold for TEV, and N(e) is therefore dose-dependent for this plant RNA virus. The mean number of virions causing systemic infection can be very small, and approaches 1 at low doses. Dose-dependency in TEV suggests that comparison of N(e) estimates for different viruses are not very meaningful unless dose effects are taken into consideration.

  14. Vagotomy attenuates the effect of lipopolysaccharide on body temperature of rats in a dose-dependent manner.

    PubMed

    Azab, A N; Kaplanski, J

    2001-01-01

    There is a growing body of evidence suggesting that vagal afferents play a major role in peripheral-neural communication. This study was undertaken to determine whether a dose-dependent effect of lipopolysaccharide (LPS) on vagotomy-induced febrile unresponsiveness exists, and to examine the effect of vagotomy on LPS-induced increase in hypothalamic prostaglandin E2 (HT PGE2) production. Vagotomized and sham-operated rats were subjected to two experimental protocols. In the first, vagotomized and sham-operated rats were injected intraperitoneally with different doses of LPS (200, 500 and 1000 microg/kg) in order to examine the dose-dependent effect of LPS on the biphasic febrile response of the rats. In the second protocol, vagotomized and sham-operated rats were injected intraperitoneally with LPS (500 microg/kg). Two hours post injection, body temperature was measured, the rats were decapitated and blood was collected. Simultaneously, the rats' hypothalami were excised and incubated for 1 h in a Krebs-Henseleit buffer. Next, HT PGE2 was determined by radioimmunoassay. Vagotomy-induced gastric enlargement was then measured to examine the correlation between the magnitude of the enlargement and that of the vagotomy-related febrile unresponsiveness. It was found that vagotomized-induced febrile unresponsiveness is a dose-dependent effect. Subdiaphragmatic resection of the vagus prevented the biphasic febrile response caused by the lowest dose (200 microg/kg) of LPS, whereas the highest dose of LPS (1000 microg/kg) caused a similar biphasic febrile response in both vagotomized and sham-operated rats. Indeed, vagotomy attenuates LPS-induced increase in HT PGE2, and blocks the hypothermic phase of the febrile response. On the other hand, no correlation between gastric enlargement and febrile unresponsiveness was found. The results of the present study may cast further light on the crucial role of the vagus nerve as a peripheral-neural pathway in the mediation of the

  15. Modeling dose-dependent neural processing responses using mixed effects spline models: with application to a PET study of ethanol.

    PubMed

    Guo, Ying; Bowman, F DuBois

    2008-04-01

    For functional neuroimaging studies that involve experimental stimuli measuring dose levels, e.g. of an anesthetic agent, typical statistical techniques include correlation analysis, analysis of variance or polynomial regression models. These standard approaches have limitations: correlation analysis only provides a crude estimate of the linear relationship between dose levels and brain activity; ANOVA is designed to accommodate a few specified dose levels; polynomial regression models have limited capacity to model varying patterns of association between dose levels and measured activity across the brain. These shortcomings prompt the need to develop methods that more effectively capture dose-dependent neural processing responses. We propose a class of mixed effects spline models that analyze the dose-dependent effect using either regression or smoothing splines. Our method offers flexible accommodation of different response patterns across various brain regions, controls for potential confounding factors, and accounts for subject variability in brain function. The estimates from the mixed effects spline model can be readily incorporated into secondary analyses, for instance, targeting spatial classifications of brain regions according to their modeled response profiles. The proposed spline models are also extended to incorporate interaction effects between the dose-dependent response function and other factors. We illustrate our proposed statistical methodology using data from a PET study of the effect of ethanol on brain function. A simulation study is conducted to compare the performance of the proposed mixed effects spline models and a polynomial regression model. Results show that the proposed spline models more accurately capture varying response patterns across voxels, especially at voxels with complex response shapes. Finally, the proposed spline models can be used in more general settings as a flexible modeling tool for investigating the effects of any

  16. Dose-dependent effects of caffeine on behavior and thermoregulation in a chronic unpredictable stress model of depression in rats.

    PubMed

    Pechlivanova, D; Tchekalarova, J; Nikolov, R; Yakimova, K

    2010-06-19

    The effects of the non-selective adenosine A(1)/A(2) receptor antagonist caffeine on behavior and thermoregulation in chronic unpredictable stress (CUS) model of depression was studied in Wistar rats. In the open field (OF) test, caffeine dose-dependently increased motor activity while decreased grooming and time spent in the corner. Five-week exposure to CUS procedure had the opposite effect in rats. Caffeine reversed CUS-induced effects on the above mentioned parameters. Caffeine (40 mg/kg) increased the motor activity in plus maze (PM) test while at doses of 20 and 40 mg/kg it decreased the number of entries in the open arms. Whereas CUS did not change the level of anxiety, caffeine (2, 20 and 40 mg/kg) administered after CUS diminished it by increasing the time in open arms. Caffeine dose-dependently decreased the immobility time while CUS had the opposite increasing effect in forced swimming test (FST). Caffeine at doses of 20 and 40 mg/kg reversed the effect of CUS on immobility in FST. Caffeine produced dose-dependent rice of body temperature in both non-treated and CUS-treated rats. The hyperthermic effect in normal rats pretreated with caffeine lasted about 90 min while in caffeine-pretreated rats exposed to CUS it lasted about 150 min. High dose of caffeine (100mg/kg) induced significant hypothermia between 90th and 150th minute in control rats and hyperthermia between 30th and 60th minute in CUS-treated rats. These results suggest a putative role of this methylxanthine in the adaptive responses to chronic unpredictable stress stimuli.

  17. 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

  18. 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

  19. 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.

  20. Therapeutic Time Window and Dose Dependence of Xenon Delivered via Echogenic Liposomes for Neuroprotection in Stroke

    PubMed Central

    Peng, Tao; Britton, George L.; Kim, Hyunggun; Cattano, Davide; Aronowski, Jaroslaw; Grotta, James; McPherson, David D.; Huang, Shao-Ling

    2013-01-01

    Aims Neurologic impairment following ischemic injury complicates the quality of life for stroke survivors. Xenon (Xe) has favorable neuroprotective properties to modify stroke. Xe delivery is hampered by a lack of suitable administration strategies. We have developed Xe-containing echogenic liposomes (Xe-ELIP) for systemic Xe delivery. We investigated the time window for Xe-ELIP therapeutic effect and the most efficacious dose for neuroprotection. Molecular mechanisms for Xe neuroprotection were investigated. Methods Xe-ELIP were created by a previously developed pressurization-freezing method. Following right middle cerebral artery occlusion (2 hours), animals were treated with Xe-ELIP at 2, 3 or 5 hours to determine time window of therapeutic effect. The neuroprotectant dosage for optimal effect was evaluated 3 hours after stroke onset. Expression of brain-derived neurotrophic factor (BDNF), protein kinase B (Akt), and mitogen-activated protein kinases (MAPK) were determined. Results Xe-ELIP administration for up to 5 hours after stroke onset reduced infract size. Treatment groups given 7 and 14 mg/kg of Xe-ELIP reduced infarct size. Behavioral outcomes corresponded to changes in infarct volume. Xe-ELIP treatment reduced ischemic neuronal cell death via activation of both MAPK and Akt. Elevated BDNF expression was shown following Xe-ELIP delivery. Conclusion This study demonstrates the therapeutic efficacy of Xe-ELIP administered within 5 hours after stroke onset with an optimal dosage range of 7–14 mg/kg for maximal neuroprotection. PMID:23981565

  1. A T-DNA mutation in the RNA helicase eIF4A confers a dose-dependent dwarfing phenotype in Brachypodium distachyon.

    PubMed

    Vain, Philippe; Thole, Vera; Worland, Barbara; Opanowicz, Magdalena; Bush, Max S; Doonan, John H

    2011-06-01

    In a survey of the BrachyTAG mutant population of Brachypodium distachyon, we identified a line carrying a T-DNA insertion in one of the two eukaryotic initiation factor 4A (eIF4A) genes present in the nuclear genome. The eif4a homozygous mutant plants were slow-growing, and exhibited reduced final plant stature due to a decrease in both cell number and cell size, consistent with roles for eIF4A in both cell division and cell growth. Hemizygous plants displayed a semi-dwarfing phenotype, in which stem length was reduced but leaf length was normal. Linkage between the insertion site and phenotype was confirmed, and we show that the level of eIF4A protein is strongly reduced in the mutant. Transformation of the Brachypodium homozygous mutant with a genomic copy of the Arabidopsis eIF4A-1 gene partially complemented the growth phenotype, indicating that gene function is conserved between mono- and dicotyledonous species. This study identifies eIF4A as a novel dose-dependent regulator of stem elongation, and demonstrates the utility of Brachypodium as a model for grass and cereals research.

  2. 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.

  3. Dose-dependent cytotoxicity evaluation of graphite nanoparticles for diamond-like carbon film application on artificial joints.

    PubMed

    Liao, T T; Deng, Q Y; Wu, B J; Li, S S; Li, X; Wu, J; Leng, Y X; Guo, Y B; Huang, N

    2017-01-24

    While a diamond-like carbon (DLC)-coated joint prosthesis represents the implant of choice for total hip replacement in patients, it also leads to concern due to the cytotoxicity of wear debris in the form of graphite nanoparticles (GNs), ultimately limiting its clinical use. In this study, the cytotoxicity of various GN doses was evaluated. Mouse macrophages and osteoblasts were incubated with GNs (<30 nm diameter), followed by evaluation of cytotoxicity by means of assessing inflammatory cytokines, results of alkaline phosphatase assays, and related signaling protein expression. Cytotoxicity evaluation showed that cell viability decreased in a dose-dependent manner (10-100 μg ml(-1)), and steeply declined at GNs concentrations greater than 30 μg ml(-1). Noticeable cytotoxicity was observed as the GN dose exceeded this threshold due to upregulated receptor of activator of nuclear factor kB-ligand expression and downregulated osteoprotegerin expression. Meanwhile, activated macrophage morphology was observed as a result of the intense inflammatory response caused by the high doses of GNs (>30 μg ml(-1)), as observed by the increased release of TNF-α and IL-6. The results suggest that GNs had a significant dose-dependent cytotoxicity in vitro, with a lethal dose of 30 μg ml(-1) leading to dramatic increases in cytotoxicity. Our GN cytotoxicity evaluation indicates a safe level for wear debris-related arthropathy and could propel the clinical application of DLC-coated total hip prostheses.

  4. Dose-dependent induction of recessive mutations with N-ethyl-N-nitrosourea in primordial germ cells of male mice.

    PubMed

    Shibuya, T; Horiya, N; Matsuda, H; Sakamoto, K; Hara, T

    1996-10-25

    Using a specific locus test, we previously found that N-ethyl-N-nitrosourea (ENU) induces recessive mutations at a relatively high rate in male mouse primordial germ cells (PGC) at 8.5, 10.5 and 13.5 days of development (G8.5, G10.5 and G13.5). A large difference was observed on the induced mutation rate between 30 and 50 mg/kg ENU in 10.5-day PGC. We therefore carried out specific locus tests to ascertain whether ENU induces recessive mutations in a dose-dependent manner in G8.5 and G10.5 PGC. We also gave multiple doses of 25 mg/kg ENU using an 18-h interval, the approximate doubling time of PGC at these developmental stages, to test for an additive effect on the induced mutations rate. A dose-dependent induction of recessive mutations by ENU was observed in both G8.5 and G10.5 PGC, and multiple dosing of 25 mg/kg ENU showed an additive effect. Comparing these results to data on spermatogonial stem cells, we conclude the capacity to repair ENU-induced premutagenic damages is less effective in male mouse PGC at these developmental stages than in spermatogonial stem cells.

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

    PubMed

    Milesi-Hallé, Alessandra; Hendrickson, Howard P; Laurenzana, Elizabeth M; Gentry, W Brooks; Owens, S Michael

    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.

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

    PubMed

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

    2016-01-20

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

  7. 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.

  8. Oleoylethanolamide dose-dependently attenuates cocaine-induced behaviours through a PPARα receptor-independent mechanism.

    PubMed

    Bilbao, Ainhoa; Blanco, Eduardo; Luque-Rojas, María Jesús; Suárez, Juan; Palomino, Ana; Vida, Margarita; Araos, Pedro; Bermúdez-Silva, Francisco J; Fernández-Espejo, Emilio; Spanagel, Rainer; Rodríguez de Fonseca, Fernando

    2013-01-01

    Oleoylethanolamide (OEA) is an acylethanolamide that acts as an agonist of nuclear peroxisome proliferator-activated receptor alpha (PPARα) to exert their biological functions, which include the regulation of appetite and metabolism. Increasing evidence also suggests that OEA may participate in the control of reward-related behaviours. However, direct experimental evidence for the role of the OEA-PPARα receptor interaction in drug-mediated behaviours, such as cocaine-induced behavioural phenotypes, is lacking. The present study explored the role of OEA and its receptor PPARα on the psychomotor and rewarding responsiveness to cocaine using behavioural tests indicative of core components of addiction. We found that acute administration of OEA (1, 5 or 20 mg/kg, i.p.) reduced spontaneous locomotor activity and attenuated psychomotor activation induced by cocaine (20 mg/kg) in C57Bl/6 mice. However, PPARα receptor knockout mice showed normal sensitization, although OEA was capable of reducing behavioural sensitization with fewer efficacies. Furthermore, conditioned place preference and reinstatement to cocaine were intact in these mice. Our results indicate that PPARα receptor does not play a critical, if any, role in mediating short- and long-term psychomotor and rewarding responsiveness to cocaine. However, further research is needed for the identification of the targets of OEA for its inhibitory action on cocaine-mediated responses.

  9. Administration of short-term immunosuppressive agents after DLI reduces the incidence of DLI-associated acute GVHD without influencing the GVL effect.

    PubMed

    Huang, X-J; Wang, Y; Liu, D-H; Xu, L-P; Liu, K-Y; Chen, H; Chen, Y-H; Han, W; Shi, H-X

    2009-09-01

    Donor lymphocyte infusion (DLI) exerts a GVL effect, but its use is limited by a high incidence of GVHD. We retrospectively evaluated the efficacy of administering short-term immunosuppressive agents for prophylaxis against DLI-associated acute GVHD, and its influence on the GVL effect. Seventy patients with leukaemia received G-CSF primed DLI after HLA-identical sibling haematopoietic stem cell transplantation (HSCT) for treatment or prophylaxis against leukaemia relapse. Short-term immunosuppressive agents were given to 54 patients for prophylaxis against DLI-associated acute GVHD. Seventeen patients experienced acute GVHD; 30 patients developed chronic GVHD; and no GVHD-related death was observed. A significant difference was observed between the group that did not receive prophylaxis against GVHD or received prophylaxis for less than 2 weeks and the group that received prophylaxis for over 2 weeks (CsA or MTX at 10 mg/week) with regard to the incidence of DLI-associated acute GVHD (14/28 vs 3/42, P=0.000); no difference was observed in the relapse rate for prophylactic DLI patients between the two groups (4/10 vs 12/29). Using immunosuppressive agents for 2-4 weeks may reduce DLI-associated acute GVHD without influencing relapse and survival after G-CSF-primed DLI.

  10. The Combination of SAT and SBT Protocols May Help Reduce the Incidence of Ventilator-Associated Pneumonia in the Burn Intensive Care Unit.

    PubMed

    Lee, Yann-Leei Larry; Sims, Kaci D; Butts, Charles C; Frotan, M Amin; Kahn, Steven; Brevard, Sidney B; Simmons, Jon D

    There are few published reports on the unique nature of burn patients using a paired spontaneous awakening and spontaneous breathing protocol. A combined protocol was implemented in our burn intensive care unit (ICU) on January 1, 2012. This study evaluates the impact of this protocol on patient outcomes in a burn ICU. We performed a retrospective review of our burn registry over 4 years, including all patients placed on mechanical ventilation. In the latter 2 years, patients meeting criteria underwent daily spontaneous awakening trial; if successful, spontaneous breathing trial was performed. Patient data included age, burn size, percent full-thickness burn, tracheostomy, and inhalation injury. Outcome measures included ventilator days, ICU and hospital lengths of stay, pneumonia, and disposition. Data were analyzed using Graphpad Prism and IBM SPSS software, with statistical significance defined as P < .05. There were 171 admissions in the preprotocol period and 136 after protocol implementation. Protocol patients had greater percent full-thickness burns, but did not differ in other characteristics. The protocol group had significantly shorter ICU length of stay, fewer ventilator days, and lower pneumonia incidence. Hospital length of stay, disposition, and mortality were not significantly different. Among patients with inhalation injuries, the protocol group exhibited fewer ventilator and ICU days. Protocol implementation in a burn ICU was accompanied by decreased ventilator days and a reduced incidence of pneumonia. A combined spontaneous awakening and breathing protocol is safe and may improve clinical practice in the burn ICU.

  11. 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.

  12. Probiotic bacteria reduced duration and severity but not the incidence of common cold episodes in a double blind, randomized, controlled trial.

    PubMed

    de Vrese, Michael; Winkler, Petra; Rautenberg, Peter; Harder, Timm; Noah, Christian; Laue, Christiane; Ott, Stephan; Hampe, Jochen; Schreiber, Stefan; Heller, Knut; Schrezenmeir, Jürgen

    2006-11-10

    To investigate the effect of long-term consumption of probiotic bacteria on viral respiratory tract infections (common cold, influenza), a randomized, double blind, controlled intervention study was performed during two winter/spring periods (3 and 5 month). Four hundred and seventy-nine healthy adults were supplemented daily with vitamins plus minerals with or without probiotic lactobacilli and bifidobacteria. The intake of the probiotic had no effect on the incidence of common cold infections (verum=158, control=153 episodes, influenza was not observed), but significantly shortened duration of episodes by almost 2 days (7.0+/-0.5 versus 8.9+/-1.0 days, p=0.045), reduced the severity of symptoms and led to larger increases in cytotoxic T plus T suppressor cell counts and in T helper cell counts.

  13. 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

  14. 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

  15. 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.

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

    PubMed Central

    2012-01-01

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

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

    EPA Science Inventory

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

  18. Trichoderma asperellum spore dose depended modulation of plant growth in vegetable crops.

    PubMed

    Singh, Vivek; Upadhyay, Ram Sanmukh; Sarma, Birinchi Kumar; Singh, Harikesh Bahadur

    2016-12-01

    In the present study we bioprimed seeds of six vegetable crops (tomato, brinjal, chilli, okra, ridge gourd and guar) with different spore doses of Trichoderma asperellum BHUT8 ranging from 10(2) to 10(8) spores ml(-1) and the effect of biopriming was seen on seed germination and development. The most effective spore dose for enhancement in seed germination and radicle length was found to be 10(3) spores ml(-1) in tomato and ridge gourd, 10(4) spores ml(-1) in brinjal and okra while 10(6) spores ml(-1) in chilli and guar. At the most effective spore dose, the increase in germination percentage was 5, 146.15, 112.5, 5.4, 28.13 and 0% while increase in radicle length was 73.17, 50.83, 171.6, 107.35, 247.19 and 90.79% in tomato, brinjal, chilli, okra, ridge gourd and guar, respectively, compared to their controls. Higher spore dose i.e. 10(7)-10(8) spores ml(-1) and 10(6)-10(8) spores ml(-1) in tomato and brinjal, respectively, reduced seed germination percentage and radicle growth compared to their controls. Biopriming with T. asperellum BHUT8 also triggered various defense like responses such as high phenylpropanoid activities and lignifications in bioprimed tomato seedlings compared to the non-bioprimed tomato seedlings demonstrating possible use of BHUT8 against phytopathogens.

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

    PubMed Central

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

    2015-01-01

    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

  20. 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.

  1. 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.

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

    PubMed

    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.

  3. 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

  4. Dose-dependent electrophysiological effects of the myosin activator omecamtiv mecarbil in canine ventricular cardiomyocytes.

    PubMed

    Szentandrassy, N; Horvath, B; Vaczi, K; Kistamas, K; Masuda, L; Magyar, J; Banyasz, T; Papp, Z; Nanasi, P P

    2016-08-01

    Omecamtiv mecarbil (OM) is a myosin activator agent recently developed for treatment of heart failure. Although its action on extending systolic ejection time and increasing left ventricular ejection fraction is well documented, no data is available regarding its possible side-effects on cardiac ion channels. Therefore, the present study was designed to investigate the effects of OM on action potential morphology and the underlying ion currents in isolated canine ventricular myocytes using sharp microelectrodes, conventional patch clamp, and action potential voltage clamp techniques. OM displayed a concentration-dependent action on action potential configuration: 1 μM OM had no effect, while action potential duration and phase-1 repolarization were reduced and the plateau potential was depressed progressively at higher concentrations (10 - 100 μM; P < 0.05 compared to control). Accordingly, OM (10 μM) decreased the density of the transient outward K(+) current (Ito), the L-type Ca(2+) current (ICa) and the rapid delayed rectifier K(+) current (IKr), but failed to modify the inward rectifier K(+) current (IK1). It is concluded, that although the therapeutic concentrations of OM are not likely to influence cardiac ion currents significantly, alterations of the major cardiac ion currents can be anticipated at concentrations above those clinically tolerated.

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

    PubMed

    El-Tahan, Mohamed R

    2011-01-01

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

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

    PubMed

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

    2014-01-01

    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.

  7. 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

  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.

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

    PubMed

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

    2015-04-01

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

  10. 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

  11. 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

  12. Time and dose-dependent effects of chondroitinase ABC on growth of engineered cartilage.

    PubMed

    O'Connell, G D; Nims, R J; Green, J; Cigan, A D; Ateshian, G A; Hung, C T

    2014-04-23

    Tissue engineering techniques have been effective in developing cartilage-like tissues in vitro. However, many scaffold-based approaches to cultivating engineered cartilage have been limited by low collagen production, an impediment for attaining native functional load-bearing tensile mechanical properties. Enzymatic digestion of glycosaminoglycans (GAG) with chondroitinase ABC (chABC) temporarily suppresses the construct's GAG content and compressive modulus and increases collagen content. Based on the promising results of these early studies, the aim of this study was to further promote collagen deposition through more frequent chABC treatments. Weekly dosing of chABC at a concentration of 0.15 U/mL resulted in a significant cell death, which impacted the ability of the engineered cartilage to fully recover GAG and compressive mechanical properties. In light of these findings, the influence of lower chABC dosage on engineered tissue (0.004 and 0.015 U/mL) over a longer duration (one week) was investigated. Treatment with 0.004 U/mL reduced cell death, decreased the recovery time needed to achieve native compressive mechanical properties and GAG content, and resulted in a collagen content that was 65 % greater than the control. In conclusion, the results of this study demonstrate that longer chABC treatment (one week) at low concentrations can be used to improve collagen content in developing engineered cartilage more expediently than standard chABC treatments of higher chABC doses administered over brief durations.

  13. Dose-dependent effects of dietary gamma-linolenic acid on rat spleen lymphocyte functions.

    PubMed

    Peterson, L D; Thies, F; Calder, P C

    1999-07-01

    Feeding rodents a diet rich in evening primrose oil (EPO), which contains 5-10 g gamma-linolenic acid (GLA)/100 g total fatty acids, has been shown to decrease lymphocyte proliferation and natural killer cell activity. However, EPO contains a very high level of linoleic acid which itself can affect lymphocyte functions and it is not clear to what extent the effects of EPO can be attributed to GLA. The current study investigated the effect of two levels of GLA in the rat diet upon immune cell functions; the level of linoleic acid was maintained below 30 g/100 g total fatty acids. Weanling rats were fed on high fat (178 g/kg) diets which contained 4.4 g or 10 g GLA/100 g total fatty acids in place of a proportion of linoleic acid. The total polyunsaturated fatty acid content and the n-6 to n-3 polyunsaturated fatty acid ratio of the diet were maintained at 35 g/100 g total fatty acids and 7, respectively. The fatty acid compositions of the serum and of spleen leukocytes were markedly influenced by that of the diet, with an increase in the proportions of GLA and dihomo-gamma-linolenic acid when the diets containing GLA were fed; these diets also increased the proportion of arachidonic acid in spleen leukocytes. Spleen lymphocyte proliferation in response to concanavalin A was significantly reduced (by 60%) by feeding the diet containing the higher level of GLA, but not by the diet containing the lower level of GLA. Spleen natural killer cell activity and prostaglandin E (PGE) production by spleen leukocytes were not significantly affected by inclusion of GLA in the diet, although there was a tendency towards decreased natural killer cell activity by cells from rats fed the high GLA diet. Thus, this study shows that dietary GLA is capable of altering the fatty acid composition of cells of the immune system and of exerting some immunomodulatory effects, but that the level of GLA in the diet must exceed 4.4 g/100 g total fatty acids for these effects to become apparent.

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

    PubMed Central

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

    2016-01-01

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

  15. Rye polyphenols and the metabolism of n-3 fatty acids in rats: a dose dependent fatty fish-like effect.

    PubMed

    Ounnas, Fayçal; de Lorgeril, Michel; Salen, Patricia; Laporte, François; Calani, Luca; Mena, Pedro; Brighenti, Furio; Del Rio, Daniele; Demeilliers, Christine

    2017-01-10

    As long-chain fatty acids (LCFA) of the n-3 series are critically important for human health, fish consumption has considerably increased in recent decades, resulting in overfishing to respond to the worldwide demand, to an extent that is not sustainable for consumers' health, fisheries economy, and marine ecology. In a recent study, it has been shown that whole rye (WR) consumption improves blood and liver n-3 LCFA levels and gut microbiota composition in rats compared to refined rye. The present work demonstrates that specific colonic polyphenol metabolites may dose dependently stimulate the synthesis of n-3 LCFA, possibly through their microbial and hepatic metabolites in rats. The intake of plant n-3 alpha-linolenic acid and WR results in a sort of fatty fish-like effect, demonstrating that the n-3 LCFA levels in blood and tissues could be increased without eating marine foods, and therefore without promoting unsustainable overfishing, and without damaging marine ecology.

  16. Rye polyphenols and the metabolism of n-3 fatty acids in rats: a dose dependent fatty fish-like effect

    PubMed Central

    Ounnas, Fayçal; de Lorgeril, Michel; Salen, Patricia; Laporte, François; Calani, Luca; Mena, Pedro; Brighenti, Furio; Del Rio, Daniele; Demeilliers, Christine

    2017-01-01

    As long-chain fatty acids (LCFA) of the n-3 series are critically important for human health, fish consumption has considerably increased in recent decades, resulting in overfishing to respond to the worldwide demand, to an extent that is not sustainable for consumers’ health, fisheries economy, and marine ecology. In a recent study, it has been shown that whole rye (WR) consumption improves blood and liver n-3 LCFA levels and gut microbiota composition in rats compared to refined rye. The present work demonstrates that specific colonic polyphenol metabolites may dose dependently stimulate the synthesis of n-3 LCFA, possibly through their microbial and hepatic metabolites in rats. The intake of plant n-3 alpha-linolenic acid and WR results in a sort of fatty fish-like effect, demonstrating that the n-3 LCFA levels in blood and tissues could be increased without eating marine foods, and therefore without promoting unsustainable overfishing, and without damaging marine ecology. PMID:28071699

  17. [Lormetazepam in preoperative sleeplessness. Dose dependance of the effect and comparison with 100 mg pentobarbital (author's transl)].

    PubMed

    Ott, H; Doenicke, A; Abress, C; Fischl, R; Hemmerling, K G; Fichte, K

    1979-01-01

    Lormetazepam (0.5, 1, 2, 4, 8 mg)--a new benzodiazepine--was tested versus Pentobarbital (100 mg) under double blind conditions on 240 preoperative inpatients for night-time sedative and side effects after acute oral intake. Results are based on p less than 0.05. Additionally p less than 0.125 in binomial-two-sample-tests was accepted. Lormetazepam shows dose dependent increase in hypnotic effects (e.g. reduction in sleep latency and number of awakenings, increase of total sleep duration), and side effects (e.g. dopiness, dizziness), but no relevant change in vital signs. About 0.5 mg of Lormetazepam are equivalent to 100 mg of Pentobarbital. 2 mg of Lormetazepam seem to be the optimum dose regarding the relation between hypnotic and side effects. In the view of anaesthesists Lormetazepam is preferable to Pentobarbital because of more favorable safety aspects.

  18. Chronic exposure to manganese sulfate leads to adverse dose-dependent effects on the neurobehavioral ability of rats.

    PubMed

    Su, Cheng; Chen, Kangcheng; Zou, Yunfeng; Shen, Yuefei; Xia, Bing; Liang, Guiqiang; Lv, Yingnan; Wang, Fenfen; Huang, Damin; Yang, Xiaobo

    2016-11-01

    Manganese sulfate is the main combustion product of methylcyclopentadienyl manganese tricarbonyl (MMT). Currently, little is known about the neurobehavioral consequences of chronic manganese sulfate exposure. In this study, rats were treated with 0, 5.0, 10.0, and 20.0 mg/kg MnSO4 ·H2 O for 24 consecutive weeks via intraperitoneal injection. During the treatment period, spatial learning-memory ability was measured using the Morris water maze (MWM). At the end of the exposure period, spontaneous motor behavior and emotional status, hippocampal histologic changes, and Hsp70 mRNA levels were measured using the open-field test (OFT), hematoxylin-eosin staining and real-time quantitative PCR (RT-PCR), respectively. A dose-dependent decrease was noted in the spatial learning-memory ability and the spontaneous activities of rats (P < 0.05), and negative emotions differed significantly between the exposed groups and the control group (P < 0.05). Moreover, overt morphological changes in the hippocampuses of the exposed rats were detected. Cellular degeneration and death were also found. The Hsp70 mRNA levels of the hippocampal areas in the 20.0 mg/kg group (1.567 ± 0.236) were significantly increased compared with the control group (P < 0.05). These results suggest that chronic exposure to manganese sulfate can have adverse dose-dependent effects on rats' neurobehavioral ability, and the mechanism of abnormal hippocampal Hsp70 expression needs to be further explored. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1571-1579, 2016.

  19. 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

  20. Pseudomonas or LPS exposure alters CFTR iodide efflux in 2WT2 epithelial cells with time and dose dependence.

    PubMed

    Haenisch, Michael D; Ciche, Todd A; Luckie, Douglas B

    2010-04-16

    The most common heritable genetic disease in the United States, cystic fibrosis (CF), is caused by mutations in the CF transmembrane conductance regulator (CFTR), a chloride channel that interacts with and regulates a number of other proteins. The bacteria Pseudomonas aeruginosa infects 80% of patients causing decreased pulmonary function and life expectancy. It is not known how malfunction of the chloride channel allows for preferential colonization of patients by a single pathogen. The hypothesis that CFTR interacts with toll-like receptor 4 (TLR4) to phagocytize bacteria was tested. A competitive antagonist of TLR4, MKLPS, was studied for its effect in gentamicin-protection-based bacterial invasion assays. Pre-incubation (15 min 50 microg/mL) with MKLPS did not alter the rate of phagocytosis of P. aeruginosa by cultured epithelia. However, further studies with GFP-transfected P. aeruginosa revealed prominent antibiotic resistant microcolonies were formed. If CFTR is involved in phagocytosis of the bacteria, then internalization was predicted to decrease in iodide efflux. Surprisingly, cultured epithelia exposed to P. aeruginosa for 15 min showed increased cAMP-activated iodide efflux through CFTR. In addition, 15-min exposure to bacterial cell wall component, LPS, purified from P. aeruginosa also increased CFTR iodide efflux in a dose-dependent manner (50, 100 and 200 microg/mL LPS had 25%, 37% and 47% increase). In a reversal of this phenomenon, shorter 5-min exposure to 100 microg/mL LPS resulted in a 25% decrease in forskolin-activated CFTR channel activity compared to controls. This data is consistent with a model in which CFTR is removed from the plasma membrane during phagocytosis of P. aeruginosa followed by recruitment of channels to the membrane to replace those removed during phagocytosis. More studies are needed to confirm this model, but this is the first report of a bacterial product causing a biphasic time-dependent and a dose-dependent alteration

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

    PubMed Central

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

    2006-01-01

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

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

    PubMed

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

    2008-04-01

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

  3. Dose-dependent effects of siRNA-mediated inhibition of SCAP on PCSK9, LDLR, and plasma lipids in mouse and rhesus monkey[S

    PubMed Central

    Jensen, Kristian K.; Tadin-Strapps, Marija; Wang, Sheng-ping; Hubert, James; Kan, Yanqing; Ma, Yong; McLaren, David G.; Previs, Stephen F.; Herath, Kithsiri B.; Mahsut, Ablatt; Liaw, Andy; Wang, Shubing; Stout, Steven J.; Keohan, CarolAnn; Forrest, Gail; Coelho, David; Yendluri, Satya; Williams, Stephanie; Koser, Martin; Bartz, Steven; Akinsanya, Karen O.; Pinto, Shirly

    2016-01-01

    SREBP cleavage-activating protein (SCAP) is a key protein in the regulation of lipid metabolism and a potential target for treatment of dyslipidemia. SCAP is required for activation of the transcription factors SREBP-1 and -2. SREBPs regulate the expression of genes involved in fatty acid and cholesterol biosynthesis, and LDL-C clearance through the regulation of LDL receptor (LDLR) and PCSK9 expression. To further test the potential of SCAP as a novel target for treatment of dyslipidemia, we used siRNAs to inhibit hepatic SCAP expression and assess the effect on PCSK9, LDLR, and lipids in mice and rhesus monkeys. In mice, robust liver Scap mRNA knockdown (KD) was achieved, accompanied by dose-dependent reduction in SREBP-regulated gene expression, de novo lipogenesis, and plasma PCSK9 and lipids. In rhesus monkeys, over 90% SCAP mRNA KD was achieved resulting in approximately 75, 50, and 50% reduction of plasma PCSK9, TG, and LDL-C, respectively. Inhibition of SCAP function was demonstrated by reduced expression of SREBP-regulated genes and de novo lipogenesis. In conclusion, siRNA-mediated inhibition of SCAP resulted in a significant reduction in circulating PCSK9 and LDL-C in rodent and primate models supporting SCAP as a novel target for the treatment of dyslipidemia. PMID:27707816

  4. 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

  5. SU-E-T-44: A Micro-Raman Spectroscopy Study of the Dose-Dependence of EBT3 GafChromicTM Films for Quantifying the Degree of Molecular Polymerization

    SciTech Connect

    Callens, M; Van Den Abeele, K; Crijns, W; Depuydt, T; Maes, F; Haustermans, K; Simons, V; De Wolf, I; D’hooge, J; D’Agostino, E; Pfeiffer, H

    2015-06-15

    Purpose: Radiochromic films, such as the poly-diacetylene-based EBT3 GafChromic{sup TM} films (Ashland Specialty Ingredients, Wayne, NY, USA), are widely used for dosimetry applications because of their clear energy independence, high spatial resolution, near tissue equivalence and easy handling. The films undergo a slight color change by radiation-induced polymerization of diacetylene monomers. But more importantly, the film becomes optically less transparent with increasing radiation dose, with a saturation starting between 10 and 20 Gy, i.e. a common SBRT dose level. In contrast to the chromatic properties, less attention has been given to the underlying molecular mechanism that induces this partial color change and strongly reduces the transparency. Therefore, the current work investigates the variation of the molecular composition of the active layer of EBT3 films for an SBRT dose range. Method: Uncoated EBT3 films were irradiated with a 6 MV photon beam using dose levels between 0 and 20 Gy. The relative variation of the polymer content as a function of the applied radiation dose was studied using micro-Raman spectroscopy. Raman spectroscopy with a 633 nm probe laser incident on the active layer allowed to identify the film constituents and to estimate the amount of poly-diacetylenes from the intensities of the unique molecular vibrations of the molecule. Results: The normalized intensity of all polymeric vibrations, and most notably the polymeric triple and double carbon-carbon bonds at 2058 cm{sup −1} and 1446 cm{sup −1} respectively, increase with increasing dose up to a saturation level starting at about 10 Gy, indicating a corresponding increase and saturation of the amount of polymers. This molecular saturation process is the main cause of the non-linear dose response (i.e. a transparency reduction) and of the limited dose range of the studied films. Conclusion: Raman spectroscopy provides new and more fundamental insights in the mechanism of the

  6. 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.

  7. Randomised controlled feasibility trial on the use of medical grade honey following microvascular free tissue transfer to reduce the incidence of wound infection.

    PubMed

    Robson, Val; Yorke, Janelle; Sen, Rachel A; Lowe, Derek; Rogers, Simon N

    2012-06-01

    The aim of this study was to assess the feasibility of using Leptospermum honey in a randomised trial to reduce the incidence of wound infection after microvascular free tissue reconstruction for cancer of the head and neck. During the one-year study period 70 consecutive patients were admitted to the regional maxillofacial ward for free tissue reconstruction. Of these, 56 (80%) consented to be randomised and 49 (70%) were actually randomised, 25 into the honey dressings group, and 24 into the conventional dressings group (control). Six patients were missed when consent was required, 8 did not consent, and 7 who had given consent were missed at the randomisation stage in theatre. Results of wound swabs were positive in 36% of the honey group and 38% of the control group. Methicillin-resistant Staphylococcus aureus (MRSA) was found in 28% and 25%, respectively. Of these, 38% were deemed to require intervention. Honey dressings were acceptable to both patients and nurses. There was a reduction (p<0.05) in duration of hospital stay in the honey group (median 12 days, IQR 10-21) compared with the control (median 18 days, IQR 13-28). The cost of standard and honey dressings was similar. This feasibility study has shown that a randomised controlled trial (RCT) is possible and that several hundreds of patients would be required to show a clinical benefit for honey. Further research is needed to confirm a shorter duration of hospital admission and if so, whether this is due to more rapid healing.

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

    PubMed

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

    2015-01-01

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

  9. The use of single embryo transfer to reduce the incidence of twins: Implications and questions for practice from the 'towardSET?' project.

    PubMed

    Roberts, Stephen A; McGowan, Linda; Vail, Andy; Brison, Daniel R

    2011-06-01

    In vitro fertilisation treatments where multiple embryos are transferred are associated with high multiple birth rates leading to a corresponding high infant morbidity. Here we review the results from a multidisciplinary project which aimed to combine state of the art statistical modelling of routine clinical data with consideration of patient perspectives to explore options for reducing multiple birth incidence by increased use of single embryo transfer (SET). Modelling was based on a large multicentre cohort, supplemented by analysis of HFEA register data. Patient perspectives were explored in qualitative interviews and focus groups. The data confirm the reduction of around one-third in the chance of a live birth for any couple in moving from double embryo transfer (DET) to SET in a fresh cycle. This can be somewhat offset by appropriate patient and cycle selection for SET, with many suggested schemes performing similarly, although many patients perceive such selection as unfair. If we take a complete cycle perspective, and consider the transfer of all good-quality embryos with cryopreservation then it is possible for SET to match or even outperform DET. However, the additional treatment cycles are seen by patients as physically and emotionally burdensome. Such treatments will require optimisation of embryo freezing policies and a number of options are explored.

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

    PubMed

    Hoffmann-Sommergruber, K

    2005-04-01

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

  11. 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

  12. Dose-dependent increases in flow-mediated dilation following acute cocoa ingestion in healthy older adults

    PubMed Central

    Feehan, Robert P.; Kunselman, Allen R.; Preston, Amy G.; Miller, Debra L.; Lott, Mary E. J.

    2011-01-01

    An inverse relation exists between intake of flavonoid-rich foods, such as cocoa, and cardiovascular-related mortality. Favorable effects of flavonoids on the endothelium may underlie these associations. We performed a randomized, double-blind, placebo-controlled study to test the hypothesis that acute cocoa ingestion dose dependently increases endothelium-dependent vasodilation, as measured by an increase in brachial artery flow-mediated dilation (FMD), in healthy older adults. Measurements were obtained before (preingestion) and after (1- and 2-h postingestion) ingestion of 0 (placebo), 2, 5, 13, and 26 g of cocoa in 23 adults (63 ± 2 yr old, mean ± SE). Changes in brachial artery FMD 1- and 2-h postingestion compared with preingestion were used to determine the effects of cocoa. FMD was unchanged 1 (Δ−0.3 ± 0.2%)- and 2-h (Δ0.1 ± 0.1%) after placebo (0 g cocoa). In contrast, FMD increased both 1-h postingestion (2 g cocoa Δ0.0 ± 0.2%, 5 g cocoa Δ0.8 ± 0.3%, 13 g cocoa Δ1.0 ± 0.3%, and 26 g cocoa Δ1.6 ± 0.3%: P < 0.05 compared with placebo for 5, 13, and 26 g cocoa) and 2-h postingestion (2 g cocoa Δ0.5 ± 0.3%, 5 g cocoa Δ1.0 ± 0.3%, 13 g cocoa Δ1.4 ± 0.2%, and 26 g cocoa Δ2.5 ± 0.4%: P < 0.05 compared with placebo for 5, 13, and 26 g cocoa) on the other study days. A serum marker of cocoa ingestion (total epicatechin) correlated with increased FMD 1- and 2-h postingestion (r = 0.44–0.48; both P < 0.05). Collectively, these results indicate that acute cocoa ingestion dose dependently increases brachial artery FMD in healthy older humans. These responses may help to explain associations between flavonoid intake and cardiovascular-related mortality in humans. PMID:21903881

  13. 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

    2016-06-01

    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

  14. 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

  15. 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

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

    PubMed Central

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

    2015-01-01

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

  17. Dose-Dependent Decrease in Mortality with No Cognitive or Muscle Function Improvements Due to Dietary EGCG Supplementation in Aged Mice.

    PubMed

    Pence, Brandt D; Bhattacharya, Tushar K; Park, Pul; Rytych, Jennifer L; Allen, Jacob M; Sun, Yi; McCusker, Robert H; Kelley, Keith W; Johnson, Rodney W; Rhodes, Justin S; Woods, Jeffrey A

    2017-01-05

    We have previously shown that a diet containing epigallocatechin gallate (EGCG) and beta-alanine is not effective in improving either cognitive or muscle function in aged (18 month) mice (Gibbons et al. Behav Brain Res 2014, Pence et al. Appl Physiol Nutr Metab 2016). However, this diet reduced oxidative stress in the brain, and previous studies using longer-term interventions and other doses have documented beneficial effects in cognitive and muscle function, especially with EGCG. Here we hypothesized that a different dose of EGCG or longer feeding period would be more efficacious in improving cognition. Aged (21-25 mo) Balb/cByJ male mice underwent 63 days of feeding with EGCG at 0, 0.09, or 3.67 mg/g AIN-93M diet and were then subjected to a battery of cognitive and muscle function tests. EGCG feeding at either of the two doses did not alter preference for novel versus familiar arm in the Y-maze test (p=0.29) and did not affect learning in the active avoidance test (p=0.76). Similarly, EGCG did not affect preference for novel versus familiar mice in a social exploration test (p=0.17). Likewise, there was no effect of EGCG on muscle function by grip strength (p=0.16), rotarod (p=0.18) or treadmill test to exhaustion (p=0.25). EGCG reduced mortality in a dose-dependent fashion (p=0.05, log rank test for trend), with 91% of high EGCG, 72% of low EGCG, and 55% of control mice surviving to the end of the study. In conclusion, EGCG improves survival in aged mice but does not affect cognitive or muscle function.

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

    PubMed

    Martin, Keith R; Wooden, Alissa

    2012-11-01

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

  19. 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.

  20. Dose-dependent genotype effects of BDNF Val66Met polymorphism on default mode network in early stage Alzheimer's disease

    PubMed Central

    Lin, Pin-Hsuan; Tsai, Shih-Jen; Huang, Chi-Wei; Mu-En, Liu; Hsu, Shih-Wei; Lee, Chen-Chang; Chen, Nai-Ching; Chang, Ya-Ting; Lan, Min-Yu; Chang, Chiung-Chih

    2016-01-01

    In humans, brain-derived neurotrophic factor (BDNF) has been shown to play a pivotal role in neurocognition, and its gene contains a functional polymorphism (Val66Met) that may explain individual differences in brain volume and memory-related activity. In this study, we enrolled 186 Alzheimer's disease (AD) patients who underwent 3D T1 magnetic resonance imaging, and explored the gray matter (GM) structural covariance networks (SCN). The patients were divided into three groups according to their genotype: Met/Met (n = 45), Val/Met (n = 86) and Val/Val (n = 55). Seed-based analysis was performed focusing on four SCN networks. Neurobehavioral scores served as the major outcome factor. Only peak cluster volumes of default mode medial temporal lobe network showed significant genotype interactions, of which the interconnected peak clusters showed dose-dependent genotype effects. There were also significant correlations between the cognitive test scores and interconnected-cluster volumes, especially in the orbitofrontal cortex. These findings support the hypothesis that BDNF rs6265 polymorphisms modulate entorhinal cortex-interconnected clusters and the valine allele was associated with stronger structural covariance patterns that determined the cognitive outcomes. PMID:27494844

  1. 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

    2016-06-03

    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.

  2. Dose-dependency and reversibility of radiation-induced injury in cardiac explant-derived cells of mice

    PubMed Central

    Luo, Lan; Yan, Chen; Urata, Yoshishige; Hasan, Al Shaimaa; Goto, Shinji; Guo, Chang-Ying; Zhang, Shouhua; Li, Tao-Sheng

    2017-01-01

    We evaluated the dose-dependency and reversibility of radiation-induced injury in cardiac explant-derived cells (CDCs), a mixed cell population grown from heart tissues. Adult C57BL/6 mice were exposed to 0, 10, 50 and 250 mGy γ-rays for 7 days and atrial tissues were collected for experiments 24 hours after last exposure. The number of CDCs was significantly decreased by daily exposure to over 250 mGy. Interestingly, daily exposure to over 50 mGy significantly decreased the c-kit expression and telomerase activity, increased 53BP1 foci in the nuclei of CDCs. However, CD90 expression and growth factors production in CDCs were not significantly changed even after daily exposure to 250 mGy. We further evaluated the reversibility of radiation-induced injury in CDCs at 1 week and 3 weeks after a single exposure to 3 Gy γ-rays. The number and growth factors production of CDCs were soon recovered at 1 week. However, the increased expression of CD90 were retained at 1 week, but recovered at 3 weeks. Moreover, the decreased expression of c-kit, impaired telomerase activity, and increased 53BP1 foci were poorly recovered even at 3 weeks. These data may help us to find the most sensitive and reliable bio-parameter(s) for evaluating radiation-induced injury in CDCs. PMID:28098222

  3. 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

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

    PubMed

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

    2015-02-01

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

  5. 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.

  6. 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.

  7. Cefepime Therapy for Monomicrobial Enterobacter cloacae Bacteremia: Unfavorable Outcomes in Patients Infected by Cefepime-Susceptible Dose-Dependent Isolates.

    PubMed

    Lee, Nan-Yao; Lee, Ching-Chi; Li, Chia-Wen; Li, Ming-Chi; Chen, Po-Lin; Chang, Chia-Ming; Ko, Wen-Chien

    2015-12-01

    A new category of cefepime susceptibility, susceptible dose dependent (SDD), for Enterobacteriaceae, has been suggested to maximize its clinical use. However, clinical evidence supporting such a therapeutic strategy is limited. A retrospective study of 305 adults with monomicrobial Enterobacter cloacae bacteremia at a medical center from 2008 to 2012 was conducted. The patients definitively treated with in vitro active cefepime (cases) were compared with those treated with a carbapenem (controls) to assess therapeutic effectiveness. The 30-day crude mortality rate is the primary endpoint, and clinical prognostic factors are assessed. Of 144 patients receiving definitive cefepime or carbapenem therapy, there were no significant differences in terms of age, sex, comorbidity, source of bacteremia, disease severity, or 30-day mortality (26.4% versus 22.2%; P = 0.7) among those treated with cefepime (n = 72) or a carbapenem (n = 72). In the multivariate analysis, the presence of critical illness, rapidly fatal underlying disease, extended-spectrum beta-lactamase (ESBL) producers, and cefepime-SDD (cefepime MIC, 4 to 8 μg/ml) isolates was independently associated with 30-day mortality. Moreover, those infected by cefepime-SDD isolates with definitive cefepime therapy had a higher mortality rate than those treated with a carbapenem (5/7 [71.4%], versus 2/11 [18.2%]; P = 0.045). Cefepime is one of the therapeutic alternatives for cefepime-susceptible E. cloacae bacteremia but is inefficient for cases of cefepime-SDD E. cloacae bacteremia compared with carbapenem therapy.

  8. Cefepime Therapy for Monomicrobial Enterobacter cloacae Bacteremia: Unfavorable Outcomes in Patients Infected by Cefepime-Susceptible Dose-Dependent Isolates

    PubMed Central

    Lee, Nan-Yao; Lee, Ching-Chi; Li, Chia-Wen; Li, Ming-Chi; Chen, Po-Lin; Chang, Chia-Ming

    2015-01-01

    A new category of cefepime susceptibility, susceptible dose dependent (SDD), for Enterobacteriaceae, has been suggested to maximize its clinical use. However, clinical evidence supporting such a therapeutic strategy is limited. A retrospective study of 305 adults with monomicrobial Enterobacter cloacae bacteremia at a medical center from 2008 to 2012 was conducted. The patients definitively treated with in vitro active cefepime (cases) were compared with those treated with a carbapenem (controls) to assess therapeutic effectiveness. The 30-day crude mortality rate is the primary endpoint, and clinical prognostic factors are assessed. Of 144 patients receiving definitive cefepime or carbapenem therapy, there were no significant differences in terms of age, sex, comorbidity, source of bacteremia, disease severity, or 30-day mortality (26.4% versus 22.2%; P = 0.7) among those treated with cefepime (n = 72) or a carbapenem (n = 72). In the multivariate analysis, the presence of critical illness, rapidly fatal underlying disease, extended-spectrum beta-lactamase (ESBL) producers, and cefepime-SDD (cefepime MIC, 4 to 8 μg/ml) isolates was independently associated with 30-day mortality. Moreover, those infected by cefepime-SDD isolates with definitive cefepime therapy had a higher mortality rate than those treated with a carbapenem (5/7 [71.4%], versus 2/11 [18.2%]; P = 0.045). Cefepime is one of the therapeutic alternatives for cefepime-susceptible E. cloacae bacteremia but is inefficient for cases of cefepime-SDD E. cloacae bacteremia compared with carbapenem therapy. PMID:26416853

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

    PubMed

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

    2010-11-01

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

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

    PubMed

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

    2015-01-01

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

  11. Dose-Dependent Protective and Inductive Effects
of Xanthohumol on Oxidative DNA Damage in
Saccharomyces cerevisiae

    PubMed Central

    Carvalho, Daniel O.; Oliveira, Rui; Johansson, Björn

    2016-01-01

    Summary The effect of xanthohumol, a prenylflavonoid isolated from the hop plant (Humulus lupulus L.), on Saccharomyces cerevisiae DNA oxidative damage and viability was evaluated. Yeast cultures under oxidative stress, induced by H2O2, displayed stronger growth in the presence of 5 mg/L of xanthohumol than cultures with only H2O2. Likewise, DNA damage assessed by the comet assay was significantly lower in cells co-incubated with xanthohumol and H2O2. Accordingly, fluorescence of dichlorofluorescein in cells treated with H2O2 and xanthohumol was considerably lower than in cells exclusively treated with H2O2, indicative of a reactive oxygen species scavenging mechanism and consequent formation of oxidation products, as detected by mass spectrometry. However, at concentrations above 5 mg/L, xanthohumol elicited an opposite effect, leading to a slower growth rate and significant increase in DNA damage. A yeast yap1 deletion mutant strain sensitive to oxidative stress grew more slowly in the presence of at least 5 mg/L of xanthohumol than cultures of the wild type, suggesting that xanthohumol toxicity is mediated by oxidative stress. This evidence provides further insight into the impact of xanthohumol on yeast cells, supporting dose-dependent antioxidant/antigenotoxic and prooxidant/genotoxic effects. PMID:27904394

  12. Dose-dependent increase and decrease in active glucose uptake in jejunal epithelium of broilers after acute exposure to ethanol.

    PubMed

    Yunus, Agha Waqar; Awad, Wageha A; Kröger, Susan; Zentek, Jürgen; Böhm, Josef

    2011-06-01

    Little is known about the effects of ethanol on gastrointestinal tract of chicken. In this study, we investigated the effects of low levels of ethanol on electrophysiological variables of jejunal epithelium of commercial broilers. Jejunal tissues from 35- to 39-day-old broilers were exposed to either 0 or 0.1% ethanol in Ussing chambers, and electrophysiological variables were monitored for 40 min. After 40 and 60 min of incubation, glucose (20 mM) and carbamoylcholine (200 μM), respectively, were introduced into the chambers. The absolute and percent increase in short-circuit current (Isc) and potential difference (Vt) induced by glucose were increased significantly with 0.1% ethanol. There was no significant effect of 0.1% ethanol on carbamoylcholine-induced electrophysiological variables. To investigate if higher levels of ethanol have similar effects, we tested the effects of 0, 0.33, and 0.66% ethanol under similar experimental conditions until the glucose-addition step. Contrary to 0.1% ethanol, both the 0.33 and 0.66% ethanol levels significantly decreased the basal and glucose-induced Isc and Vt. Tissue conductivity remained unaffected in all cases. These results indicate that intestinal epithelia of chicken may be more sensitive to the effects of ethanol as compared with other species. This is the first report indicating dose-dependent increase and decrease in active glucose absorption in intestinal epithelia in the presence of ethanol.

  13. 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.

  14. Ribosomal Protein RPL27a Promotes Female Gametophyte Development in a Dose-Dependent Manner1[C][W][OPEN

    PubMed Central

    Zsögön, Agustin; Szakonyi, Dóra; Shi, Xiuling; Byrne, Mary E.

    2014-01-01

    Ribosomal protein mutations in Arabidopsis (Arabidopsis thaliana) result in a range of specific developmental phenotypes. Why ribosomal protein mutants have specific phenotypes is not fully known, but such defects potentially result from ribosome insufficiency, ribosome heterogeneity, or extraribosomal functions of ribosomal proteins. Here, we report that ovule development is sensitive to the level of Ribosomal Protein L27a (RPL27a) and is disrupted by mutations in the two paralogs RPL27aC and RPL27aB. Mutations in RPL27aC result in high levels of female sterility, whereas mutations in RPL27aB have a significant but lesser effect on fertility. Progressive reduction in RPL27a function results in increasing sterility, indicating a dose-dependent relationship between RPL27a and female fertility. RPL27a levels in both the sporophyte and gametophyte affect female gametogenesis, with different developmental outcomes determined by the dose of RPL27a. These results demonstrate that RPL27aC and RPL27aB act redundantly and reveal a function for RPL27a in coordinating complex interactions between sporophyte and gametophyte during ovule development. PMID:24872379

  15. Baroreceptor mediated blood pressure regulation is not affected during dose dependent inhibition of prostatic contractions by terazosin.

    PubMed

    Pawar, A; Fahim, M

    2004-10-01

    Benign prostatic hyperplasia (BPH), common in aging males is often treated with alpha1-adrenoceptor (AR) antagonists. In view of known hypotensive effect of most of the alpha1-AR antagonists, this work examined the effect of a selected alpha1-AR antagonist, terazosin on the baroreceptor mediated regulation of blood pressure. The three doses of terazosin (10, 100, 300 microg/kg body weight) used in anesthetized dogs inhibited in a dose-dependent manner the prostatic contractions and rise in blood pressure induced by phenylphrine. Impairment of arterial baroreflex, an important neural regulatory mechanism for the maintenance of normal arterial pressure, by alpha1-AR antagonist (prazosin) has been suggested in an earlier study. Hence, the effects of terazosin in doses 10, 100 and 300 microg/kg on baroreflex sensitivity (calculated as the ratio of heart rate change to acute increase in blood pressure by phenylephrine) were investigated. Terazocin did not produce any change in the baroreflex sensitivity. Therefore, in the absence of any adverse effect on the baroreceptor mediated regulation of the blood pressure, terazosin can be treated as a safer drug for the symptomatic treatment of BPH.

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

    PubMed Central

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

    2015-01-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2014-03-01

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

  18. Dose dependent effects of platelet derived chondroitinsulfate A on the binding of CCL5 to endothelial cells

    PubMed Central

    Weingart, Christian; Nelson, Peter J; Krämer, Bernhard K; Mack, Matthias

    2008-01-01

    Background Chemokines immobilized on endothelial cells play a central role in the induced firm adhesion and transendothelial migration of leukocytes. Activation of platelets at sites of vascular injury is considered to support leukocyte adhesion and extravasation. However, activated platelets also secrete soluble glycosaminoglycans that can interfere with immobilization of chemokines. We therefore analyzed the impact of platelet derived glycosaminoglycans on the immobilization of the chemokine CCL5 (RANTES) on human microvascular endothelial cells and their influence on CCL5-CCR5 interactions. Results We confirm that undiluted serum in contrast to plasma decreases binding of CCL5 to endothelial cells. However, when lower concentrations of serum were used, CCL5-presentation on endothelial cells was markedly enhanced. This enhancement was neutralized if serum was digested with chondroinitase ABC. Using different chondroitinsulfate-subtypes we demonstrate that chondroitinsulfate A mediates the enhanced presentation of CCL5 on endothelial cells, whereas chondroitinsulfate B/C even at low concentrations block CCL5 binding. CCR5 downregulation on CCR5-transfected CHO cells or human monocytes is increased by preincubation of CCL5 with serum or chondroitinsulfate A. Conclusion We show that chondroitinsulfate A released from platelets increases the binding of chemokines to endothelial cells and supports receptor internalization in a dose dependent manner. These data help to understand the proinflammatory effects of activated platelets. PMID:19068144

  19. Dose-Dependent Protective and Inductive Effects
of Xanthohumol on Oxidative DNA Damage in
Saccharomyces cerevisiae.

    PubMed

    Carvalho, Daniel O; Oliveira, Rui; Johansson, Björn; Guido, Luís F

    2016-03-01

    The effect of xanthohumol, a prenylflavonoid isolated from the hop plant (Humulus lupulus L.), on Saccharomyces cerevisiae DNA oxidative damage and viability was evaluated. Yeast cultures under oxidative stress, induced by H2O2, displayed stronger growth in the presence of 5 mg/L of xanthohumol than cultures with only H2O2. Likewise, DNA damage assessed by the comet assay was significantly lower in cells co-incubated with xanthohumol and H2O2. Accordingly, fluorescence of dichlorofluorescein in cells treated with H2O2 and xanthohumol was considerably lower than in cells exclusively treated with H2O2, indicative of a reactive oxygen species scavenging mechanism and consequent formation of oxidation products, as detected by mass spectrometry. However, at concentrations above 5 mg/L, xanthohumol elicited an opposite effect, leading to a slower growth rate and significant increase in DNA damage. A yeast yap1 deletion mutant strain sensitive to oxidative stress grew more slowly in the presence of at least 5 mg/L of xanthohumol than cultures of the wild type, suggesting that xanthohumol toxicity is mediated by oxidative stress. This evidence provides further insight into the impact of xanthohumol on yeast cells, supporting dose-dependent antioxidant/antigenotoxic and prooxidant/genotoxic effects.

  20. Gamma-radiation-induced phosphorylation of p53 on serine 15 is dose-dependent in MOLT-4 leukaemia cells.

    PubMed

    Tichý, A; Záskodová, D; Zoelzer, F; Vávrová, J; Sinkorová, Z; Pejchal, J; Osterreicher, J; Rezácová, M

    2009-01-01

    Molecular indicators of the absorbed dose of ionizing radiation are powerful tools in biodosimetry. The studies reported here were undertaken with the motivation to find such a marker among the mo lecules involved in ataxia-telangiectasia mutated kinase- dependent signalling induced by ionizing radiation (ATM-kinase, checkpoint kinase-2, protein p53, and oncoprotein Mdm2). In our previous work on T-lymphocyte leukaemia MOLT-4 cells we described the mentioned molecules of ATM-dependent pathway and none of them showed a pronounced dosedependent response. Here we employed Western blotting and ELISA assay to investigate the response of post-translationally modified p53 (particularly phosphorylated on serine 15) after gamma-irradiation. We have found the amount of phosphorylated p53 to be homogenously increased after irradiation by the doses of 0.5 to 7.5 Gy. The dose-dependent response was pronounced especially after the doses up to 3.0 Gy. The presented data indicate that p53 phosphorylated on serine 15 might be used as a potential biodosimetric marker.

  1. 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

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

    PubMed

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

    2014-09-01

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

  3. 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.

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

    PubMed

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

    2015-01-01

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

  5. 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

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

    PubMed

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

    2014-11-01

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

  7. Inhibition of Wnt signalling dose-dependently impairs the acquisition and expression of amphetamine-induced conditioned place preference.

    PubMed

    Islam, Farhana; Xu, Kathleen; Beninger, Richard J

    2017-03-09

    The mechanisms by which dopaminergic neurotransmission in the nucleus accumbens (NAc) is involved in incentive learning produced by rewarding stimuli remain unclear. Recently, Wnt signalling has been implicated in synaptic plasticity and learning and memory. Functional interactions between Wnt and dopamine (DA) signalling has been demonstrated using in vitro and tissue physiology approaches, however there remains a lack of in vivo research into the involvement of Wnt in DA-mediated learning in behaving animals. The present study assessed the role of Wnt signalling in DA-mediated incentive learning using the conditioned place preference (CPP) paradigm. We hypothesized that inhibition of Wnt with intra-NAc microinjections of Wnt palmitoylation inhibitor IWP-2 will dose-dependently block the acquisition and expression of amphetamine (AMPH)-induced CPP in rats. Intra-NAc IWP-2 (0.001, 0.05, 1.0 but not 0.0001μg/0.5μl/side) prior to conditioning with AMPH (20.0μg/0.5μl/side) blocked acquisition of CPP. Intra-NAc IWP-2 (0.05, 0.5, 1.0 but not 0.001μg/0.5μl/side) during test following conditioning with AMPH blocked expression but at a higher dose than was need to block acquisition. Sensitization of locomotor activity to AMPH was observed during conditioning and this effect was blocked in groups given IWP-2 prior to AMPH. However, intra-NAc IWP-2 during conditioning did not block the locomotor stimulant effects of AMPH. These results implicate Wnt in DA-mediated incentive learning and suggest that Wnt signalling may be more important for the acquisition of CPP then for its expression. However, mechanisms by which Wnt and DA signalling pathways interact to influence DA-mediated reward-related learning remain to be elucidated.

  8. Different Dose-Dependent Mechanisms Are Involved in Early Cyclosporine A-Induced Cholestatic Effects in HepaRG Cells

    PubMed Central

    Sharanek, Ahmad; Azzi, Pamela Bachour-El; Al-Attrache, Houssein; Savary, Camille C.; Humbert, Lydie; Rainteau, Dominique; Guguen-Guillouzo, Christiane; Guillouzo, André

    2014-01-01

    Mechanisms involved in drug-induced cholestasis in humans remain poorly understood. Although cyclosporine A (CsA) and tacrolimus (FK506) share similar immunosuppressive properties, only CsA is known to cause dose-dependent cholestasis. Here, we have investigated the mechanisms implicated in early cholestatic effects of CsA using the differentiated human HepaRG cell line. Inhibition of efflux and uptake of taurocholate was evidenced as early as 15 min and 1 h respectively after addition of 10μM CsA; it peaked at around 2 h and was reversible. These early effects were associated with generation of oxidative stress and deregulation of cPKC pathway. At higher CsA concentrations (≥50μM) alterations of efflux and uptake activities were enhanced and became irreversible, pericanalicular F-actin microfilaments were disorganized and bile canaliculi were constricted. These changes were associated with induction of endoplasmic reticulum stress that preceded generation of oxidative stress. Concentration-dependent changes were observed on total bile acid disposition, which were characterized by an increase and a decrease in culture medium and cells, respectively, after a 24-h treatment with CsA. Accordingly, genes encoding hepatobiliary transporters and bile acid synthesis enzymes were differently deregulated depending on CsA concentration. By contrast, FK506 induced limited effects only at 25–50μM and did not alter bile canaliculi. Our data demonstrate involvement of different concentration-dependent mechanisms in CsA-induced cholestasis and point out a critical role of endoplasmic reticulum stress in the occurrence of the major cholestatic features. PMID:24973091

  9. Glutathione conjugation dose-dependently increases brain-specific liposomal drug delivery in vitro and in vivo.

    PubMed

    Maussang, David; Rip, Jaap; van Kregten, Joan; van den Heuvel, Angelique; van der Pol, Susanne; van der Boom, Burt; Reijerkerk, Arie; Chen, Linda; de Boer, Marco; Gaillard, Pieter; de Vries, Helga

    2016-06-01

    The blood-brain barrier (BBB) represents a major obstacle for the delivery and development of drugs curing brain pathologies. However, this biological barrier presents numerous endogenous specialized transport systems that can be exploited by engineered nanoparticles to enable drug delivery to the brain. In particular, conjugation of glutathione (GSH) onto PEGylated liposomes (G-Technology(®)) showed to safely enhance delivery of encapsulated drugs to the brain. Yet, understanding of the mechanism of action remains limited and full mechanistic understanding will aid in the further optimization of the technology. In order to elucidate the mechanism of brain targeting by GSH-PEG liposomes, we here demonstrate that the in vivo delivery of liposomal ribavirin is increased in brain extracellular fluid according to the extent of GSH conjugation onto the liposomes. In vitro, using the hCMEC/D3 human cerebral microvascular endothelial (CMEC) cell line, as well as primary bovine and porcine CMEC (and in contrast to non-brain derived endothelial and epithelial cells), we show that liposomal uptake occurs through the process of endocytosis and that the brain-specific uptake is also glutathione conjugation-dependent. Interestingly, the uptake mechanism is an active process that is temperature-, time- and dose-dependent. Finally, early endocytosis events rely on cytoskeleton remodeling, as well as dynamin- and clathrin-dependent endocytosis pathways. Overall, our data demonstrate that the glutathione-dependent uptake mechanism of the G-Technology involves a specific endocytosis pathway indicative of a receptor-mediated mechanism, and supports the benefit of this drug delivery technology for the treatment of devastating brain diseases.

  10. 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

  11. 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.

  12. 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.

  13. Mortality risk is dose-dependent on the number of packed red blood cell transfused after coronary artery bypass graft

    PubMed Central

    dos Santos, Antônio Alceu; Sousa, Alexandre Gonçalves; Piotto, Raquel Ferrari; Pedroso, Juan Carlos Montano

    2013-01-01

    Introduction Transfusions of one or more packed red blood cells is a widely strategy used in cardiac surgery, even after several evidences of increased morbidity and mortality. The world's blood shortage is also already evident. Objective To assess whether the risk of mortality is dose-de>pendent on the number of packed red blood cells transfused after coronary artery bypass graft. Methods Between June 2009 and July 2010, were analyzed 3010 patients: transfused and non-transfused. Transfused patients were divided into six groups according to the number of packed red blood cells received: one, two, three, four, five, six or more units, then we assess the mortality risk in each group after a year of coronary artery bypass graft. To calculate the odds ratio was used the multivariate logistic regression model. Results The increasing number of allogeneic packed red blood cells transfused results in an increasing risk of mortality, highlighting a dose-dependent relation. The odds ratio values increase with the increased number of packed red blood cells transfused. The death's gross odds ratio was 1.42 (P=0.165), 1.94 (P=0.005), 4.17; 4.22, 8.70, 33.33 (P<0.001) and the adjusted death's odds ratio was 1.22 (P=0.43), 1.52 (P=0.08); 2.85; 2.86; 4.91 and 17.61 (P<0.001), as they received one, two, three, four, five, six or more packed red blood cells, respectively. Conclusion The mortality risk is directly proportional to the number of packed red blood cells transfused in coronary artery bypass graft. The greater the amount of allogeneic blood transfused the greater the risk of mortality. The current transfusion practice needs to be reevaluated. PMID:24598957

  14. Dose dependency of the effect of ornithine alpha-ketoglutarate on tissue glutamine concentrations and hypercatabolic response in endotoxaemic rats.

    PubMed

    Pernet, Pascal; Coudray-Lucas, Colette; Schneid, Christina; Jardel, Alain; Cynober, Luc

    2004-10-01

    The optimal dosage of ornithine alpha-ketoglutarate (OKG) for repleting tissue glutamine (Gln) concentrations and maintaining N homeostasis after injury is unknown. We set out to perform 'dose-ranging' of OKG supplementation after an endotoxaemic challenge. Sixty-one male Wistar rats were injected with 3 mg lipopolysaccharide (LPS) from Escherichia coli/kg (n 50) or saline vehicle (9 g NaCl/l; controls n 11). After a 24 h fast, survivors were fed by gavage for 48 h with a polymeric standard diet (879 kJ/kg per d and 1.18 g N/kg per d) supplemented with non-essential amino acids (control, n 11; LPS-OKG-0.0, n 9), or with 0.5 g OKG/kg per d (LPS-OKG-0.5, n 12), 1.5 OKG/kg per d (LPS-OKG-1.5, n 11) or 4.5 g OKG/kg per d (LPS-OKG-4.5, n 10). The diets for all groups were made isonitrogenous with the LPS-OKG-4.5 diet by adding an appropriate amount of non-essential amino acids. Rats were killed on day 3 for blood and tissue sampling (muscle, jejunum mucosa, liver). Urine was collected daily for 3-methylhistidine and total N assays. The OKG dose was correlated with Gln concentrations in every tissue and with cumulative N balance (Spearman test, P<0.01). 3-Methylhistidine excretion was increased in endotoxaemic groups compared with controls (ANOVA, P<0.05) except in the LPS-OKG-4.5 group. Only the LPS-OKG-4.5 group achieved a positive post-injury N balance (t test, P<0.05). In conclusion, OKG exerted a dose-dependent effect on tissue Gln concentration and N balance, but only the highest dosage counteracted myofibrillar hypercatabolism and caused a positive N balance.

  15. Daily injections of fluoxetine induce dose-dependent desensitization of hypothalamic 5-HT1A receptors: reductions in neuroendocrine responses to 8-OH-DPAT and in levels of Gz and Gi proteins.

    PubMed

    Raap, D K; Evans, S; Garcia, F; Li, Q; Muma, N A; Wolf, W A; Battaglia, G; Van De Kar, L D

    1999-01-01

    The present studies examined the dose-response relationship of fluoxetine-induced desensitization of hypothalamic postsynaptic 5-HT1A receptors, as measured from the reduced neuroendocrine responses to a 5-HT1A agonist. Because hypothalamic Gz proteins mediate the ACTH and oxytocin responses to 5-HT1A receptor activation, we also determined the effect of fluoxetine on the levels of Gz proteins in the hypothalamus. Rats were injected daily for 14 days with saline or with fluoxetine doses of 0.3, 1, 3, 5, 7. 5, or 10 mg/kg/day. Fluoxetine produced a dose-dependent reduction in the oxytocin, ACTH, and corticosterone responses to the 5-HT1A agonist 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT, 50 micrograms/kg, s.c.). The lowest fluoxetine dose that significantly, although incompletely, reduced the neuroendocrine responses to 8-OH-DPAT was 5 mg/kg/day. The 10 mg/kg/day dose of fluoxetine maximally inhibited all neuroendocrine responses to 8-OH-DPAT. Hypothalamic levels of Gz protein were reduced by both the 7.5 and 10 mg/kg/day doses of fluoxetine, whereas Gi1 protein levels were reduced only after the highest dose (10 mg/kg/day) of fluoxetine. Gi2, Gi3, and Go levels were not reduced by any fluoxetine dose. Cytosolic levels of Gi1 and Gz proteins were unaltered, indicating that reductions in Gz and Gi1 proteins are not caused by a redistribution of the proteins from the membrane into the cytosol. The results from the present study indicate that fluoxetine-induced desensitization of hypothalamic postsynaptic 5-HT1A receptor systems is dose-dependent and may be caused in part by reductions in the hypothalamic levels of Gz proteins.

  16. Innovative Multimodal Physical Therapy Reduces Incidence of Repeat Manipulation under Anesthesia in Post-Total Knee Arthroplasty Patients Who Had an Initial Manipulation under Anesthesia.

    PubMed

    Chughtai, Morad; McGinn, Tanner; Bhave, Anil; Khan, Sabahat; Vashist, Megha; Khlopas, Anton; Mont, Michael A

    2016-11-01

    Manipulation under anesthesia (MUA) is performed for knee stiffness following a total knee arthroplasty (TKA) when nonoperative treatments fail. It is important to develop an optimal outpatient physical therapy protocol following an MUA, to avoid a repeat procedure. The purpose of this study was to evaluate and compare: (1) range of motion and (2) the rate of repeat MUA in patients who either underwent innovative multimodal physical therapy (IMMPT) or standard-of-care physical therapy (standard) following an MUA after a TKA. We performed a retrospective database study of patients who underwent an MUA following a TKA between January 2013 to December 2014 (N = 57). There were 16 (28%) men and 41 (72%) women who had a mean age of 59 years (range, 32-81 years). The patients were stratified into those who underwent IMMPT (n = 22) and those who underwent standard physical therapy (n = 35). The 6-month range of motion and rate of repeat manipulation between the two cohorts was analyzed by using Student t-test and Chi-square tests. In addition, we performed a Kaplan-Meier analysis of time to repeat MUA. The IMMPT cohort had a statistically significant higher proportion of TKAs with an optimal range of motion as compared with the standard cohort. There was statistically significant lower proportion of patients who underwent a repeat MUA in the IMMPT as compared with the standard cohort. There was also a significantly lower incidence and longer time to MUA in the IMMPT cohort as compared with the standard cohort in the Kaplan-Meier analysis. The group who underwent IMMPT utilizing Astym therapy had a significantly higher proportion of patients with optimal range of motion, which implies the potential efficacy of this regimen to improve range of motion. Furthermore, the IMMPT cohort had a significantly lower proportion of repeat manipulations as compared with the standard cohort, which implies that an IMMPT approach could potentially reduce the need for a repeat

  17. Dose-Dependent Effects of Theta Burst rTMS on Cortical Excitability and Resting-State Connectivity of the Human Motor System

    PubMed Central

    Nettekoven, Charlotte; Volz, Lukas J.; Kutscha, Martha; Pool, Eva-Maria; Rehme, Anne K.; Eickhoff, Simon B.; Fink, Gereon R.

    2014-01-01

    Theta burst stimulation (TBS), a specific protocol of repetitive transcranial magnetic stimulation (rTMS), induces changes in cortical excitability that last beyond stimulation. TBS-induced aftereffects, however, vary between subjects, and the mechanisms underlying these aftereffects to date remain poorly understood. Therefore, the purpose of this study was to investigate whether increasing the number of pulses of intermittent TBS (iTBS) (1) increases cortical excitability as measured by motor-evoked potentials (MEPs) and (2) alters functional connectivity measured using resting-state fMRI, in a dose-dependent manner. Sixteen healthy, human subjects received three serially applied iTBS blocks of 600 pulses over the primary motor cortex (M1 stimulation) and the parieto-occipital vertex (sham stimulation) to test for dose-dependent iTBS effects on cortical excitability and functional connectivity (four sessions in total). iTBS over M1 increased MEP amplitudes compared with sham stimulation after each stimulation block. Although the increase in MEP amplitudes did not differ between the first and second block of M1 stimulation, we observed a significant increase after three blocks (1800 pulses). Furthermore, iTBS enhanced resting-state functional connectivity between the stimulated M1 and premotor regions in both hemispheres. Functional connectivity between M1 and ipsilateral dorsal premotor cortex further increased dose-dependently after 1800 pulses of iTBS over M1. However, no correlation between changes in MEP amplitudes and functional connectivity was detected. In summary, our data show that increasing the number of iTBS stimulation blocks results in dose-dependent effects at the local level (cortical excitability) as well as at a systems level (functional connectivity) with a dose-dependent enhancement of dorsal premotor cortex-M1 connectivity. PMID:24828639

  18. 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

    2015-07-02

    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

  19. The immunomodulatory effect of vitamin D in chickens is dose-dependent and influenced by calcium and phosphorus levels.

    PubMed

    Rodriguez-Lecompte, J C; Yitbarek, A; Cuperus, T; Echeverry, H; van Dijk, A

    2016-11-01

    Vitamin D requirement is estimated to be higher than recommended values for the first two weeks of a broiler chicken's life, and is heavily dependent on the concentrations of Ca and P in the diet. There are data indicating the beneficial effect of higher vitamin D levels on performance and overall health of the chickens. However, data on the role of higher vitamin D levels on the innate immune response of chickens are limited. Therefore, in the current study, we examined the effect of higher doses of vitamin D supplementation on the innate immune response in broiler chickens receiving optimal or calcium (Ca) and phosphorus (P) deficient diets. Three hundred Ross-308 male broiler chicks were randomly allocated into 60 cages with 5 birds per cage in a 3 × 2 factorial design with three levels of vitamin D and two levels of Ca/P with each experimental diet fed to 10 cages (10 replicates). Quantitative reverse transcription PCR (n = 5) was used to assess Toll-like receptor (TLR2b and 4), cytokine/chemokine (IL-12, IFN-γ, IL-10, IL-4, IL-13, IL-18, CxCLi2) and cathelicidin (CATH1, CATHB1, CATH3) transcription levels in peripheral blood mononuclear cells (PBMCs), spleen, and bursa of Fabricius. Vitamin D supplementation of the Ca and P deficient diet considerably augmented transcription of TLR2b, TLR4, CATH1, and CATHB1 and predominantly Th2 cytokines in spleen. Supplementation of the control diet with vitamin D downregulated TLR4 transcription, and dose-dependently increased CATH1, CATHB1, Th1, and Th2 cytokine transcription (Th2>Th1). All diets downregulated CATH3 transcription. In conclusion, vitamin D or its derivative 25-OH-D3 both have a robust immunomodulatory property with a more favorable Th2 response, while at the same time enhancing observed Th2 cytokine responses under both optimal and lower Ca and P inclusion levels in the diets of broiler chickens.

  20. Time and dose dependent effects of oxidative stress induced by cumene hydroperoxide in neuronal excitability of rat motor cortex neurons.

    PubMed

    Pardillo-Díaz, R; Carrascal, L; Muñoz, M F; Ayala, A; Nunez-Abades, P

    2016-03-01

    It has been claimed that oxidative stress and the production of reactive oxygen radicals can contribute to neuron degeneration and might be one factor in the development of different neurological diseases. In our study, we have attempted to clarify how oxidative damage induces dose dependent changes in functional membrane properties of neurons by means of whole cell patch clamp techniques in brain slices from young adult rats. Our research demonstrates physiological changes in membrane properties of pyramidal motor cortex neurons exposed to 3 concentrations of cumene hydroperoxide (CH; 1, 10 and 100μM) during 30min. Results show that oxidative stress induced by CH evokes important changes, in a concentration and time dependent manner, in the neuronal excitability of motor cortex neurons of the rat: (i) Low concentration of the drug (1μM) already blocks inward rectifications (sag) and decreases action potential amplitude and gain, a drug concentration which has no effects on other neuronal populations, (ii) 10μM of CH depresses the excitability of pyramidal motor cortex neurons by decreasing input resistance, amplitude of the action potential, and gain and maximum frequency of the repetitive firing discharge, and (iii) 100μM completely blocks the capability to produce repetitive discharge of action potentials in all cells. Both larger drug concentrations and/or longer times of exposure to CH narrow the current working range. This happens because of the increase in the rheobase, and the reduction of the cancelation current. The effects caused by oxidative stress, including those produced by the level of lipid peroxidation, are practically irreversible and, this, therefore, indicates that neuroprotective agents should be administered at the first symptoms of alterations to membrane properties. In fact, the pre-treatment with melatonin, acting as an antioxidant, prevented the lipid peroxidation and the physiological changes induced by CH. Larger cells (as estimated

  1. 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

  2. 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

  3. Geraniol attenuates α-synuclein expression and neuromuscular impairment through increase dopamine content in MPTP intoxicated mice by dose dependent manner.

    PubMed

    Rekha, Karamkolly R; Selvakumar, Govindasamy P; Santha, Karunanithi; Inmozhi Sivakamasundari, Ramu

    2013-11-01

    Parkinson's disease (PD) is characterized by progressive loss of dopamine (DA) neurons in the nigrostriatal system and by the presence of Lewy bodies (LB), proteinaceous inclusions mainly composed of filamentous α-synuclein (α-Syn) aggregates. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was adopted to generate PD models in C57BL/6 mice. In the present study, we investigated the effect of geraniol (GE) against α-Syn aggregation on MPTP induced mouse model of PD in dose dependant manner. When pretreatment of GE improved neuromuscular impairment, TH expressions and decreases α-Syn expressions in MPTP intoxicated PD mice by dose dependent manner. In addition, we confirmed that sub-chronic administration of MPTP in mice leads to permanent neuromuscular deficits and depletion of dopamine and its metabolites. Our results suggest that GE is beneficial for the treatment of PD associated with neuromuscular disability and LB aggregation.

  4. Intestinal invasion of Salmonella enterica serovar Typhimurium in the avian host is dose dependent and does not depend on motility and chemotaxis.

    PubMed

    Olsen, John Elmerdahl; Hoegh-Andersen, Kirsten Hobolt; Rosenkrantz, Jesper Tjørnholt; Schroll, Casper; Casadesús, Josep; Aabo, Søren; Christensen, Jens Peter

    2013-08-30

    Salmonella enterica serotype Typhimurium (S. Typhimurium) can invade in the intestine of the avian host, and knowledge on the mechanisms that govern this is potentially important for prevention of disease. This study investigated the invasion of S. Typhimurium in the avian host and to which extent it depended on motility and chemotaxis. Wild type and previously well-characterized transposon mutants in flagella genes fliC and fljB and in chemotaxis genes cheA, cheB and cheR were used as challenge strains in intestinal loop experiments. Invasion was shown to be dose dependent, but did not require functional flagella or chemotaxis genes. In support of the results from intestinal loop experiments, flagella and chemotaxis genes were not significantly important to the outcome of an oral infection. The results showed that S. Typhimurium invasion in the avian host was dose dependent and was not affected by the loss of flagella and chemotaxis genes.

  5. Dose-dependent Toxicity of Humanized Renilla reniformis GFP (hrGFP) Limits Its Utility as a Reporter Gene in Mouse Muscle.

    PubMed

    Wallace, Lindsay M; Moreo, Andrew; Clark, K Reed; Harper, Scott Q

    2013-04-16

    Gene therapy has historically focused on delivering protein-coding genes to target cells or tissues using a variety of vectors. In recent years, the field has expanded to include gene-silencing strategies involving delivery of noncoding inhibitory RNAs, such as short hairpin RNAs or microRNAs (miRNAs). Often called RNA interference (RNAi) triggers, these small inhibitory RNAs are difficult or impossible to visualize in living cells or tissues. To circumvent this detection problem and ensure efficient delivery in preclinical studies, vectors can be engineered to coexpress a fluorescent reporter gene to serve as a marker of transduction. In this study, we set out to optimize adeno-associated viral (AAV) vectors capable of delivering engineered miRNAs and green fluorescent protein (GFP) reporter genes to skeletal muscle. Although the more broadly utilized enhanced GFP (eGFP) gene derived from the jellyfish, Aequorea victoria was a conventional choice, we were concerned about some previous studies suggesting this protein was myotoxic. We thus opted to test vectors carrying the humanized Renilla reniformis-derived GFP (hrGFP) gene, which has not seen as extensive usage as eGFP but was purported to be a safer and less cytotoxic alternative. Employing AAV6 vector dosages typically used in preclinical gene transfer studies (3×10(10) -1 × 10(11) particles), we found that hrGFP caused dose-dependent myopathy when delivered to wild-type (wt) mouse muscle, whereas identical titers of AAV6 carrying eGFP were relatively benign. Dose de-escalation at or below 8 × 10(9) AAV particles effectively reduced or eliminated hrGFP-associated myotoxicity, but also had dampening effects on green fluorescence and miRNA-mediated gene silencing in whole muscles. We conclude that hrGFP is impractical for use as a transduction marker in preclinical, AAV-based RNA interference therapy studies where adult mouse muscle is the target organ. Moreover, our data support that eGFP is superior to hr

  6. Dose depending effect of the complex action hemocorrector "Lactosorbal" on the motility of the distal colon in the paralitic ileus dogs.

    PubMed

    Oborin, A; Ivankiv, T; Pavlovsky, M; Drapaka, V; Uspensky, B

    1997-01-01

    For the model of paralytic ileus caused by the severe surgery it has been studied the influence of different doses of hemocorrector of "Lactosorbal" on distal colon motility. It has been established that stimulating effect of "Lactosorbal" on the motility of distal colon is of the dose-dependent nature. The results of the current survey are making the ground for multiple use of "Lactosorbal" to reach the most beneficial outcome of severe paralytic ileus resulting from major traumatic surgery in clinic.

  7. The 30 degree tilt position vs the 90 degree lateral and supine positions in reducing the incidence of non-blanching erythema in a hospital inpatient population: a randomised controlled trial.

    PubMed

    Young, Trudie

    2004-07-01

    Manual repositioning of patients by nursing staff is a recognised technique for preventing pressure ulcer formation. The 30 degree tilt is a method of positioning patients that, in the laboratory setting, reduced the contact pressure between the patient and the support surface. A randomised controlled trial was used to examine the effects of the 30 degree tilt position in reducing the incidence of non-blanching erythema (i.e. established pressure damage) in a hospital inpatient population (n=23) when compared to the use of the 90 degree lateral and supine position (n=23). The primary outcome of the trial was the incidence of pressure damage, defined as non-blanching erythema. In this study no subject developed pressure damage that presented with visible breaks in the epidermis, but all damage was restricted to areas of non-blanching erythema (five of the 39 subjects who completed the study exhibited such injury). The main findings of this study were that patient positioning using the 30 degree tilt method did not reduce the incidence of pressure damage compared with either the 90 degree lateral or supine positions. This study also investigated the feasibility of using the 30 degree tilt position with medical inpatients; it found that 78% of subjects experienced difficulty in adopting and maintaining the position. This finding seriously questions the practicality of using the 30 degree tilt method with a predominantly ill population.

  8. 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...

  9. 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.

  10. A structural abnormality associated with graded levels of thyroid hormone insufficiency: Dose dependent increases in heterotopia volume

    EPA Science Inventory

    A large number of environmental contaminants reduce circulating levels of thyroid hormone (TH), but clear markers of neurological insult associated with modest TH insufficiency are lacking. We have previously identified the presence of an abnormal cluster of misplaced neurons in ...

  11. Sirolimus reduces the incidence and progression of UVB-induced skin cancer in SKH mice even with co-administration of cyclosporine A.

    PubMed

    Wulff, Brian C; Kusewitt, Donna F; VanBuskirk, Anne M; Thomas-Ahner, Jennifer M; Duncan, F Jason; Oberyszyn, Tatiana M

    2008-10-01

    Transplant immunosuppressants have been implicated in the increased incidence of non-melanoma skin cancer in transplant recipients, most of whom harbor considerable UVB-induced DNA damage in their skin prior to transplantation. This study was designed to evaluate the effects of two commonly used immunosuppressive drugs, cyclosporine A (CsA) and sirolimus (SRL), on the development and progression of UVB-induced non-melanoma skin cancer. SKH-1 hairless mice were exposed to UVB alone for 15 weeks, and then were treated with CsA, SRL, or CsA+SRL for 9 weeks following cessation of UVB treatment. Compared with vehicle, CsA treatment resulted in enhanced tumor size and progression. In contrast, mice treated with SRL or CsA+SRL had decreased tumor multiplicity, size, and progression compared with vehicle-treated mice. CsA, but not SRL or combined treatment, increased dermal mast cell numbers and TGF-beta1 levels in the skin. These findings demonstrate that specific immunosuppressive agents differentially alter the cutaneous tumor microenvironment, which in turn may contribute to enhanced development of UVB-induced skin cancer in transplant recipients. Furthermore, these results suggest that CsA alone causes enhanced growth and progression of skin cancer, whereas co-administration of SRL with CsA causes the opposite effect. JID JOURNAL CLUB ARTICLE: For questions, answers, and open discussion about this article please go to http://network.nature.com/group/jidclub

  12. A Jasmonate-Inducible Defense Trait Transferred from Wild into Cultivated Tomato Establishes Increased Whitefly Resistance and Reduced Viral Disease Incidence

    PubMed Central

    Escobar-Bravo, Rocío; Alba, Juan M.; Pons, Clara; Granell, Antonio; Kant, Merijn R.; Moriones, Enrique; Fernández-Muñoz, Rafael

    2016-01-01

    Whiteflies damage tomatoes mostly via the viruses they transmit. Cultivated tomatoes lack many of the resistances of their wild relatives. In order to increase protection to its major pest, the whitefly Bemisia tabaci and its transmitted Tomato Yellow Leaf Curl Virus (TYLCV), we introgressed a trichome-based resistance trait from the wild tomato Solanum pimpinellifolium into cultivated tomato, Solanum lycopersicum. The tomato backcross line BC5S2 contains acylsucrose-producing type-IV trichomes, unlike cultivated tomatoes, and exhibits increased, yet limited protection to whiteflies at early development stages. Treatment of young plants with methyl jasmonate (MeJA) resulted in a 60% increase in type-IV trichome density, acylsucrose production, and enhanced resistance to whiteflies, leading to 50% decrease in the virus disease incidence compared to cultivated tomato. Using transcriptomics, metabolite analysis, and insect bioassays we established the basis of this inducible resistance. We found that MeJA activated the expression of the genes involved in the biosynthesis of the defensive acylsugars in young BC5S2 plants leading to enhanced chemical defenses in their acquired type-IV trichomes. Our results show that not only constitutive but also these inducible defenses can be transferred from wild into cultivated crops to aid sustainable protection, suggesting that conventional breeding strategies provide a feasible alternative to increase pest resistance in tomato. PMID:27920785

  13. The antioxidants vitamins A and E and selenium do not reduce the incidence of asbestos-induced disease in a mouse model of mesothelioma.

    PubMed

    Robinson, Cleo; Woo, Samantha; Walsh, Amy; Nowak, Anna K; Lake, Richard A

    2012-01-01

    Epidemiological evidence indicates that supplementation with some dietary factors is associated with a lower incidence of cancer. An effective cancer prevention strategy for the millions of people worldwide who have been exposed to asbestos could have enormous benefit. We tested whether dietary supplementation of the antioxidants vitamin A, E, and selenium could alter the pattern of disease in the MexTAg transgenic mouse model, in which mice uniformly develop mesothelioma after asbestos exposure. We focused on antioxidants because one of the most widely accepted hypotheses for the mechanism by which asbestos fibers cause cancer proposes the involvement of reactive oxygen and nitrogen species. We compared the survival of MexTAg mice that had been inoculated with asbestos fed on diets supplemented with 250,000 IU/kg vitamin A (retinoic acid), or 1,000 mg/kg vitamin E (α-tocopherol acetate) or 3 mg/kg selenium, or both vitamin E and selenium concurrently and, additionally, diets deficient in each antioxidant. We found that neither the time to develop symptoms of disease nor overall survival times were altered by any of the diets. We conclude that the data do not support the notion that dietary antioxidants will moderate the rate of mesothelioma in asbestos-exposed populations.

  14. Incidence rates of treatment-emergent adverse events and related hospitalization are reduced with azacitidine compared with conventional care regimens in older patients with acute myeloid leukemia.

    PubMed

    Seymour, John F; Döhner, Hartmut; Minden, Mark D; Stone, Richard; Gambini, Dominique; Dougherty, Donna; Beach, C L; Weaver, Jerry; Dombret, Hervé

    2017-06-01

    Relative risks of treatment-emergent adverse events (TEAEs) and related hospitalization is most accurate when accounting for treatment exposure. AZA-AML-001 showed azacitidine (AZA) prolonged overall survival versus conventional care regimens (CCR) in older patients (≥65 years) with acute myeloid leukemia (AML) by 3.9 months. Preselection of CCR before study randomization allows evaluation of AZA safety in patient subgroups with similar clinical features. Within preselection groups, AZA exposure was greater than each CCR. Incidence rates (IRs; numbers of events normalized for drug exposure time) of hospitalizations and days in hospital for TEAEs per patient-year of exposure were to varying degrees lower with AZA versus each CCR. Overall survival was significantly prolonged with AZA versus best supportive care (BSC) in AZA-AML-001; this analysis showed 55% and 41% reductions in IRs of TEAE-related hospitalization and days in hospital, respectively, with AZA versus BSC. Older patients with AML unable to tolerate intensive therapy should be offered active low-intensity treatment.

  15. Dose-Dependent Effects of Focal Fractionated Irradiation on Secondary Malignant Neoplasms in Nf1 mutant mice

    PubMed Central

    Nakamura, Jean L; Phong, Connie; Pinarbasi, Emile; Kogan, Scott C; Vandenberg, Scott; Horvai, Andrew E; Faddegon, Bruce A; Fiedler, Dorothea; Shokat, Kevan; Houseman, Benjamin T; Chao, Richard; Pieper, Russell O; Shannon, Kevin

    2010-01-01

    Secondary malignant neoplasms (SMNs) are increasingly common complications of cancer therapy that have proven difficult to model in mice. Clinical observations suggest that the development of SMN correlates with radiation dose; however, this relationship has not been investigated systematically. We developed a novel procedure for administering fractionated cranial irradiation (CI) and investigated the incidence and spectrum of cancer in control and heterozygous Nf1 mutant mice irradiated to a moderate (15 Gy) or high dose (30 Gy). Heterozygous Nf1 inactivation cooperated with CI to induce solid tumors and myeloid malignancies, with mice developing many of the most common SMNs found in human patients. CI-induced malignancies segregated according to radiation dose as Nf1+/− mice developed predominately hematologic abnormalities after 15 Gy, while solid tumors predominated at 30 Gy, suggesting that radiation dose thresholds exist for hematologic and non-hematologic cancers. Genetic and biochemical studies revealed discrete patterns of somatic Nf1 and Trp53 inactivation and we observed hyperactive Ras signaling in many radiation-induced solid tumors. This technique for administering focal fractionated irradiation will facilitate mechanistic and translational studies of SMNs. PMID:21199799

  16. Characterization of the neuroprotective effects of estrogens on hydrogen peroxide-induced cell death in hippocampal HT22 cells: time and dose-dependency.

    PubMed

    Vedder, H; Teepker, M; Fischer, S; Krieg, J C

    2000-01-01

    Time and dose-dependency of the effects of estrogens (17-beta estradiol, estrone) and non-estrogenic steroids (progesterone, dexamethasone and methylprednisolone) on the toxicity of hydrogen peroxide were examined in mouse hippocampal HT22 cells. Hydrogen peroxide, an important intermediate of various disease-relevant oxidative stressors, induced cell death in HT22 cells in extracellular concentrations between 0.5 and 1.5 mM in a dose-dependent manner (EC50=0.95 mM). Regarding the underlying mechanisms of toxicity, incubation with hydrogen peroxide did not induce lipid peroxidation in living HT22 cells under these conditions. After preincubation with estrogens and non-estrogenic steroids for 22 hours, estrogen compounds protected the cells against hydrogen peroxide toxicity. Estrogens showed a maximal protective effect at 60-70% of hydrogen peroxide toxicity which diminished at higher and lower concentrations of the toxic challenge. Dose-dependency studies of estrogens revealed that concentrations of 1 microM already exerted a significant cytoprotective effect. Co- and postincubation with 17-beta estradiol and estrone also resulted in significant cell protection even if the estrogens were added 30 min after the initiation of the challenge with hydrogen peroxide. In contrast, preincubation with other steroids like progesterone, a physiological gonadal steroid, dexamethasone, a synthetic glucocorticoid and methylprednisolone, a glucocorticoid with radical scavenging properties, did not protect the cells against hydrogen peroxide toxicity but resulted in a dose-related decrease of HT22 cell survival in the course of the toxic challenge.

  17. The Dose-Dependent Organ-Specific Effects of a Dipeptidyl Peptidase-4 Inhibitor on Cardiovascular Complications in a Model of Type 2 Diabetes

    PubMed Central

    Seo, Jung-Woo; Lee, Arah; Kim, Dong Jin; Kim, Yang-Gyun; Kim, Se-Yeun; Lee, Kyung Hye; Lim, Sung-Jig; Cheng, Xian Wu; Lee, Sang-Ho; Kim, Weon

    2016-01-01

    Objective Although dipeptidyl peptidase-4 (DPP-4) inhibitors have been suggested to have a non-glucoregulatory protective effect in various tissues, the effects of long-term inhibition of DPP-4 on the micro- and macro-vascular complications of type 2 diabetes remain uncertain. The aim of the present study was to investigate the organ-specific protective effects of DPP-4 inhibitor in rodent model of type 2 diabetes. Methods Eight-week-old diabetic and obese db/db mice and controls (db/m mice) received vehicle or one of two doses of gemigliptin (0.04 and 0.4%) daily for 12 weeks. Urine albumin excretion and echocardiography measured at 20 weeks of age. Heart and kidney tissue were subjected to molecular analysis and immunohistochemical evaluation. Results Gemigliptin effectively suppressed plasma DPP-4 activation in db/db mice in a dose-dependent manner. The HbA1c level was normalized in the 0.4% gemigliptin, but not in the 0.04% gemigliptin group. Gemigliptin showed a dose-dependent protective effect on podocytes, anti-apoptotic and anti-oxidant effects in the diabetic kidney. However, the dose-dependent effect of gemigliptin on diabetic cardiomyopathy was ambivalent. The lower dose significantly attenuated left ventricular (LV) dysfunction, apoptosis, and cardiac fibrosis, but the higher dose could not protect the LV dysfunction and cardiac fibrosis. Conclusion Gemigliptin exerted non-glucoregulatory protective effects on both diabetic nephropathy and cardiomyopathy. However, high-level inhibition of DPP-4 was associated with an organ-specific effect on cardiovascular complications in type 2 diabetes. PMID:26959365

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

    PubMed Central

    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.

    2016-01-01

    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

  19. 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.

  20. 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.

  1. 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...

  2. [Critical incidents].

    PubMed

    Scheidegger, D

    2005-03-01

    In medicine real severe mishaps are rare. On the other hand critical incidents are frequent. Anonymous critical incident reporting systems allow us to learn from these mishaps. This learning process will make our daily clinical work safer Unfortunately, before these systems can be used efficiently our professional culture has to be changed. Everyone in medicine has to admit that errors do occur to see the need for an open discussion. If we really want to learn from errors, we cannot punish the individual, who reported his or her mistake. The interest is primarily in what has happened and why it has happened and not who has committed this mistake. The cause for critical incidents in medicine is in over 80% the human factor Poor communication, work under enormous stress, conflicts and hierarchies are the main cause. This has been known for many years, therefore have already 15 years ago high-tech industries, like e.g. aviation, started to invest in special courses on team training. Medicine is a typical profession were until now only the individual performance decided about the professional career Communication, conflict management, stress management, decision making, risk management, team and team resource management were subjects that have never been taught during our preor postgraduate education. These points are the most important ones for an optimal teamwork. A multimodular course designed together with Swissair (Human Aspect Development medical, HADmedical) helps to cover, as in aviation, the soft factor and behavioural education in medicine and to prepare professionals in health care to work as a real team.

  3. Improved compliance with venous thromboembolism (VTE) pharmacologic prophylaxis for patients with gynecologic malignancies hospitalized for nonsurgical indications did not reduce VTE incidence

    PubMed Central

    Prescott, Lauren S.; Kidin, Lisa M.; Downs, Rebecca L.; Cleveland, David J.; Wilson, Ginger L.; Munsell, Mark F.; DeJesus, Alma Y.; Cain, Katherine E.; Ramirez, Pedro T.; Kroll, Michael H.; Levenback, Charles F.; Schmeler, Kathleen M.

    2014-01-01

    Objective National guidelines recommend prophylactic anticoagulation for all hospitalized patients with cancer to prevent hospital-acquired venous thromboembolism (VTE). However, adherence to these evidence-based recommended practice patterns remains low. We performed a quality improvement project to increase VTE pharmacologic prophylaxis rates among patients with gynecologic malignancies hospitalized for nonsurgical indications and evaluated the resulting effect on rates of development of VTE. Methods/materials In June 2011, departmental VTE practice guidelines were implemented for patients with gynecologic malignancies who were hospitalized for nonsurgical indications. A standardized VTE prophylaxis module was added to the admission electronic order sets. Outcome measures included: number of admissions receiving VTE pharmacologic prophylaxis within 24 hours of admission; and number of potentially preventable hospital-acquired VTEs diagnosed within 30 and 90 days of discharge. Outcomes were compared between a pre-guideline implementation cohort (N=99), a post-guideline implementation cohort (N=127), and a sustainability cohort assessed 2 years after implementation (N=109). Patients were excluded if upon admission they had a VTE, were considered low risk for VTE, or had a documented contraindication to pharmacologic prophylaxis. Results Administration of pharmacologic prophylaxis within 24 hours of admission increased from 20.8% to 88.2% immediately following the implementation of guidelines, but declined to 71.8% in our sustainability cohort (p<0.001). There was no difference in VTE incidence among the three cohorts (n=2 (4.2%) v. n=3 (3.9%) v. n=3 (4.2%), respectively; p=1.00). Conclusions Our quality improvement project improved pharmacologic VTE prophylaxis rates. A small decrease in prophylaxis over the subsequent 2 years suggests a need for continued surveillance to optimize quality improvement initiatives. Despite increased adherence to guidelines, VTE rates

  4. An oral DNA vaccine against infectious haematopoietic necrosis virus (IHNV) encapsulated in alginate microspheres induces dose-dependent immune responses and significant protection in rainbow trout (Oncorrhynchus mykiss).

    PubMed

    Ballesteros, Natalia A; Alonso, Marta; Saint-Jean, Sylvia Rodríguez; Perez-Prieto, Sara I

    2015-08-01

    Administered by intramuscular injection, a DNA vaccine (pIRF1A-G) containing the promoter regions upstream of the rainbow trout interferon regulatory factor 1A gene (IRF1A) driven the expression of the infectious hematopoietic necrosis virus (IHNV) glycoprotein (G) elicited protective immune responses in rainbow trout (Oncorhynchus mykiss). However, less laborious and cost-effective routes of DNA vaccine delivery are required to vaccinate large numbers of susceptible farmed fish. In this study, the pIRF1A-G vaccine was encapsulated into alginate microspheres and orally administered to rainbow trout. At 1, 3, 5, and 7 d post-vaccination, IHNV G transcripts were detected by quantitative real-time PCR in gills, spleen, kidney and intestinal tissues of vaccinated fish. This result suggested that the encapsulation of pIRF1A-G in alginate microparticles protected the DNA vaccine from degradation in the fish stomach and ensured vaccine early delivery to the hindgut, vaccine passage through the intestinal mucosa and its distribution thought internal and external organs of vaccinated fish. We also observed that the oral route required approximately 20-fold more plasmid DNA than the injection route to induce the expression of significant levels of IHNV G transcripts in kidney and spleen of vaccinated fish. Despite this limitation, increased IFN-1, TLR-7 and IgM gene expression was detected by qRT-PCR in kidney of vaccinated fish when a 10 μg dose of the oral pIRF1A-G vaccine was administered. In contrast, significant Mx-1, Vig-1, Vig-2, TLR-3 and TLR-8 gene expression was only detected when higher doses of pIRF1A-G (50 and 100 μg) were orally administered. The pIRF1A-G vaccine also induced the expression of several markers of the adaptive immune response (CD4, CD8, IgM and IgT) in kidney and spleen of immunized fish in a dose-dependent manner. When vaccinated fish were challenged by immersion with live IHNV, evidence of a dose-response effect of the oral vaccine could also

  5. The impact of resveratrol and hydrogen peroxide on muscle cell plasticity shows a dose-dependent interaction

    PubMed Central

    Bosutti, Alessandra; Degens, Hans

    2015-01-01

    While reactive oxygen species (ROS) play a role in muscle repair, excessive amounts of ROS for extended periods may lead to oxidative stress. Antioxidants, as resveratrol (RS), may reduce oxidative stress, restore mitochondrial function and promote myogenesis and hypertrophy. However, RS dose-effectiveness for muscle plasticity is unclear. Therefore, we investigated RS dose-response on C2C12 myoblast and myotube plasticity 1. in the presence and 2. absence of different degrees of oxidative stress. Low RS concentration (10 μM) stimulated myoblast cell cycle arrest, migration and sprouting, which were inhibited by higher doses (40–60 μM). RS did not increase oxidative capacity. In contrast, RS induced mitochondria loss, reduced cell viability and ROS production, and activated stress response pathways [Hsp70 and pSer36-p66(ShcA) proteins]. However, the deleterious effects of H2O2 (1000 µM) on cell migration were alleviated after preconditioning with 10 µM-RS. This dose also enhanced cell motility mediated by 100 µM-H2O2, while higher RS-doses augmented the H2O2-induced impaired myoblast regeneration and mitochondrial dehydrogenase activity. In conclusion, low resveratrol doses promoted in vitro muscle regeneration and attenuated the impact of ROS, while high doses augmented the reduced plasticity and metabolism induced by oxidative stress. Thus, the effects of resveratrol depend on its dose and degree of oxidative stress. PMID:25627702

  6. Statins Attenuate Helicobacter pylori CagA Translocation and Reduce Incidence of Gastric Cancer: In Vitro and Population-Based Case-Control Studies.

    PubMed

    Lin, Chun-Jung; Liao, Wei-Chih; Lin, Hwai-Jeng; Hsu, Yuan-Man; Lin, Cheng-Li; Chen, Yu-An; Feng, Chun-Lung; Chen, Chih-Jung; Kao, Min-Chuan; Lai, Chih-Ho; Kao, Chia-Hung

    2016-01-01

    Gastric cancer is the second leading cause of cancer-related death worldwide. The correlation of Helicobacter pylori and the etiology of gastric cancer was substantially certain. Cholesterol-rich microdomains (also called lipid rafts), which provide platforms for signaling, are associated with H. pylori-induced pathogenesis leading to gastric cancer. Patients who have been prescribed statins, inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase, have exhibited a reduced risk of several types of cancer. However, no studies have addressed the effect of statins on H. pylori-associated gastric cancer from the antineoplastic perspective. In this study, we showed that treatment of gastric epithelial cells with simvastatin reduced the level of cellular cholesterol and led to attenuation of translocation and phosphorylation of H. pylori cytotoxin-associated gene A (CagA), which is recognized as a major determinant of gastric cancer development. Additionally, a nationwide case-control study based on data from the Taiwanese National Health Insurance Research Database (NHIRD) was conducted. A population-based case-control study revealed that patients who used simvastatin exhibited a significantly reduced risk of gastric cancer (adjusted odds ratio (OR) = 0.76, 95% confidence interval (CI) = 0.70-0.83). In patients exhibiting H. pylori infection who were prescribed simvastatin, the adjusted OR for gastric cancer was 0.25 (95% CI = 0.12-0.50). Our results combined an in vitro study with a nationwide population analysis reveal that statin use might be a feasible approach to prevent H. pylori-associated gastric cancer.

  7. [The dose dependent effect of glycosaminoglycan peptide complex on corticosteroid-induced disordered metabolism in cartilage tissue of rats].

    PubMed

    Annefeld, M

    1989-01-01

    Systemic corticosteroid treatment induces morphological and functional changes in the articular cartilage similar to those in human osteoarthritis. In animal experiments the dexamethasone-induced inhibition of chondrocyte metabolism can be reduced in a dose-related manner by concomitant treatment with glycosaminoglycan-peptide complexes (GP-C)***). The metabolic changes in cartilage tissues of the joint and Processus Xiphoideus measured quantitatively by 35S-sulphate incorporation are comparable. The results indicate that GP-C could also have a dose-related effect on human osteoarthritic cartilage.

  8. 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.

  9. 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

  10. 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

  11. Estimating the Cost-Effectiveness of Pre-Exposure Prophylaxis to Reduce HIV-1 and HSV-2 Incidence in HIV-Serodiscordant Couples in South Africa

    PubMed Central

    Jewell, Britta L.; Cremin, Ide; Pickles, Michael; Celum, Connie; Baeten, Jared M.; Delany-Moretlwe, Sinead; Hallett, Timothy B.

    2015-01-01

    Objective To estimate the cost-effectiveness of daily oral tenofovir-based PrEP, with a protective effect against HSV-2 as well as HIV-1, among HIV-1 serodiscordant couples in South Africa. Methods We incorporated HSV-2 acquisition, transmission, and interaction with HIV-1 into a microsimulation model of heterosexual HIV-1 serodiscordant couples in South Africa, with use of PrEP for the HIV-1 uninfected partner prior to ART initiation for the HIV-1 1infected partner, and for one year thereafter. Results We estimate the cost per disability-adjusted life-year (DALY) averted for two scenarios, one in which PrEP has no effect on reducing HSV-2 acquisition, and one in which there is a 33% reduction. After a twenty-year intervention, the cost per DALY averted is estimated to be $10,383 and $9,757, respectively – a 6% reduction, given the additional benefit of reduced HSV-2 acquisition. If all couples are discordant for both HIV-1 and HSV-2, the cost per DALY averted falls to $1,445, which shows that the impact is limited by HSV-2 concordance in couples. Conclusion After a 20-year PrEP intervention, the cost per DALY averted with a reduction in HSV-2 is estimated to be modestly lower than without any effect, providing an increase of health benefits in addition to HIV-1 prevention at no extra cost. The small degree of the effect is in part due to a high prevalence of HSV-2 infection in HIV-1 serodiscordant couples in South Africa. PMID:25616135

  12. A high dietary concentration of inulin is necessary to reduce the incidence of swine dysentery in pigs experimentally challenged with Brachyspira hyodysenteriae.

    PubMed

    Hansen, Christian F; Hernández, Aracely; Mansfield, Josie; Hidalgo, Álvaro; La, Tom; Phillips, Nyree D; Hampson, David J; Pluske, John R

    2011-11-01

    A total of sixty surgically castrated male pigs (Large White × Landrace) weighing 31·2 (sd 4·3) kg were used in a randomised block experiment to examine the effect of added dietary inulin (0, 20, 40 and 80 g/kg) on the occurrence of swine dysentery (SD) and on fermentation characteristics in the large intestine after experimental challenge with the causative spirochaete Brachyspira hyodysenteriae. The pigs were allowed to adapt to the diets for 2 weeks before each pig was challenged orally four times with a broth culture containing B. hyodysenteriae on consecutive days. Increasing dietary levels of inulin linearly (P = 0·001) reduced the risk of pigs developing SD; however, eight out of fifteen pigs fed the diet with 80 g/kg inulin still developed the disease. The pH values in the caecum (P = 0·072) tended to decrease, and in the upper colon, the pH values did decrease (P = 0·047) linearly with increasing inulin levels in the diets, most probably due to a linear increase in the concentration of total volatile fatty acids in the caecum (P = 0·018), upper colon (P = 0·001) and lower colon (P = 0·013). In addition, there was a linear reduction in the proportion of the branched-chain fatty acids isobutyric acid and isovaleric acid in the caecum (P = 0·015 and 0·026) and upper colon (P = 0·011 and 0·013) with increasing levels of dietary inulin. In conclusion, the present study showed that a diet supplemented with a high level of inulin (80 g/kg) but not lower levels reduced the risk of pigs developing SD, possibly acting through a modification of the microbial fermentation patterns in the large intestine.

  13. Dose-dependent, therapeutic potential of angiotensin-(1–7) for the treatment of pulmonary arterial hypertension

    PubMed Central

    Breitling, Siegfried; Krauszman, Adrienn; Parihar, Richa; Walther, Thomas; Friedberg, Mark K.

    2015-01-01

    Abstract The effects of the heptapeptide angiotensin-(1–7) (Ang-(1–7)), via its receptor Mas, oppose many of the effects of the classic angiotensin II signaling pathway, and pharmacological exploitation of this effect is currently actively pursued for a wide range of cardiovascular, neoplastic, or immunological disorders. On the basis of its vasodilatory and antiproliferative properties, Ang-(1–7) has consequentially also been proposed as a novel therapeutic strategy for the treatment of pulmonary arterial hypertension (PAH). In this study, we tested the effectiveness of Ang-(1–7) and its stable, cyclic analog cAng-(1–7) over a range of doses for their therapeutic potential in experimental PAH. In the monocrotaline (MCT) rat model of PAH, Ang-(1–7) or cAng-(1–7) were injected in doses of 30, 100, 300, or 900 μg kg−1 day−1, and effects on pulmonary hemodynamics and vascular remodeling were assessed. Five weeks after MCT injection, right ventricular systolic pressure (RVSP) was significantly reduced for 3 dose groups treated with Ang-(1–7) (100, 300, and 900 μg kg−1 day−1) and for all dose groups treated with cAng-(1–7), as compared to untreated controls, yet the total reduction of RVSP was <50% at best and thus markedly lower than that with a positive treatment control with ambrisentan. Medial-wall thickness in pulmonary arterioles was only slightly reduced, without reaching significance, for any of the tested Ang-(1–7) compounds and doses. The reported moderate attenuation of PAH does not confirm the previously postulated high promise of this strategy, and the therapeutic usefulness of Ang-(1–7) may be limited in PAH relative to that in other cardiovascular diseases. PMID:26697172

  14. Dose-dependent reduction of hazardous alcohol use in a placebo-controlled trial of naltrexone for smoking cessation.

    PubMed

    O'Malley, Stephanie S; Krishnan-Sarin, Suchitra; McKee, Sherry A; Leeman, Robert F; Cooney, Ned L; Meandzija, Boris; Wu, Ran; Makuch, Robert W

    2009-06-01

    The opiate antagonist naltrexone (Ntx) has demonstrated efficacy in the treatment of alcohol dependence and as a component of treatment to reduce heavy drinking. At present, there are no published dose-ranging clinical trials of the oral preparation for treatment of problem drinking. The present study evaluated the effects of Ntx on alcohol use among the subset of hazardous drinkers (n=102) who participated in a placebo-controlled, dose-ranging trial of oral Ntx (25-mg, 50-mg and 100-mg doses) combined with open-label transdermal nicotine patch for enhancing smoking cessation. On the primary outcome--no hazardous drinking (drinking that exceeded weekly or daily limits) during treatment--25 mg and 50 mg Ntx were superior to placebo (each p<0.05). These findings remained after controlling for baseline predictors or smoking abstinence during treatment. Time to remission of hazardous drinking was examined as a secondary outcome with definitions of hazardous drinking based on weekly limits, daily limits and the combination of weekly and daily limits and the results were consistent with the primary findings. In conclusion, the findings suggest that Ntx can reduce the risk of hazardous drinking in smokers who are not seeking or receiving alcohol treatment, providing strong evidence for the pharmacological effects of Ntx on drinking. This effect appears to favour lower doses that may be better tolerated and less expensive than the higher 100-mg dose. Given its efficacy and favourable side-effect profile, the 25-mg dose should be considered for future studies of combination therapy.

  15. Dose Dependent Reduction of Hazardous Alcohol Use in a Placebo-Controlled Trial of Naltrexone for Smoking Cessation

    PubMed Central

    O’Malley, Stephanie S.; Krishnan-Sarin, Suchitra; McKee, Sherry A.; Leeman, Robert F.; Cooney, Ned L.; Meandzija, Boris; Wu, Ran; Makuch, Robert W.

    2011-01-01

    The opiate antagonist naltrexone has demonstrated efficacy in the treatment of alcohol dependence and as a component of treatment to reduce heavy drinking. At present, there are no published dose-ranging clinical trials of the oral preparation for treatment of problem drinking. The present study evaluated the effects of naltrexone on alcohol use among the subset of hazardous drinkers (N = 102) who participated in a placebo-controlled, dose-ranging trial of oral naltrexone (25 mg, 50 mg and 100 mg doses) combined with open-label transdermal nicotine patch for enhancing smoking cessation. On the primary outcome—no hazardous drinking (drinking that exceeded weekly or daily limits) during treatment—25 mg and 50 mg naltrexone were superior to placebo (each p < 0.05). These findings remained after controlling for baseline predictors or smoking abstinence during treatment. Time to remission of hazardous drinking was examined as a secondary outcome with definitions of hazardous drinking based on weekly limits, daily limits and the combination of weekly and daily limits and the results were consistent with the primary findings. In conclusion, the findings suggest that naltrexone can reduce the risk of hazardous drinking in smokers who are not seeking or receiving alcohol treatment, providing strong evidence for the pharmacological effects of naltrexone on drinking. This effect appears to favor lower doses that may be better tolerated and less expensive than the higher 100 mg dose. Given its efficacy and favorable side effect profile, the 25 mg dose should be considered for future studies of combination therapy. PMID:18796184

  16. Anatomy of an incident

    SciTech Connect

    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 identified 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.

  17. Anatomy of an incident

    DOE PAGES

    Cournoyer, Michael E.; Trujillo, Stanley; Lawton, Cindy M.; ...

    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

  18. Dose-dependent effects of 17-beta-estradiol on pituitary thyrotropin content and secretion in vitro.

    PubMed

    Moreira, R M; Lisboa, P C; Curty, F H; Pazos-Moura, C C

    1997-09-01

    We studied the basal and thyrotropin-releasing hormone (TRH) (50 nM) induced thyrotropin (TSH) release in isolated hemipituitaries of ovariectomized rats treated with near-physiological or high doses of 17-beta-estradiol benzoate (EB; sc, daily for 10 days) or with vehicle (untreated control rats, OVX). One group was sham-operated (normal control). The anterior pituitary glands were incubated in Krebs-Ringer bicarbonate medium, pH 7.4, at 37 degrees C in an atmosphere of 95% O2/5% CO2. Medium and pituitary TSH was measured by specific RIA (NIDDK-RP-3). Ovariectomy induced a decrease (P < 0.05) in basal TSH release (normal control = 44.1 +/- 7.2; OVX = 14.7 +/- 3.0 ng/ml) and tended to reduce TRH-stimulated TSH release (normal control = 33.0 +/- 8.1; OVX = 16.6 +/- 2.4 ng/ml). The lowest dose of EB (0.7 microgram/100 g body weight) did not reverse this alteration, but markedly increased the pituitary TSH content (0.6 +/- 0.06 microgram/hemipituitary; P < 0.05) above that of OVX (0.4 +/- 0.03 microgram/hemipituitary) and normal rats (0.46 +/- 0.03 microgram/hemipituitary). The intermediate EB dose (1.4 micrograms/100 g body weight) induced a nonsignificant tendency to a higher TSH response to TRH compared to OVX and a lower response compared to normal rats. Conversely, in the rats treated with the highest dose (14 micrograms/100 g body weight), serum 17-beta-estradiol was 17 times higher than normal, and the basal and TRH-stimulated TSH release, as well as the pituitary TSH content, was significantly (P < 0.05) reduced compared to normal rats and tended to be even lower than the values observed for the vehicle-treated OVX group, suggesting an inhibitory effect of hyperestrogenism. In conclusion, while reinforcing the concept of a positive physiological regulatory role of estradiol on the TSH response to TRH and on the pituitary stores of the hormone, the present results suggest an inhibitory effect of high levels of estrogen on these responses.

  19. 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

  20. Dose-Dependent Anti-Inflammatory and Neuroprotective Effects of an ανβ3 Integrin-Binding Peptide

    PubMed Central

    Han, Shu; Zhang, Fan; Hu, Zhiying; Sun, Yayi; Yang, Jing; Davies, Henry; Yew, David T. W.; Fang, Marong

    2013-01-01

    Previous studies have shown that prevention of leukocyte infiltration by targeting integrins involved in transendothelial migration may suppress the clinical and pathological features of neuroinflammatory disease. This study was designed to investigate the effects of C16, an ανβ3 integrin-binding peptide, in an acute experimental allergic encephalomyelitis (EAE) rat model. Multiple histological and immunohistochemical staining, electron microscopy observation, ELISA assay, Western blot, and magnetic resonance imaging (MRI) were employed to assess the degree of inflammation, axonal loss, neuronal apoptosis, white matter demyelination, and extent of gliosis in the brain and spinal cord of differently treated EAE models. The results showed that C16 treatment could inhibit extensive leukocyte and macrophage accumulation and infiltration and reduce cytokine tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) expression levels. A significantly lower clinical score at the peak time of disease was also demonstrated in the C16 treated group. Moreover, astrogliosis, demyelination, neuronal death, and axonal loss were all alleviated in C16 treated EAE animals, which may be attributed to the improvement of microenvironment. The data suggests that C16 peptide may act as a protective agent by attenuating inflammatory progression and thus affecting the expression of some proinflammatory cytokines during neuroinflammatory disease. PMID:24347822

  1. Longitudinal functional connectivity changes correlate with mood improvement after regular exercise in a dose-dependent fashion.

    PubMed

    Tozzi, Leonardo; Carballedo, Angela; Lavelle, Grace; Doolin, Kelly; Doyle, Myles; Amico, Francesco; McCarthy, Hazel; Gormley, John; Lord, Anton; O'Keane, Veronica; Frodl, Thomas

    2016-04-01

    Exercise increases wellbeing and improves mood. It is however unclear how these mood changes relate to brain function. We conducted a randomized controlled trial investigating resting-state modifications in healthy adults after an extended period of aerobic physical exercise and their relationship with mood improvements. We aimed to identify novel functional networks whose activity could provide a physiological counterpart to the mood-related benefits of exercise. Thirty-eight healthy sedentary volunteers were randomised to either the aerobic exercise group of the study or a control group. Participants in the exercise group attended aerobic sessions with a physiotherapist twice a week for 16 weeks. Resting-state modifications using magnetic resonance imaging were assessed before and after the programme and related to mood changes. An unbiased approach using graph metrics and network-based statistics was adopted. Exercise reduced mood disturbance and improved emotional wellbeing. It also induced a decrease in local efficiency in the parahippocampal lobe through strengthening of the functional connections from this structure to the supramarginal gyrus, precentral area, superior temporal gyrus and temporal pole. Changes in mood disturbance following exercise were correlated with those in connectivity between parahippocampal gyrus and superior temporal gyrus as well as with the amount of training. No changes were detected in the control group. In conclusion, connectivity from the parahippocampal gyrus to motor, sensory integration and mood regulation areas was strengthened through exercise. These functional changes might be related to the benefits of regular physical activity on mood.

  2. Dose-dependent effects of cannabis on the neural correlates of error monitoring in frequent cannabis users.

    PubMed

    Kowal, Mikael A; van Steenbergen, Henk; Colzato, Lorenza S; Hazekamp, Arno; van der Wee, Nic J A; Manai, Meriem; Durieux, Jeffrey; Hommel, Bernhard

    2015-11-01

    Cannabis has been suggested to impair the capacity to recognize discrepancies between expected and executed actions. However, there is a lack of conclusive evidence regarding the acute impact of cannabis on the neural correlates of error monitoring. In order to contribute to the available knowledge, we used a randomized, double-blind, between-groups design to investigate the impact of administration of a low (5.5 mg THC) or high (22 mg THC) dose of vaporized cannabis vs. placebo on the amplitudes of the error-related negativity (ERN) and error positivity (Pe) in the context of the Flanker task, in a group of frequent cannabis users (required to use cannabis minimally 4 times a week, for at least 2 years). Subjects in the high dose group (n=18) demonstrated a significantly diminished ERN in comparison to the placebo condition (n=19), whereas a reduced Pe amplitude was observed in both the high and low dose (n=18) conditions, as compared to placebo. The results suggest that a high dose of cannabis may affect the neural correlates of both the conscious (late), as well as the initial automatic processes involved in error monitoring, while a low dose of cannabis might impact only the conscious (late) processing of errors.

  3. 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.

  4. Mechanism of Dose-Dependent Regulation of UBE1L by Polyphenols in Human Bronchial Epithelial Cells.

    PubMed

    Jiang, Apei; Li, Yuan; Wang, Pengqi; Shan, Xiaoyun; Jiang, Pan; Wang, Xuemin; Feng, Qing

    2015-08-01

    Ubiquitin activating enzyme E1-like (UBE1L) is the activating enzyme for ISG15ylation (ISG15, interferon stimulated gene 15). UBE1L is thought to be a candidate tumor suppressor gene and has positive activity against stress responses such as viral infections. Both type I interferon and retinoic acid are known to induce UBE1L expression. However, the molecular mechanism of UBE1L regulation is unclear. Here, the effect of several chemopreventive polyphenols on UBE1L expression in human bronchial epithelial cells (Beas-2B) was investigated. Lower concentrations of curcumin, (-)-epigallocatechin-3-gallate (EGCG) and resveratrol upregulated UBE1L, while high concentrations of curcumin, EGCG and resveratrol downregulated UBE1L levels. Interestingly, curcumin, EGCG and resveratrol diminished intracellular reactive oxygen species (ROS) at lower concentrations but generated ROS at higher concentrations. The antioxidant N-acetylcysteine (NAC) increased UBE1L protein levels, while pro-oxidants such as hydrogen peroxide and tert-butyl hydroperoxide (tBHP) decreased UBE1L protein levels, indicating that the intracellular redox status is associated with UBE1L expression. Kinase inhibitors were used to examine the contribution of mitogen-activated protein kinase (MAPK) activity to the polyphenol-regulated UBE1L. Only the inhibition of c-Jun N-terminal kinase (JNK) significantly reduced UBE1L expression. Knockdown of nuclear factor erythroid-2 related factor-2 (Nrf2) caused a concomitant decrease in UBE1L protein levels. It is concluded from the above mentioned results that JNK/Nrf2 signal pathway is involved in the regulation of UBE1L via intracellular ROS status when cells came in contact with polyphenols.

  5. Relationships between quencher diffusion constant and exposure dose dependences of line width, line edge roughness, and stochastic defect generation in extreme ultraviolet lithography

    NASA Astrophysics Data System (ADS)

    Kozawa, Takahiro

    2015-01-01

    Control of the acid catalytic chain reaction is essential in the pattern formation of chemically amplified resists used for the high-volume production of semiconductor devices. In this study, the relationships between the quencher diffusion constant and the exposure dose dependences of the line width, line edge roughness (LER), and stochastic defect generation were investigated assuming extreme ultraviolet (EUV) lithography. The dependence of the latent images of line-and-space patterns with 16 nm half-pitch on the quencher diffusion constant was calculated on the basis of sensitization and reaction mechanisms of chemically amplified EUV resists. The exposure latitude of the line width increased with the quencher diffusion constant. The dependences of LER and stochastic defect (bridges and pinching) generation on the deviation of the exposure dose became weak by increasing the quencher diffusion constant, similarly to the case for the dependence of the line width.

  6. BPA exposure during in vitro oocyte maturation results in dose-dependent alterations to embryo development rates, apoptosis rate, sex ratio and gene expression.

    PubMed

    Ferris, Jacqueline; Mahboubi, Kiana; MacLusky, Neil; King, W Allan; Favetta, Laura A

    2016-01-01

    Alterations in the oocyte's environment can negatively affect embryo development. Oocyte quality, which can determine embryonic viability, is easily perturbed, thus factors affecting normal oocyte maturation are a concern. Bisphenol A (BPA) is an endocrine disrupting chemical that elicits a variety of reproductive effects. BPA has previously been found to disrupt meiosis, however the embryonic effects in mammals are not well documented. Here, bovine oocytes were matured in vitro with and without BPA treatment. Resulting embryos exhibited decreased embryonic development rates, increased apoptosis, and a skewed sex ratio. Gene expression in blastocysts was not altered, whereas treatment with 15ng/mL BPA resulted in increased expression of several of the genes studies, however this increase was largely due to a vehicle effect. BPA exposure during oocyte maturation in vitro can therefore, in a dose-dependent way, decrease oocyte and embryo quality and developmental potential and affect gene expression of developmentally important transcripts.

  7. 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

  8. Preclinical characterization of a recombinant adeno-associated virus type 1-pseudotyped vector demonstrates dose-dependent injection site inflammation and dissemination of vector genomes to distant sites.

    PubMed

    Flotte, Terence R; Conlon, Thomas J; Poirier, Amy; Campbell-Thompson, Martha; Byrne, Barry J

    2007-03-01

    To translate the potential advantages of recombinant adeno-associated virus type 1 (rAAV1) vectors into a clinical application for muscle-directed gene therapy for alpha1 -antitrypsin (AAT) deficiency, we performed safety studies in 170 C57BL/6 mice and 26 New Zealand White rabbits. A mouse toxicology study included 8 cohorts of 10 mice each (5 per sex). Mice were killed either 21 or 90 days after intramuscular injection of doses ranging up to 1x10(13)vector genomes (VG), equivalent to 4 x 10(14)VG/kg. A mouse biodistribution study was performed in 5 cohorts of 10 mice, receiving intramuscular injections at the same doses; as well as in a lower dose cohort (3 x 10(8) VG; equivalent to 1.2 x 10(10)VG/kg); and in 4 other cohorts (excluding the vehicle control) injected with identical doses intravenously. Finally, biodistribution was examined in rabbits, with serial collection of blood and semen, as well as terminal tissue collection. Two significant findings were present, both of which were dose dependent. First, inflammatory cell infiltrates were detected at the site of injection 21, 60, or 90 days after intramuscular injection of 1 x 10(13)VG. This was not associated with loss of transgene expression. Second, vector DNA sequences were detected in most animals, levels being highest with the highest doses and earliest time points. Vector DNA was also present in liver, spleen, kidneys, and a number of other organs, including the gonads of animals receiving the highest dose. Likewise, vector DNA was present in the semen of male rabbits at higher doses. The copy number of vector DNA in the blood and semen declined over time throughout the study. These two dose-dependent findings have served to guide to the design of a phase 1 human trial of rAAV1-AAT.

  9. Dose dependent effect of C-type natriuretic peptide signaling in glycosaminoglycan synthesis during TGF-β1 induced chondrogenic differentiation of mesenchymal stem cells.

    PubMed

    Tezcan, Berna; Serter, Sema; Kiter, Esat; Tufan, A Cevik

    2010-10-01

    Recent investigations credited important roles to C-type natriuretic peptide (CNP) signaling during chondrogenesis. This study investigated the putative role of CNP in transforming growth factor (TGF)-β1 induced in vitro chondrogenic differentiation of mesenchymal stem cells (MSCs) in pellet culture. MSCs were derived from human trabecular bone and were characterized on the basis of their cell surface antigens and adipogenic, osteogenic, and chondrogenic differentiation potential. TGF-β1 induced chondrogenic differentiation and glycosaminoglycan (GAG) synthesis was analyzed on the basis of basic histology, collagen type II, Sox 9 and aggrecan expressions, and Alcian blue staining. Results revealed that human trabecular bone-derived MSCs express CNP and NPR-B analyzed on the basis of RT-PCR and immunohistochemistry. In pellet cultures of MSCs TGF-β1 successfully induced chondrogenic differentiation and GAG synthesis. RT-PCR analyses of both CNP and NPR-B during this process revealed an activation of this signaling pathway in response to TGF-β1. Similar cultures induced with TGF-β1 and treated with different doses of CNP showed that CNP supplementation at 10(-8) and 10(-7) M concentrations significantly increased GAG synthesis in a dose dependent manner, whereas at 10(-6) M concentration this stimulatory effect was diminished. In conclusion, CNP/NPR-B signaling pathway is activated during TGF-β1 induced chondrogenic differentiation of human trabecular bone-derived MSCs and may strongly be involved in GAG synthesis during this process. This effect is likely to be a dose-dependent effect.

  10. The dipeptidyl peptidase-4 inhibitor linagliptin exhibits time- and dose-dependent localization in kidney, liver, and intestine after intravenous dosing: results from high resolution autoradiography in rats.

    PubMed

    Greischel, Andreas; Binder, Rudolf; Baierl, Juergen

    2010-09-01

    Linagliptin is an orally active dipeptidyl peptidase-4 (DPP-4) inhibitor that is under development for the treatment of type 2 diabetes and shows dose-dependent pharmacokinetics in rats and humans. With microscopic autoradiography, the dose dependence of cellular distribution of [(3)H]linagliptin-related radioactivity was investigated in kidney at 3 h after intravenous injection of 7.4, 100, and 2000 microg/kg [(3)H]linagliptin. Furthermore, distribution of radioactivity in kidney, liver, and small intestine was investigated in relation to time (2 min, 3 h, and 192 h) after intravenous injection of 7.4 microg/kg [(3)H]linagliptin. The localization of radioactivity in the kidney at 3 h after administration of 7.4, 100, and 2000 microg/kg [(3)H]linagliptin changed with increasing dose from cortical glomeruli and parts of proximal tubule parts to parts of medullar proximal tubule. In addition, the compound distribution in the kidney shifted with time after administration of 7.4 microg/kg [(3)H]linagliptin from glomeruli (2 min) to the lower parts of proximal tubules (192 h). The radioactivity within proximal tubules was located primarily in the brush border. In the liver, the radioactivity persisted mainly around the portal triads and in the bile duct from 2 min to 192 h. In the small intestine, the radioactivity shifted from the lamina propria (2 min) to the surface of the villi and/or intestinal lumen (192 h). In conclusion, the cellular distribution pattern of [(3)H]linagliptin-related radioactivity reflected the known distribution of DPP-4. Together with the persistence of binding, this result supports the high relevance of DPP-4 binding of linagliptin for its pharmacokinetics and pharmacodynamics.

  11. Adenosine triphosphate regulates the activity of guinea pig Cav1.2 channel by direct binding to the channel in a dose-dependent manner.

    PubMed

    Feng, Rui; Xu, Jianjun; Minobe, Etsuko; Kameyama, Asako; Yang, Lei; Yu, Lifeng; Hao, Liying; Kameyama, Masaki

    2014-05-01

    The present study is to investigate the mechanism by which ATP regulates Cav1.2 channel activity. Ventricular tissue was obtained from adult guinea pig hearts using collagenase. Ca(2+) channel activity was monitored using the patch-clamp technique. Proteins were purified using wheat germ agglutinin-Sepharose, and the concentration was determined using the Coomassie brilliant blue technique. ATP binding to the Cav1.2 channel was examined using the photoaffinity method. EDA-ATP-biotin maintains Ca(2+) channel activity in inside-out membrane patches. ATP directly bound to the Cav1.2 channel in a dose-dependent manner, and at least two molecules of ATP bound to one molecule of the Cav1.2 channel. Low levels of calmodulin (CaM) increased ATP binding to the Cav1.2 channel, but higher levels of CaM decreased ATP binding to the Cav1.2 channel. In addition, Ca(2+) was another regulator for ATP binding to the Cav1.2 channel. Furthermore, ATP bound to GST-fusion peptides of NH2-terminal region (amino acids 6-140) and proximal COOH-terminal region (amino acids 1,509-1,789) of the main subunit (α1C) of the Cav1.2 channel. Our data suggest that ATP might regulate Cav1.2 channel activity by directly binding to the Cav1.2 channel in a dose-dependent manner. In addition, the ATP-binding effect to the Cav1.2 channel was both CaM- and Ca(2+) dependent.

  12. 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.

  13. Polychlorinated biphenyls as oxidative stress inducers in liver of subacutely exposed rats: implication for dose-dependence toxicity and benchmark dose concept.

    PubMed

    Buha, Aleksandra; Antonijević, Biljana; Milovanović, Vesna; Janković, Saša; Bulat, Zorica; Matović, Vesna

    2015-01-01

    Hepatotoxicity is one of the well-documented adverse health effects of polychlorinated biphenyls (PCBs)-persistent organic pollutants widely present in the environment. Although previous studies suggest possible role of oxidative stress, the precise mechanisms of PCB-induced ROS production in liver still remain to be fully assessed. The aim of this study was to evaluate the effects of different doses of PCBs on the parameters of oxidative stress and to investigate whether these effects are dose dependent. Furthermore, a comparison between calculated benchmark doses (BMD) and estimated NOAEL values for investigated parameters, was made. Six groups of male albino Wistar rats (7 animals per group) were receiving Aroclor 1254 dissolved in corn oil in the doses of 0.5, 1, 2, 4, 8, 16 mg PCBs/kg b.w./day by oral gavage during 28 days while control animals were receiving corn oil only. The following parameters of oxidative stress were analyzed in liver homogenates: superoxide dismutase activity, glutathione, malondialdehyde (MDA) and total protein thiol levels. Hepatic enzymes AST, ALT, ALP and protein albumin were also determined in serum as clinical parameters of liver function. Collected data on the investigated parameters were analyzed by the BMD method. The results of this study demonstrate that subacute exposure to PCBs causes induction of oxidative stress in liver with dose-dependent changes of the investigated parameters, although more pronounced adverse effects were observed on enzymatic than on non-enzymatic components of antioxidant protection. The obtained values for BMD and NOAEL support the use of BMD concept in the prediction of health risks associated with PCBs exposure. Furthermore, our results implicate possible use of MDA in PCBs risk assessment, since MDA was the most sensitive investigated parameter with calculated low critical effect dose of 0.07 mg/kg b.w.

  14. Progressive gene dose-dependent disruption of the methamphetamine-sensitive circadian oscillator-driven rhythms in a knock-in mouse model of Huntington's disease.

    PubMed

    Ouk, Koliane; Aungier, Juliet; Morton, A Jennifer

    2016-12-01

    Huntington's disease (HD) is a progressive genetic neurodegenerative disorder characterised by motor and cognitive deficits, as well as sleep and circadian abnormalities. In the R6/2 mouse, a fragment model of HD, rest-activity rhythms controlled by the suprachiasmatic nucleus disintegrate completely by 4months of age. Rhythms driven by a second circadian oscillator, the methamphetamine-sensitive circadian oscillator (MASCO), are disrupted even earlier, and cannot be induced after 2months of age. Here, we studied the effect of the HD mutation on the expression of MASCO-driven rhythms in a more slowly developing, genetically relevant mouse model of HD, the Q175 'knock-in' mouse. We induced expression of MASCO output by administering low dose methamphetamine (0.005%) chronically via the drinking water. We measured locomotor activity in constant darkness in wild-type and Q175 mice at 2 (presymptomatic), 6 (early symptomatic), and 12 (symptomatic) months of age. At 2months, all mice expressed MASCO-driven rhythms, regardless of genotype. At older ages, however, there was a progressive gene dose-dependent deficit in MASCO output in Q175 mice. At 6months of age, these rhythms could be observed in only 45% of heterozygous and 15% of homozygous mice. By 1year of age, 90% of homozygous mice had an impaired MASCO output. There was also an age-dependent disruption of MASCO output seen in wild-type mice. The fact that the progressive deficit in MASCO-driven rhythms in Q175 mice is HD gene dose-dependent suggests that, whatever its role in humans, abnormalities in MASCO output may contribute to the HD circadian phenotype.

  15. Prebiotic fibres dose-dependently increase satiety hormones and alter Bacteroidetes and Firmicutes in lean and obese JCR:LA-cp rats

    PubMed Central

    Parnell, Jill A.; Reimer, Raylene A.

    2013-01-01

    There is a growing interest in modulating gut microbiota with diet in the context of obesity. The purpose of the present study was to evaluate the dose-dependent effects of prebiotics (inulin and oligofructose) on gut satiety hormones, energy expenditure, gastric emptying and gut microbiota. Male lean and obese JCR:LA-cp rats were randomised to either of the following: lean 0 % fibre (LC), lean 10 % fibre (LF), lean 20 % fibre (LHF), obese 0 % fibre (OC), obese 10 % fibre (OF) or obese 20 % fibre (OHF). Body composition, gastric emptying, energy expenditure, plasma satiety hormone concentrations and gut microbiota (using quantitative PCR) were measured. Caecal proglucagon and peptide YY mRNA levels were up-regulated 2-fold in the LF, OF and OHF groups and 3-fold in the LHF group. Ghrelin O-acyltransferase mRNA levels were higher in obese v. lean rats and decreased in the OHF group. Plasma ghrelin response was attenuated in the LHF group. Microbial species measured in the Bacteroidetes division decreased, whereas those in the Firmicutes increased in obese v. lean rats and improved with prebiotic intake. Bifidobacterium and Lactobacillus increased in the OHF v. OC group. Bacteroides and total bacteria negatively correlated with percentage of body fat and body weight. Enterobacteriaceae increased in conjunction with glucose area under the curve (AUC) and glucagon-like peptide-1 AUC. Bacteroides and total bacteria correlated positively with ghrelin AUC yet negatively with insulin AUC and energy intake (P<0·05). Several of the mechanisms through which prebiotics act (food intake, satiety hormones and alterations in gut microbiota) are regulated in a dose-dependent manner. The combined effects of prebiotics may have therapeutic potential for obesity. PMID:21767445

  16. High phosphorus intakes acutely and negatively affect Ca and bone metabolism in a dose-dependent manner in healthy young females.

    PubMed

    Kemi, Virpi E; Kärkkäinen, Merja U M; Lamberg-Allardt, Christel J E

    2006-09-01

    Ca and P are both essential nutrients for bone and are known to affect one of the most important regulators of bone metabolism, parathyroid hormone (PTH). Too ample a P intake, typical of Western diets, could be deleterious to bone through the increased PTH secretion. Few controlled dose-response studies are available on the effects of high P intake in man. We studied the short-term effects of four P doses on Ca and bone metabolism in fourteen healthy women, 20-28 years of age, who were randomized to four controlled study days; thus each study subject served as her own control. P supplement doses of 0 (placebo), 250, 750 or 1500 mg were taken, divided into three doses during the study day. The meals served were exactly the same during each study day and provided 495 mg P and 250 mg Ca. The P doses affected the serum PTH (S-PTH) in a dose-dependent manner (P=0.0005). There was a decrease in serum ionized Ca concentration only in the highest P dose (P=0.004). The marker of bone formation, bone-specific alkaline phosphatase, decreased (P=0.05) and the bone resorption marker, N-terminal telopeptide of collagen type I, increased in response to the P doses (P=0.05). This controlled dose-response study showed that P has a dose-dependent effect on S-PTH and increases PTH secretion significantly when Ca intake is low. Acutely high P intake adversely affects bone metabolism by decreasing bone formation and increasing bone resorption, as indicated by the bone metabolism markers.

  17. 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…

  18. Probiotic Supplements Beneficially Affect Tryptophan–Kynurenine Metabolism and Reduce the Incidence of Upper Respiratory Tract Infections in Trained Athletes: A Randomized, Double-Blinded, Placebo-Controlled Trial

    PubMed Central

    Strasser, Barbara; Geiger, Daniela; Schauer, Markus; Gostner, Johanna M.; Gatterer, Hannes; Burtscher, Martin; Fuchs, Dietmar

    2016-01-01

    Background: Prolonged intense exercise has been associated with transient suppression of immune function and an increased risk of infections. In this context, the catabolism of amino acid tryptophan via kynurenine may play an important role. The present study examined the effect of a probiotic supplement on the incidence of upper respiratory tract infections (URTI) and the metabolism of aromatic amino acids after exhaustive aerobic exercise in trained athletes during three months of winter training. Methods: Thirty-three highly trained individuals were randomly assigned to probiotic (PRO, n = 17) or placebo (PLA, n = 16) groups using double blind procedures, receiving either 1 × 1010 colony forming units (CFU) of a multi-species probiotic (Bifidobacterium bifidum W23, Bifidobacterium lactis W51, Enterococcus faecium W54, Lactobacillus acidophilus W22, Lactobacillus brevis W63, and Lactococcus lactis W58) or placebo once per day for 12 weeks. The serum concentrations of tryptophan, phenylalanine and their primary catabolites kynurenine and tyrosine, as well as the concentration of the immune activation marker neopterin were determined at baseline and after 12 weeks, both at rest and immediately after exercise. Participants completed a daily diary to identify any infectious symptoms. Results: After 12 weeks of treatment, post-exercise tryptophan levels were lowered by 11% (a significant change) in the PLA group compared to the concentrations measured before the intervention (p = 0.02), but remained unchanged in the PRO group. The ratio of subjects taking the placebo who experienced one or more URTI symptoms was increased 2.2-fold compared to those on probiotics (PLA 0.79, PRO 0.35; p = 0.02). Conclusion: Data indicate reduced exercise-induced tryptophan degradation rates in the PRO group. Daily supplementation with probiotics limited exercise-induced drops in tryptophan levels and reduced the incidence of URTI, however, did not benefit athletic performance. PMID

  19. 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

  20. (n-3) Long chain PUFA dose-dependently increase oxygen utilization efficiency and inhibit arrhythmias after saturated fat feeding in rats.

    PubMed

    Pepe, Salvatore; McLennan, Peter L

    2007-11-01

    Fish oil (FO) modifies cardiac membrane phospholipid fatty acid composition to confer increased efficiency of oxygen utilization and antiarrhythmic effects. We tested the capacity of low-dose increments of FO, rich in (n-3) PUFA, to reverse the detrimental pro-arrhythmic and inefficient oxygen usage effects of dietary saturated fat (SAT) [including high ratio of (n-6) PUFA:(n-3) PUFA] during ischemia and reperfusion. Wistar rats were fed an SAT-enriched diet (15.3% fat, including 12% SAT, added by weight) for 6 wk and were then divided into 4 groups (n = 10/group) fed that diet or a 12% fat diet containing 3, 6, or 12% FO in place of SAT for 6 wk. Paced (300/min), erythrocyte-perfused isolated working hearts were subjected to low coronary flow ischemia (15 min) and were then reperfused. At normoxic baseline, external work capacity increased marginally at 6 and 12% FO; however, marked dose-related reductions in oxygen consumption were evident due to FO-dependent reduction in oxygen-energy utilization efficiency and associated reductions in coronary flow and oxygen extraction. Postischemic recovery resulted in lower oxygen consumption, greater oxygen-energy utilization efficiency, reduced coronary release of creatine kinase, and reduced incidence of arrhythmias in all FO groups compared with the SAT group. FO at a dose as low as 3% of total fat dietary supplement effectively reversed the high oxygen requirements and pro-arrhythmic effects of a SAT-rich diet even with continued consumption of SAT (9%) in this ex vivo animal model.

  1. 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

  2. Incidence, risk factors and outcome of de novo tumors in liver transplant recipients focusing on alcoholic cirrhosis

    PubMed Central

    Jiménez-Romero, Carlos; Justo-Alonso, Iago; Cambra-Molero, Félix; Calvo-Pulido, Jorge; García-Sesma, Álvaro; Abradelo-Usera, Manuel; Caso-Maestro, Oscar; Manrique-Municio, Alejandro

    2015-01-01

    Orthotopic liver transplantation (OLT) is an established life-saving procedure for alcoholic cirrhotic (AC) patients, but the incidence of de novo tumors ranges between 2.6% and 15.7% and is significantly increased in comparison with patients who undergo OLT for other etiologies. Tobacco, a known carcinogen, has been reported to be between 52% and 83.3% in AC patients before OLT. Other risk factors that contribute to the development of malignancies are dose-dependent immunosuppression, advanced age, viral infections, sun exposure, and premalignant lesions (inflammatory bowel disease, Barrett’s esophagus). A significantly more frequent incidence of upper aerodigestive (UAD) tract, lung, skin, and kidney-bladder tumors has been found in OLT recipients for AC in comparison with other etiologies. Liver transplant recipients who develop de novo non-skin tumors have a decreased long-term survival rate compared with controls. This significantly lower survival rate is more evident in AC recipients who develop UAD tract or lung tumors after OLT mainly because the diagnosis is usually performed at an advanced stage. All transplant candidates, especially AC patients, should be encouraged to cease smoking and alcohol consumption in the pre- and post-OLT periods, use skin protection, avoid sun exposure and over-immunosuppression, and have a yearly otopharyngolaryngeal exploration and chest computed tomography scan in order to prevent or reduce the incidence of de novo malignancies. Although still under investigation, substitution of calcineurin inhibitors for sirolimus or everolimus may reduce the incidence of de novo tumors after OLT. PMID:25954477

  3. 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.

  4. Zoledronic acid induces dose-dependent increase of antigen-specific CD8 T-cell responses in combination with peptide/poly-IC vaccine.

    PubMed

    Park, Hye-Mi; Cho, Hyun-Il; Shin, Chang-Ae; Shon, Hyun-Jung; Kim, Tai-Gyu

    2016-03-04

    Zoledronic acid (ZA) is used for treating osteoporosis and for preventing skeletal fractures in cancer patients suffering from myeloma and prostate cancer. It is also reported to directly induce cancer cell apoptosis and indirectly modulate T-cell immune response as an antitumor agent. In this study, the effect of ZA following peptide/polyinosinic-polycytidylic acid (poly-IC) vaccination was investigated in a murine tumor model. The combination of ZA with peptide/poly-IC vaccine showed a synergistic effect on the induction of antigen-specific CD8 T-cell response. Three consecutive intravenous administrations of ZA was defined to induce the highest CD8 T-cell response. Further, total splenocyte counts and antigen-specific CD8 T-cell response gradually increased depending on the dose of ZA. In tumor-bearing mice, ZA showed a dose-dependent decrease of growth and prolonged survival. Treatment with ZA only decreased the number of CD11b(+)Gr1(+) myeloid cells in blood. Our results demonstrate that the use of ZA could improve antitumor immune responses induced by the peptide/poly-IC vaccine.

  5. Nanosilica induced dose-dependent cytotoxicity and cell type-dependent multinucleation in HepG2 and L-02 cells

    NASA Astrophysics Data System (ADS)

    Yu, Yongbo; Duan, Junchao; Li, Yang; Yu, Yang; Hu, Hejing; Wu, Jing; Zhang, Yannan; Li, Yanbo; CaixiaGuo; Zhou, Xianqing; Sun, Zhiwei

    2016-11-01

    The prevalent exposure to nanosilica gained concerns about health effects of these particles on human beings. Although nanosilica-induced multinucleation has been confirmed previously, the underlying mechanism was still not clear; this study was to investigate the origination of multinucleated cells caused by nanosilica (62 nm) in both HepG2 and L-02 cells. Cell viability and cellular uptake was determined by MTT assay and transmission electron microscope (TEM), respectively. Giemsa staining was applied to detect multinucleation. To clarify the origination of multinucleated cells, fluorescent probes, PKH26 and PKH67, time-lapse observation were further conducted by confocal microscopy. Results indicated that nanosilica particles were internalized into cells and induced cytotoxicity in a dose-dependent manner. Quantification analysis showed that nanosilica significantly increased the rates of binucleated and multinucleated cells, which suggested mitotic catastrophe induction. Moreover, dynamic visualization verified that multinucleation resulted from cell fusion in HepG2 cells not in L-02 cells after nanosilica exposure, suggesting cell type-dependent multinucleation formation. Both multinucleation and cell fusion were involved in genetic instability, which emphasized the significance to explore the multinucleation induced by nanosilica via environmental, occupational and consumer product exposure.

  6. 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.

  7. 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.

  8. The serine protease motif of Pic mediates a dose-dependent mucolytic activity after binding to sugar constituents of the mucin substrate.

    PubMed

    Gutiérrez-Jiménez, Javier; Arciniega, Ivonne; Navarro-García, Fernando

    2008-08-01

    The pic gene is harbored on the chromosomes of three important pathogens: enteroaggregative Escherichia coli (EAEC), uropathogenic E. coli (UPEC), and Shigella flexneri. Since Pic is secreted into the intestinal lumen during EAEC infection, we sought to identify intestinal-mucosal substrates for Pic. Pic did not damage epithelial cells, cleave fodrin, or degrade host defense proteins embedded in the mucus layer (sIgA, lactoferrin and lysozyme). However, by using a solid-phase assay to evaluate the mucinolytic activity of EAEC Pic, we documented a specific, dose-dependent mucinolytic activity. A serine protease inhibitor and an enzymatically inactive variant of Pic were used to show that the Pic serine protease motif is required for mucinolytic activity. Pic binds mucin, and this binding was blocked in competition assays using monosaccharide constituents of the oligosaccharide side chains of mucin. Moreover, Pic mucinolytic activity decreased when sialic acid was removed from mucin. Thus, Pic is a mucinase with lectin-like activity that can be related to its reported hemagglutinin activity. Our results suggest that EAEC may secrete Pic into the intestinal lumen as a strategy for penetrating the gel-like mucus layer during EAEC colonization.

  9. 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.

  10. 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.

  11. Time- and dose-dependent responses of brain histamine to intracerebroventricular and intraperitoneal administrations of growth hormone-releasing factor (GRF1-44).

    PubMed

    Cacabelos, R; Yamatodani, A; Fukui, H; Niigawa, H; Miyake, A; Watanabe, T; Nishimura, T; Wada, H

    1987-04-01

    Changes in the level of histamine (HA) in rat brain induced by intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) administrations of growth hormone-releasing factor (GRF1-44) were studied. HA was determined by high-performance liquid chromatography (HPLC) in the anterior hypothalamic region, posterior hypothalamic region, median eminence, adenohypophysis, neurohypophysis, hippocampus and prefrontal cortex. GRF1-44 (1-10 micrograms, i.c.v.) induced significant time- and dose-dependent increases in the concentration of HA in the hypothalamo-hypophyseal system and time-dependent decrease of HA in the hippocampus. In contrast, after i.p. administration of GRF1-44 (10 micrograms) the level of HA in the hypothalamus tended to decrease but the total amount of H-1 receptors in the hypothalamo-hypophyseal system did not change. Circadian variations in the GRF-induced HA and growth hormone responses were also observed, responses being lower in the evening than in the morning. It is concluded that GRF interacts with HA at the central level to optimize the function of the somatotropinergic system.

  12. 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.

  13. Time- and radiation-dose dependent changes in the plasma proteome after total body irradiation of non-human primates: Implications for biomarker selection

    PubMed Central

    Burdine, Marie S.; Orr, Lisa; Mackintosh, Samuel G.; Authier, Simon; Pouliot, Mylene; Hauer-Jensen, Martin; Tackett, Alan J.

    2017-01-01

    Acute radiation syndrome (ARS) is a complex multi-organ disease resulting from total body exposure to high doses of radiation. Individuals can be exposed to total body irradiation (TBI) in a number of ways, including terrorist radiological weapons or nuclear accidents. In order to determine whether an individual has been exposed to high doses of radiation and needs countermeasure treatment, robust biomarkers are needed to estimate radiation exposure from biospecimens such as blood or urine. In order to identity such candidate biomarkers of radiation exposure, high-resolution proteomics was used to analyze plasma from non-human primates following whole body irradiation (Co-60 at 6.7 Gy and 7.4 Gy) with a twelve day observation period. A total of 663 proteins were evaluated from the plasma proteome analysis. A panel of plasma proteins with characteristic time- and dose-dependent changes was identified. In addition to the plasma proteomics study reported here, we recently identified candidate biomarkers using urine from these same non-human primates. From the proteomic analysis of both plasma and urine, we identified ten overlapping proteins that significantly differentiate both time and dose variables. These shared plasma and urine proteins represent optimal candidate biomarkers of radiation exposure. PMID:28350824

  14. The dose-dependent influence of zinc and cadmium contamination of soil on their uptake and glucosinolate content in white cabbage (Brassica oleracea var. capitata f. alba).

    PubMed

    Kusznierewicz, Barbara; Bączek-Kwinta, Renata; Bartoszek, Agnieszka; Piekarska, Anna; Huk, Anna; Manikowska, Anna; Antonkiewicz, Jacek; Namieśnik, Jacek; Konieczka, Piotr

    2012-11-01

    The relationship between the ability to accumulate heavy metals (represented by Cd and Zn) and to synthesize bioactive compounds (represented by glucosinolates [GLS]) was investigated in two cabbage cultivars. Plants were grown in the greenhouse of a phytotron under controlled conditions in soils spiked with two different Zn or Cd concentrations. The measurements of Cd and Zn contents in soil and cabbage (leaf) samples were performed by atomic absorption spectroscopy, whereas GLS levels in cabbage were determined by high-performance liquid chromatography. The ranges of metal contents in soil were 80 to 450 mg/kg dry weight for Zn and 0.3 to 30 mg/kg dry weight for Cd, whereas the levels of accumulated Zn and Cd in cabbage amounted to 15 to 130 and 0.02 to 3 mg/kg dry weight, respectively. After initial symptoms of toxicity, during a later stage of growth, the plants exhibited very good tolerance to both metals. Enhanced biosynthesis of GLS was observed in a dose-dependent manner following exposure to the heavy metals. The GLS content in Zn-exposed cabbage rose from 3.2 to 12 µmol/g dry weight, and the corresponding values for Cd-treated plants were 3.5 to 10 µmol/g dry weight. Thus, the increased soil contamination by metals caused greater accumulation in cabbage, as well as stimulation of GLS biosynthesis. The results obtained point to the high phytoremediation and biofumigation potential of white cabbage.

  15. Dose-Dependent Protective Effect of Lithium Chloride on Retinal Ganglion Cells Is Interrelated with an Upregulated Intraretinal BDNF after Optic Nerve Transection in Adult Rats

    PubMed Central

    Wu, Ming-Mei; Zhu, Ting-Ting; Wang, Peng; Kuang, Fang; Hao, Ding-Jun; You, Si-Wei; Li, Yao-Yu

    2014-01-01

    Neuroprotection of lithium for axotomized retinal ganglion cells (RGCs) is attributed to upregulated intraretinal Bcl-2. As lithium also upregulates brain-derived neurotrophic factor (BDNF) which can rescue axotomized RGCs, it is hypothesized that lithium could protect RGCs through BDNF. This study investigated this hypothesis and a possible relationship between the dose and protection of lithium. All adult experimental rats received daily intraperitoneal injections of lithium chloride (LiCl) at 30, 60 or 85 mg/kg·bw until they were euthanized 2, 7 or 14 days after left intraorbital optic nerve (ON) transection. Our results revealed that RGC densities promoted and declined with increased dose of LiCl and the highest RGC densities were always in the 60 mg/kg·bw LiCl group at both 7 and 14 day points. Similar promotion and decline in the mRNA and protein levels of intraretinal BDNF were also found at the 14 day point, while such BDNF levels increased in the 30 mg/kg·bw LiCl group but peaked in the 60 and 85 mg/kg·bw LiCl groups at the 7 day point. These findings suggested that lithium can delay the death of axotomized RGCs in a dose-dependent manner within a certain period after ON injury and such beneficial effect is interrelated with an upregulated level of intraretinal BDNF. PMID:25100168

  16. Patterning an epidermal field: Drosophila lozenge, a member of the AML-1/Runt family of transcription factors, specifies olfactory sense organ type in a dose-dependent manner.

    PubMed

    Gupta, B P; Flores, G V; Banerjee, U; Rodrigues, V

    1998-11-15

    Sense organ development in the Drosophila antenna is initiated by the selection of a founder cell from an epidermal field. This cell is believed to recruit neighbours to form a cluster of cells which then divides to form a mature sense organ. In most systems so far studied, sense organ type appears to be specified by the identity of proneural genes involved in the selection of precursors. The regulation of proneural gene expression is, in turn, controlled by the prepatterning genes. In the antenna, the only known proneural function is that of atonal, a gene that is involved in founder cell choice in the sensilla coeloconica, and no prepatterning gene function has yet been demonstrated. In this study, we show that Lozenge, a protein which possesses a DNA binding domain similar to that of the Acute myeloid leukemia-1/Runt transcription factors, functions in a dose-dependent manner to specify the fate of the other two types of sense organs in the antenna: the sensilla trichoidea and the sensilla basiconica. Our results suggest that Lozenge may act on the epidermal field, resulting in founder cells acquiring specific cell fates that lead to the development of an appropriate type of sense organ.

  17. The fibrosis of ketamine, a noncompetitive N-methyl-d-aspartic acid receptor antagonist dose-dependent change in a ketamine-induced cystitis rat model.

    PubMed

    Song, Miho; Yu, Hwan Yeul; Chun, Ji-Youn; Shin, Dong-Myung; Song, Soo Hyun; Choo, Myung-Soo; Song, Yun Seob

    2016-01-01

    Ketamine abusers have greatly increased in number worldwide during recent years. The consumption of ketamine has increased, as have the number of published accounts of devastating urological sequelae. However, the mechanism of ketamine-associated urinary tract dysfunction remains unclear. This study was to evaluate the ketamine dose-dependency of ketamine-induced cystitis (KC) in a rat model. A total of 42 Sprague-Dawley rats (female, 10-week-old) were used. Each of the 7 KC rat models were induced by 1, 5, 10, 25 and 50 mg/kg ketamine intravenous injection for two weeks. For the sham group (n = 7), a phosphate-buffered saline (PBS) vehicle was used rather than ketamine hydrochloride. The cystometric parameters, histological examinations, staining for Masson's trichome, cytokeratin, toluidine blue and quantitative PCR were measured at two weeks following the intervention. The voiding interval gradually decreased depending upon the ketamine dose of 1, 5, 10, 25, or 50 mg/kg, respectively, and was decreased compared with Sham. Bladder capacity was decreased as ketamine dose increased. In particular, the increase of fibrosis and submucosal apoptosis were found according to the increase of the ketamine dose. The bladder apoptosis in the KC rat model makes the fibrotic bladder change, and led us to hypothesize that fibrosis could contribute to the lower urinary-tract symptoms. We suggest that according to the pathophysiology evidence, fibrosis induced by apoptosis plays a key role in KC.

  18. Time- and radiation-dose dependent changes in the plasma proteome after total body irradiation of non-human primates: Implications for biomarker selection.

    PubMed

    Byrum, Stephanie D; Burdine, Marie S; Orr, Lisa; Mackintosh, Samuel G; Authier, Simon; Pouliot, Mylene; Hauer-Jensen, Martin; Tackett, Alan J

    2017-01-01

    Acute radiation syndrome (ARS) is a complex multi-organ disease resulting from total body exposure to high doses of radiation. Individuals can be exposed to total body irradiation (TBI) in a number of ways, including terrorist radiological weapons or nuclear accidents. In order to determine whether an individual has been exposed to high doses of radiation and needs countermeasure treatment, robust biomarkers are needed to estimate radiation exposure from biospecimens such as blood or urine. In order to identity such candidate biomarkers of radiation exposure, high-resolution proteomics was used to analyze plasma from non-human primates following whole body irradiation (Co-60 at 6.7 Gy and 7.4 Gy) with a twelve day observation period. A total of 663 proteins were evaluated from the plasma proteome analysis. A panel of plasma proteins with characteristic time- and dose-dependent changes was identified. In addition to the plasma proteomics study reported here, we recently identified candidate biomarkers using urine from these same non-human primates. From the proteomic analysis of both plasma and urine, we identified ten overlapping proteins that significantly differentiate both time and dose variables. These shared plasma and urine proteins represent optimal candidate biomarkers of radiation exposure.

  19. 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

    2015-08-21

    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.

  20. Use of a Structured Mirrors Intervention Does Not Reduce Delirium Incidence But May Improve Factual Memory Encoding in Cardiac Surgical ICU Patients Aged Over 70 Years: A Pilot Time-Cluster Randomized Controlled Trial

    PubMed Central

    Giraud, Kimberly; Pontin, Megan; Sharples, Linda D.; Fletcher, Paul; Dalgleish, Tim; Eden, Allaina; Jenkins, David P.; Vuylsteke, Alain

    2016-01-01

    Introduction: Post-operative delirium remains a significant problem, particularly in the older surgical patient. Previous evidence suggests that the provision of supplementary visual feedback about ones environment via the use of a mirror may positively impact on mental status and attention (core delirium diagnostic domains). We aimed to explore whether use of an evidence-based mirrors intervention could be effective in reducing delirium and improving post-operative outcomes such as factual memory encoding of the Intensive Care Unit (ICU) environment in older cardiac surgical patients. Methods: This was a pilot time-cluster randomized controlled trial at a 32-bed ICU, enrolling 223 patients aged 70 years and over, admitted to ICU after elective or urgent cardiac surgery from October 29, 2012 to June 23, 2013. The Mirrors Group received a structured mirrors intervention at set times (e.g., following change in mental status). The Usual Care Group received the standard care without mirrors. Primary outcome was ICU delirium incidence; secondary outcomes were ICU delirium days, ICU days with altered mental status or inattention, total length of ICU stay, physical mobilization (balance confidence) at ICU discharge, recall of factual and delusional ICU memories at 12 weeks, Health-Related Quality of Life at 12 weeks, and acceptability of the intervention. Results: The intervention was not associated with a significant reduction in ICU delirium incidence [Mirrors: 20/115 (17%); Usual Care: 17/108 (16%)] or duration [Mirrors: 1 (1–3); Usual Care: 2 (1–8)]. Use of the intervention on ICU was predictive of significantly higher recall of factual (but not delusional) items at 12 weeks after surgery (p = 0.003) and acceptability was high, with clinicians using mirrors at 86% of all recorded hourly observations. The intervention did not significantly impact on other secondary outcomes. Conclusion: Use of a structured mirrors intervention on the post-operative ICU does not

  1. Introduction to Pesticide Incidents

    EPA Pesticide Factsheets

    Pesticides incidents must be reported by pesticide registrants. Others, such as members of the public and environmental professionals, would like to report pesticide incidents. This website will explain and facilitate such incident reporting.

  2. 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.

  3. 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.

  4. 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

  5. Dose-dependent insulin regulation of insulin-like growth factor binding protein-1 in human endometrial stromal cells is mediated by distinct signaling pathways.

    PubMed

    Lathi, R B; Hess, A P; Tulac, S; Nayak, N R; Conti, M; Giudice, L C

    2005-03-01

    IGF binding protein-1 (IGFBP-1) is a major product of decidualized human endometrial stromal cells and decidua, and as a modulator of IGF action and/or by independent mechanisms, it regulates cell growth and differentiation and embryonic implantation in these tissues. IGFBP-1 secretion is primarily stimulated by progesterone and cAMP and is inhibited by insulin and IGFs. The signaling pathways mediating the latter are not well defined, and the current study was conducted to determine which pathways mediate the effects of insulin on IGFBP-1 mRNA and protein expression by human endometrial stromal cells decidualized in vitro by progesterone. Cells were cultured and treated with different combinations of insulin; wortmannin, an inhibitor of the phosphatidylinositide-3-kinase (PI3-kinase) pathway; and PD98059, an inhibitor of the MAPK pathway. IGFBP-1 mRNA was determined by real-time PCR, and protein secretion in the conditioned medium was measured by ELISA. Activation of the PI3-kinase and the MAPK pathways was assessed by the detection of phosphorylated AKT and ERK in Western blots, respectively. Insulin inhibited IGFBP-1 mRNA and protein secretion in a dose-dependent fashion, with an ED(50) for the latter 0.127 ng/ml (21.6 pm). Inhibitor studies revealed that at low doses, insulin acts through the PI3-kinase pathway, whereas at higher levels it also activates the MAPK pathway in the inhibition of IGFBP-1. The data demonstrate that human endometrium is a target for insulin action in the regulation of IGFBP-1. At physiological levels insulin likely plays a homeostatic role for energy metabolism in the endometrium, and in hyperinsulinemic states, insulin action on the endometrium may activate cellular mitosis via the MAPK pathway and perhaps predispose this tissue to hyperplasia and/or cancer.

  6. 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

  7. Pachytene spermatocyte protein(s) stimulate Sertoli cells grown in bicameral chambers: dose-dependent secretion of ceruloplasmin, sulfated glycoprotein-1, sulfated glycoprotein-2, and transferrin.

    PubMed

    Onoda, M; Djakiew, D

    1991-03-01

    Interactions between pachytene spermatocytes and Sertoli cells were investigated using the bicameral culture chamber system. Pachytene spermatocytes were isolated from adult rats with a purity in excess of 90% by centrifugal elutriation. The pachytene spermatocytes were cultured in a defined media and pachytene spermatocyte protein prepared from the conditioned media by dialysis and lyophilization. This pachytene spermatocyte protein was reconstituted at various concentrations and incubated with confluent epithelial sheets of immature Sertoli cells cultured in bicameral chambers. Pachytene spermatocyte protein stimulated secretion of total [35S]methionine-labeled protein from Sertoli cells in a dose-dependent manner predominantly in an apical direction. This stimulatory effect of pachytene spermatocyte protein was domain specific from the apical surface of Sertoli cells, and seemed specific for secretion because total intracellular protein did not increase under the influence of pachytene spermatocyte protein. Pachytene spermatocyte protein and follicle-stimulating hormone additively stimulated Sertoli cell secretion. The physicochemical characteristics of the stimulatory pachytene spermatocyte protein are indicative of heat stability, whereas the stimulatory pachytene spermatocyte protein exhibit acid, dithiothreitol and trypsin sensitivity, and partial urea sensitivity. Furthermore, Sertoli cell secretion of ceruloplasmin, sulfated glycoprotein-1, sulfated glycoprotein-2, and transferrin in response to various concentrations of pachytene spermatocyte protein were determined by immunoprecipitate of these [35S]methionine-labeled proteins with polyclonal antibodies. Maximal stimulation of ceruloplasmin and sulfated glycoprotein-1 secretion from Sertoli cells was observed at a dose of 50 micrograms/ml pachytene spermatocyte protein, whereas maximal stimulation of sulfated glycoprotein-2 and transferrin secretion from Sertoli cells was observed at a dose of 100

  8. Sorghum bran in the diet dose dependently increased the excretion of catechins and microbial-derived phenolic acids in female rats.

    PubMed

    Gu, Liwei; House, Suzanne E; Rooney, Lloyd; Prior, Ronald L

    2007-06-27

    Sorghum bran is concentrated with procyanidins (predominately polymers), which may be beneficial for health in humans; however, the bioavailability of procyanidins is not well-understood. Female Sprague-Dawley rats were fed an AIN93G diet containing 0, 5, 10, 20, or 40% Hi-tannin sorghum bran (n = 5-7 for each group) for 50 days. Sorghum bran contained 23.3 mg/g of procyanidins. The urinary excretions of catechin, epicatechin, methylated catechins, and phenolic acids were analyzed using liquid chromatography-tandem mass spectrometry. Sorghum bran dose dependently increased the urinary excretion of catechin (0-2.2 nmol/day) and 3'-O-methylcatechin (0-9.5 nmol/day). Their serum concentrations also increased with dose (range of 0-14 nM for 3'-O-methylcatechin). Among the 14 phenolic acids analyzed, 3,4-dihydroxybenzoic acid, 3-methoxy-4-hydroxybenzoic acid, and 4-hydroxyphenylacetic acid dominated in the serum (1.8-8 micromol/L). In the urine, 3-methoxy-4-hydroxyphenylacetic acid, 3-hydroxyphenylacetic acid, and 3-hydroxyphenylpropionic acid dominated and their excretion increased significantly with the level of sorghum bran in the diet. The summed phenolic acid excretion was 0.8 micromol/day in the control group and increased to 23 micromol/day for 40% sorghum bran group. The hippuric acid excretion ranged from 2.2 to 16.2 micromol/day and peaked in the 10% sorghum bran group. On the basis of chromic oxide, a nonabsorbable marker, total procyanidins and polymers disappeared progressively, and significant degradation occurred in the cecum and colon. Catechins and procyanidins in sorghum were bioavailable; however, bacteria-derived phenolic acids were the predominant metabolites of procyanidins. Procyanidins degraded in the gastrointestinal tract. Depolymerization was not observed.

  9. 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.

  10. Regulation of glucose and protein metabolism in growing steers by long-chain n-3 fatty acids in muscle membrane phospholipids is dose-dependent

    PubMed Central

    Fortin, M.; Julien, P.; Couture, Y.; Dubreuil, P.; Chouinard, P. Y.; Latulippe, C.; Davis, T. A.; Thivierge, M. C.

    2017-01-01

    A previous study showed that long-chain n-3 polyunsaturated fatty acids (LCn-3PUFA; >18 carbons n-3) exert an anabolic effect on protein metabolism through the upregulation of insulin sensitivity and activation of the insulin signaling pathway. This study further delineates for the first time whether the anabolic effect of LCn-3PUFA on metabolism is dose responsive. Six steers were used to test three graded amounts of menhaden oil rich in LCn-3PUFA (0%, 2% and 4%; enteral infusions) according to a double 3 × 3 Latin square design. Treatment comparisons were made using iso-energetic substitutions of control oil for menhaden oil and using 6-week experimental periods. The LCn-3PUFA in muscle total membrane phospholipids increased from 8%, 14% to 20% as dietary menhaden oil increased. Feeding graded amounts of menhaden oil linearly decreased plasma insulin concentration (49, 35 and 25 μU/ml, P = 0.01). The insulin-stimulated amino acid disposal rates as assessed using hyperinsulinemic–euglycemic–euaminoacidemic clamps (20, 40 and 80 mU/kg per h) were linearly increased by the incremental administrations of menhaden oil from 169, 238 to 375 μmol/kg per h (P = 0.005) during the 40 mU/kg per h clamp, and from 295, 360 and 590 mmol/kg per h (P = 0.02) during the 80 mU/kg per h clamp. Glucose disposal rate responded according to a quadratic relationship with the incremental menhaden oil amounts (P < 0.05). A regression analysis showed that 47% of the amino acid disposal rates elicited during the hyperinsulinemic clamp was related to muscle membrane LCn-3PUFA content (P = 0.003). These results show for the first time that both protein and glucose metabolism respond in a dose-dependent manner to menhaden oil and to muscle membrane LCn-3PUFA. PMID:22443622

  11. Substantiation in Enterococcus faecalis of Dose-Dependent Resistance and Cross-Resistance to Pore-Forming Antimicrobial Peptides by Use of a Polydiacetylene-Based Colorimetric Assay▿

    PubMed Central

    Mehla, Jitender; Sood, S. K.

    2011-01-01

    A better understanding of the antimicrobial peptide (AMP) resistance mechanisms of bacteria will facilitate the design of effective and potent AMPs. Therefore, to understand resistance mechanisms and for in vitro assessment, variants of Enterococcus faecalis that are resistant to different doses of the fungal AMP alamethicin (Almr) were selected and characterized. The resistance developed was dose dependent, as both doses of alamethicin and degrees of resistance were colinear. The formation of bacterial cell aggregates observed in resistant cells may be the prime mechanism of resistance because overall, a smaller cell surface in aggregated cells is exposed to AMPs. Increased rigidity of the membranes of Almr variants, because of their altered fatty acids, was correlated with limited membrane penetration by alamethicin. Thus, resistance developed against alamethicin was an adaptation of the bacterial cells through changes in their morphological features and physiological activity and the composition of membrane phospholipids. The Almr variants showed cross-resistance to pediocin, which indicated that resistance developed against both AMPs may share a mechanism, i.e., an alteration in the cell membrane. High percentages of colorimetric response by both AMPs against polydiacetylene/lipid biomimetic membranes of Almr variants confirmed that altered phospholipid and fatty acid compositions were responsible for acquisition of resistance. So far, this is the only report of quantification of resistance and cross-resistance using an in vitro colorimetric approach. Our results imply that a single AMP or AMP analog may be effective against bacterial strains having a common mechanism of resistance. Therefore, an understanding of resistance would contribute to the development of a single efficient, potent AMP against resistant strains that share a mechanism of resistance. PMID:21115699

  12. Dose-dependent differential response of mammalian cells to cytoplasmic stress is mediated through the heme-regulated eIF2α kinase.

    PubMed

    Mittal, Smriti P K; Kulkarni, Abhijeet P; Mathai, Jinumary; Chattopadhyay, Samit; Pal, Jayanta K

    2014-09-01

    The heme-regulated inhibitor (HRI), a regulator of translation initiation, is known to be activated and upregulated, and it acts as either a cytoprotective player promoting cell survival or as an inducer of apoptosis during stress. However, the exact role of HRI in these two responses has not been elucidated. In the present investigation, using human cell lines, we attempted to unravel the molecular mechanism(s) of HRI-mediated differential response and the involved signaling pathways. While during low dose (5 μM) lead acetate treatment, cells did not show any diminished cell survival, significant level of apoptosis was observed at high dose (100 μM) lead acetate. Based on the results of an interactome analysis, we determined the interaction of HRI with PI-3-Kca, only at a low dose stress, which is followed by phosphorylation and activation of its downstream target, AKT. Interestingly, such an interaction and AKT activation was not observed at a high dose stress. On the other hand, an increased level of APAF-1 and activation of caspases were observed. These results indicate a critical role of HRI in cell survival during low dose stress, and in apoptosis at high dose stress. Furthermore, HRI knockdown cells are sensitized even to 5 μM lead treatment leading to caspase activation and apoptosis. Our results taken together thus elucidate for the first time the molecular mechanism and the involved signaling pathways for dose-dependent differential response of mammalian cells to lead exposure. These findings thus suggest the possibility of using HRI downregulation as a therapeutic strategy to sensitize cancer cells subjected to apoptogenic drugs.

  13. Dose-dependent misrejoining of radiation-induced DNA double-strand breaks in human fibroblasts: experimental and theoretical study for high- and low-LET radiation.

    PubMed

    Rydberg, Bjorn; Cooper, Brian; Cooper, Priscilla K; Holley, William R; Chatterjee, Aloke

    2005-05-01

    Misrejoining of DNA double-strand breaks (DSBs) was measured in human primary fibroblasts after exposure to X rays and high-LET particles (helium, nitrogen and iron) 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 h of repair incubation. It was found that the misrejoining frequency for X rays was nonlinearly 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 the data for both low- and high-LET radiation could be fitted with an interaction distance (sigma of the Gaussian curve) of 0.25 microm. 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 be partly due to differences between fibroblasts and lymphocytes.

  14. 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

  15. Dose-dependent de novo germline mutations detected by whole-exome sequencing in progeny of ENU-treated male gpt delta mice.

    PubMed

    Masumura, Kenichi; Toyoda-Hokaiwado, Naomi; Ukai, Akiko; Gondo, Yoichi; Honma, Masamitsu; Nohmi, Takehiko

    2016-11-01

    Germline mutations are an important component of genetic toxicology; however, mutagenicity tests of germline cells are limited. Recent advances in sequencing technology can be used to detect mutations by direct sequencing of genomic DNA (gDNA). We previously reported induced de novo mutations detected using whole-exome sequencing in the offspring of N-ethyl-N-nitrosourea (ENU)-treated mice in a single-dose experiment (85mg/kg, i.p., weekly on two occasions). In this study, two lower doses (10 and 30mg/kg) were added, and dose-response of inherited germline mutations was analyzed. Male gpt delta transgenic mice treated with ENU in three dose groups were mated with untreated females 10 weeks after the last treatment, and offspring were obtained. The ENU-treated male mice showed dose-dependent increases in gpt mutant frequencies in their sperm, testis, and liver. gDNA of one family (parents and four offspring) from each dose group was used for whole-exome sequencing, and unique de novo mutations in the offspring were detected. Frequencies of inherited mutations increased with dosage more than 25-fold in the highest dose group. The mutation spectrum of the inherited mutations showed characteristics of ENU-induced mutations, such as A:T base substitutions. No confirmed mutations were observed in the control group. Filtering using the alternate reads ratio resulted in the mutation frequencies and spectra similar to those obtained by the Sanger sequencing confirmation. These results suggest that direct sequencing analysis may be a useful tool to investigate inherited germline mutations induced by environmental mutagens.

  16. Dose-dependent effects on sphingoid bases and cytokines in chickens fed diets prepared with fusarium verticillioides culture material containing fumonisins.

    PubMed

    Grenier, Bertrand; Schwartz-Zimmermann, Heidi E; Caha, Sylvia; Moll, Wulf Dieter; Schatzmayr, Gerd; Applegate, Todd J

    2015-04-13

    In chickens, the effect of mycotoxins, especially fumonisins (FB), in the gastrointestinal tract (GIT) is not well documented. Thus, this study in broiler chicks determined the effects of consuming diets prepared with Fusarium verticillioides culture material containing FB on intestinal gene expression and on the sphinganine (Sa)/sphingosine (So) ratio (Sa/So; a biomarker of FB effect due to disruption of sphingolipid metabolism). Male broilers were assigned to 6 diets (6 cages/diet; 6 birds/cage) from hatch to 20 days containing 0.4, 5.6, 11.3, 17.5, 47.8, or 104.8 mg FB/kg diet. Exposure to FB altered the Sa/So ratio in all tissues analyzed, albeit to varying extents. Linear dose-responses were observed in the kidney, jejunum and cecum. The liver and the ileum were very sensitive and data fit a cubic and quadratic polynomial model, respectively. Gene expression in the small intestine revealed low but significant upregulations of cytokines involved in the pro-inflammatory, Th1/Th17 and Treg responses, especially at 10 days of age. Interestingly, the cecal tonsils exhibited a biphasic response. Unlike the sphingolipid analysis, the effects seen on gene expression were not dose dependent, even showing more effects when birds were exposed to 11.3 mg FB/kg. In conclusion, this is the first report on the disruption of the sphingolipid metabolism by FB in the GIT of poultry. Further studies are needed to reach conclusions on the biological meaning of the immunomodulation observed in the GIT, but the susceptibility of chickens to intestinal pathogens when exposed to FB, at doses lower than those that would cause overt clinical symptoms, should be addressed.

  17. 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.

  18. 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...

  19. 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.

  20. Long-term, low-level adolescent nicotine exposure produces dose-dependent changes in cocaine sensitivity and reward in adult mice.

    PubMed

    Kelley, Brian M; Rowan, James D

    2004-01-01

    Cigarette smoking by adolescents is a strong predictor of future drug use, abuse, and dependence. While this "gateway drug effect" is assumed to be related to psychosocial factors, data from our laboratory suggests that adolescent nicotine use may permanently disrupt reward systems through changes in dopamine receptor function. Behavioral pharmacological methods known to be indirectly (motor activity) and directly (conditioned-place-preference) related to drug reinforcement were used to examine changes in cocaine sensitivity. Testing was performed on adult mice that were exposed to nicotine (0.3, 1.0, and 3.0 mg/kg, SC, M-F, b.i.d.) or saline during adolescence (postnatal days 25-57). Prior to testing, subjects had a 28 day drug-free, time-off period. After acclimation to the testing apparatus, the locomotor effects (30 min, 30 cm traveled) of cocaine (5, 10, and 20 mg/kg, IP) were measured daily; cocaine tests were preceded and followed by saline control tests. Following the acute dose-response curve, mice received saline followed by 5 days of 20.0 mg/kg cocaine. Thereafter, mice underwent condition-place-preference testing. A pre-test was performed to determine compartment preference (i.e., no injection, 20 min test). Cocaine (10 mg/kg, IP) was paired with the subjects non-preferred side and saline with the other. Conditioning sessions were conducted for 8 days with the order of drug/saline injections counter-balanced across subjects. A drug-free, post-test occurred on the day following the final conditioning session. A dose-dependent relationship between adolescent nicotine exposure and cocaine reward was noted in the adult mice across both test conditions. Subjects exposed to nicotine showed an increased response to cocaine's motor activating effects and a decreased response to cocaine's rewarding effects. A follow-up study was undertaken to evaluate dopamine D1, D2, and D3 receptor function in adult mice exposed to the highest dose of nicotine from the first

  1. 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

  2. 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

  3. Grazing incidence beam expander

    NASA Astrophysics Data System (ADS)

    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.

  4. Critical incident reporting systems.

    PubMed

    Ahluwalia, Jag; Marriott, Lin

    2005-02-01

    Approximately 10% of all hospital admissions are complicated by critical incidents in which harm is caused to the patient - this amounts to more than 850,000 incidents annually. Critical incident reporting (CIR) systems refer to the structured reporting, collation and analysis of such incidents. This article describes the attributes required for an effective CIR system. Example neonatal trigger events and a management pathway for handling a critical incident report are described. The benefits and limitations of CIR systems, reactive and prospective approaches to the analysis of actual or potential critical incidents and the assessment of risk are also reviewed. Individual human error is but one contributor in the majority of critical incidents. Recognition of this and the fostering of an organisational culture that views critical incident reports as an opportunity to learn and to improve future patient care is vital if CIR systems are to be effective.

  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. 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 ...

  7. Neonatal ethanol exposure results in dose-dependent impairments in the acquisition and timing of the conditioned eyeblink response and altered cerebellar interpositus nucleus and hippocampal CA1 unit activity in adult rats.

    PubMed

    Lindquist, Derick H; Sokoloff, Greta; Milner, Eric; Steinmetz, Joseph E

    2013-09-01

    Exposure to ethanol in neonatal rats results in reduced neuronal numbers in the cerebellar cortex and deep nuclei of juvenile and adult animals. This reduction in cell numbers is correlated with impaired delay eyeblink conditioning (EBC), a simple motor learning task in which a neutral conditioned stimulus (CS; tone) is repeatedly paired with a co-terminating unconditioned stimulus (US; periorbital shock). Across training, cell populations in the interpositus (IP) nucleus model the temporal form of the eyeblink-conditioned response (CR). The hippocampus, though not required for delay EBC, also shows learning-dependent increases in CA1 and CA3 unit activity. In the present study, rat pups were exposed to 0, 3, 4, or 5 mg/kg/day of ethanol during postnatal days (PD) 4-9. As adults, CR acquisition and timing were assessed during 6 training sessions of delay EBC with a short (280 ms) interstimulus interval (ISI; time from CS onset to US onset) followed by another 6 sessions with a long (880 ms) ISI. Neuronal activity was recorded in the IP and area CA1 during all 12 sessions. The high-dose rats learned the most slowly and, with the moderate-dose rats, produced the longest CR peak latencies over training to the short ISI. The low dose of alcohol impaired CR performance to the long ISI only. The 3E (3 mg/kg/day of ethanol) and 5E (5 mg/kg/day of ethanol) rats also showed slower-than-normal increases in learning-dependent excitatory unit activity in the IP and CA1. The 4E (4 mg/kg/day of ethanol) rats showed a higher rate of CR production to the long ISI and enhanced IP and CA1 activation when compared to the 3E and 5E rats. The results indicate that binge-like ethanol exposure in neonatal rats induces long-lasting, dose-dependent deficits in CR acquisition and timing and diminishes conditioning-related neuronal excitation in both the cerebellum and hippocampus.

  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. 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.

  10. 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).

  11. Hazard based models for freeway traffic incident duration.

    PubMed

    Tavassoli Hojati, Ahmad; Ferreira, Luis; Washington, Simon; Charles, Phil

    2013-03-01

    Assessing and prioritising cost-effective strategies to mitigate the impacts of traffic incidents and accidents on non-recurrent congestion on major roads represents a significant challenge for road network managers. This research examines the influence of numerous factors associated with incidents of various types on their duration. It presents a comprehensive traffic incident data mining and analysis by developing an incident duration model based on twelve months of incident data obtained from the Australian freeway network. Parametric accelerated failure time (AFT) survival models of incident duration were developed, including log-logistic, lognormal, and Weibul-considering both fixed and random parameters, as well as a Weibull model with gamma heterogeneity. The Weibull AFT models with random parameters were appropriate for modelling incident duration arising from crashes and hazards. A Weibull model with gamma heterogeneity was most suitable for modelling incident duration of stationary vehicles. Significant variables affecting incident duration include characteristics of the incidents (severity, type, towing requirements, etc.), and location, time of day, and traffic characteristics of the incident. Moreover, the findings reveal no significant effects of infrastructure and weather on incident duration. A significant and unique contribution of this paper is that the durations of each type of incident are uniquely different and respond to different factors. The results of this study are useful for traffic incident management agencies to implement strategies to reduce incident duration, leading to reduced congestion, secondary incidents, and the associated human and economic losses.

  12. Incident analysis report

    SciTech Connect

    Gregg, D.W.; Buerer, A.; Leeds, S.

    1996-02-20

    This document presents information about a fire that occurred in January 1996 at Lawrence Livermore National Laboratory. This fire was caused by the spontaneous combustion of 100% fuming nitric acid. Topics discussed include: Summary of the incident; technical background; procedural background; supervision; previous incidents with 100% fuming nitric acid; and judgment of potential hazards.

  13. Incidence of Menkes disease.

    PubMed

    Tønnesen, T; Kleijer, W J; Horn, N

    1991-02-01

    We have calculated the incidence of Menkes disease for Denmark, France, The Netherlands, the United Kingdom and West Germany, based on known Menkes patients born during the time period 1976-87. Considering live-born Menkes patients, the combined incidence for these five countries is 1 Menkes patient per 298,000 live-born babies. If the number of affected aborted fetuses are taken into account, the incidence is 1 Menkes per 254,000 live-born babies. This incidence, which is 2-4 times lower than earlier published incidence figures, places Menkes disease as an extremely rare disease. The mutation rate for Menkes disease is estimated to be 1.96 x 10(-6), based on the number of isolated Menkes cases born during the time period 1976-87 and the total number of newborn males during this time.

  14. 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

  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. Dose dependent inhibitory effect of dietary caraway on 1,2-dimethylhydrazine induced colonic aberrant crypt foci and bacterial enzyme activity in rats.

    PubMed

    Deeptha, Kumaraswami; Kamaleeswari, Muthaiyan; Sengottuvelan, Murugan; Nalini, Namasivayam

    2006-11-01

    Colon cancer has become one of the major causes of cancer mortality. We determined the effect of caraway (Carum carvi L.) on the development of aberrant crypt foci (ACF) and modulation of fecal bacterial enzyme activities in 1,2-dimethylhydrazine (DMH)-induced experimental rat colon carcinogenesis. Male Wistar albino rats were divided into six groups and all the animals were fed 15.8% peanut oil making a total of 20% fat in the diet. Group 1 served as control and group 2 animals received 90 mg/kg body weight caraway p.o. daily for 15 weeks. To induce ACF, DMH (20 mg/kg body weight) was injected subcutaneously once a week for the first four weeks (groups 3-6). In addition caraway was administered at the dose of 30, 60 and 90 mg/kg body weight everyday orally for the entire period of 15 weeks (groups 4-6). First, we analyzed ACF number (incidence), multiplicity and its distribution along the colon in all experimental groups at the end of 15 weeks. Subsequently, we also assayed the fecal bacterial enzyme activities. ACF formation and the fecal bacterial enzyme activities were found to be significantly high in DMH-alone treated group as compared to control group. Caraway supplementation at three different doses significantly suppressed ACF development, bacterial enzyme activities and modulated oxidative stress significantly as compared to the unsupplemented DMH-treated group. Results of our present study indicate that dietary caraway markedly inhibited DMH-induced colon carcinogenesis and the optimal dose of 60 mg/kg body weight was more effective than the other two doses.

  17. 2011 Japanese Nuclear Incident

    EPA Pesticide Factsheets

    EPA’s RadNet system monitored the environmental radiation levels in the United States and parts of the Pacific following the Japanese Nuclear Incident. Learn about EPA’s response and view historical laboratory data and news releases.

  18. Investigation of a “Sharps” Incident

    SciTech Connect

    Cournoyer, Michael Edward; Trujillo, Stanley; Schreiber, Stephen Bruce

    2016-08-03

    Special nuclear material research, process development, technology demonstration, and manufacturing capabilities are provided at the Los Alamos National Laboratory Plutonium Facility. Engineered barriers provide the most effective protection from radioactive and hazardous materials. The Worker Safety Security Team augments these passive safety feature by investigating incidents to identify appropriate prevention and mitigation measures. “Learning Teams” facilitate employee feedback loop and integration toward process improvement. Here, this article reports an investigation of a “Sharps” incident and reviews a case study of a technician that cuts his left thumb while making a gasket. Causal analysis of the sharps incident uncovered contributing factors that created the environment in which the incident occurred. Finally, latent organizational conditions that created error-likely situations or weakened defenses were identified and controlled. Effective improvements that reduce the probability or consequence of similar sharps incidents were implemented.

  19. Investigation of a “Sharps” Incident

    DOE PAGES

    Cournoyer, Michael Edward; Trujillo, Stanley; Schreiber, Stephen Bruce

    2016-08-03

    Special nuclear material research, process development, technology demonstration, and manufacturing capabilities are provided at the Los Alamos National Laboratory Plutonium Facility. Engineered barriers provide the most effective protection from radioactive and hazardous materials. The Worker Safety Security Team augments these passive safety feature by investigating incidents to identify appropriate prevention and mitigation measures. “Learning Teams” facilitate employee feedback loop and integration toward process improvement. Here, this article reports an investigation of a “Sharps” incident and reviews a case study of a technician that cuts his left thumb while making a gasket. Causal analysis of the sharps incident uncovered contributing factorsmore » that created the environment in which the incident occurred. Finally, latent organizational conditions that created error-likely situations or weakened defenses were identified and controlled. Effective improvements that reduce the probability or consequence of similar sharps incidents were implemented.« less

  20. INCIDENCE OF ENDOMETRIAL HYPERPLASIA

    PubMed Central

    REED, Susan D.; NEWTON, Katherine M.; CLINTON, Walter L.; EPPLEIN, Meira; GARCIA, Rochelle; ALLISON, Kimberly; VOIGT, Lynda F.; Weiss, Noel S.

    2009-01-01

    Objective Estimate age-specific incidence of endometrial hyperplasia: simple, complex, and atypical, in order of increasing likelihood of progression to carcinoma. Study design Women ages 18–90 years with endometrial pathology specimens (1985–2003) at a large integrated health plan were identified using automated data. Incidence rates were obtained by dividing the number of cases by the estimated number of female health plan enrollees who retained a uterus. Results Endometrial hyperplasia peak incidence was: simple-142/100,000 woman-years, complex-213/100,000 woman-years, both in the early 50s; and atypical-56/100,000 woman-years in the early 60s. Age-adjusted incidence decreased over the study period, especially for atypical hyperplasia. Conclusions Endometrial hyperplasia incidence without and with atypia peaks in the early postmenopausal years and in the early 60s, respectively. Given that some cases of endometrial hyperplasia likely go undiagnosed, the figures provided should be viewed as minimum estimates of the true incidence. PMID:19393600

  1. Dose-dependent catch-up growth after 2 years of growth hormone treatment in intrauterine growth-retarded children. Belgian and French Pediatric Clinics and Sanofi-Choay (France).

    PubMed

    Chatelain, P; Job, J C; Blanchard, J; Ducret, J P; Oliver, M; Sagnard, L; Vanderschueren-Lodeweyckx, M

    1994-06-01

    This study reports the results of a 2-yr clinical trial with GH in 95 short prepubertal children with non-GH-deficient intrauterine growth retardation. This randomized, double blind, controlled study compared the effects of placebo (restricted to the first 6 months) and two doses of GH (0.4 and 1.2 IU/kg.week) given sc 6 days/week for 2 yr. A significant GH dose-dependent growth acceleration was observed. Mean height gain (SDS/CA) was 0.66 +/- 0.07 in group I (low dose, 0.4 IU/kg.week) compared to 1.25 +/- 0.07 in group II (high dose, 1.2 IU/kg.week). Mean bone maturation progression (expressed in months) was 26.2 +/- 1.7 and 30.2 +/- 1.5 over 24 months in groups I and II, respectively. Onset of puberty was observed in some patients of both groups. Whether chronic use of a high GH dose will advance the onset of puberty remains to be established. A great variability of growth acceleration was seen among GH dose groups, suggesting that factors in addition to GH dose might modulate individual responses to treatment. In conclusion, it is suggested that in these patients, dose-dependent catch-up growth could be induced by GH treatment.

  2. Calcium- and ammonium ion-modification of zeolite amendments affects the metal-uptake of Hieracium piloselloides in a dose-dependent way.

    PubMed

    Peter, Anca; Mihaly-Cozmuta, Leonard; Mihaly-Cozmuta, Anca; Nicula, Camelia; Indrea, Emil; Tutu, Hlanganani

    2012-10-26

    The role of natural zeolite and of two types of modified zeolite (with ammonium and with calcium ions) in reducing the accumulation of ions of heavy metals in roots and leaves of Hieracium piloselloides grown on tailing ponds was investigated. The variation of the content of zeolite (5% w/w and 10% w/w) is another parameter that significantly and positively affects the accumulation of the metal ions in Hieracium piloselloides. The results showed that zeolite used as an amendment in the soil in tailing ponds significantly reduces the accumulation of heavy metal ions in Hieracium piloselloides. The highest concentrations of heavy metals were accumulated in plants grown on soil without zeolite, being followed by the plants grown on the substrate with natural zeolite. Moreover, the translocation factors of heavy metal ions uptake in roots and leaves grown on substrates with modified zeolites are lower than those calculated for the organs grown on the substrate amended with natural zeolite. This behaviour has demonstrated the positive effect of those changes of zeolite amendments in the potential phytoremediation practice.

  3. 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.

  4. Effect of hesperetin, a citrus flavonoid, on bacterial enzymes and carcinogen-induced aberrant crypt foci in colon cancer rats: a dose-dependent study.

    PubMed

    Aranganathan, Selvaraj; Selvam, Jayabal Panneer; Nalini, Namasivayam

    2008-10-01

    Hesperetin, an important bioactive compound in Chinese traditional medicine, has antioxidant and anticarcinogenic properties. Hesperetin is found in abundance in orange and grape juices (200-590 mg L(-1)) consumed in the daily diet. We have investigated the effect of different doses of hesperetin on faecal and colonic mucosal bacterial enzymes and aberrant crypt foci (ACF) in 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis in male Wistar rats. The rats were divided into six groups and were fed a modified pellet diet for 16 weeks. Group 1 served as control and group 2 received the modified pellet diet along with hesperetin (30 mg kg(-1)). The rats in groups 3-6 rats were given a weekly subcutaneous injection of DMH (20 mg kg(-1)) for the first four weeks. Hesperetin was supplemented orally at different doses (10, 20 or 30 mg kg(-1)) for a total of 16 weeks. At the end of the experimental period all rats were killed. In DMH-treated rats, the activity of faecal and colonic mucosal bacterial enzymes, such as beta-glucuronidase, beta-galactosidase, beta-glucosidase, nitroreductase, sulfatase and mucinase, were significantly elevated, but in rats supplemented hesperetin along with DMH the activity was significantly lowered (P < 0.05). The total number of aberrant crypts was significantly increased in unsupplemented DMH-treated rats, while hesperetin supplementation to DMH-treated rats significantly reduced the total number of crypts. The results demonstrated that hesperetin supplementation at a dose of 20 mg kg(-1) played a potent role in suppressing the formation of aberrant crypt foci and reducing the activity of bacterial enzymes in colon cancer.

  5. Genetically Altered Mutant Mouse Models of Guanylyl Cyclase/Natriuretic Peptide Receptor-A Exhibit the Cardiac Expression of Proinflammatory Mediators in a Gene-Dose-Dependent Manner

    PubMed Central

    Vellaichamy, Elangovan; Das, Subhankar; Subramanian, Umadevi; Maeda, Nobuyo

    2014-01-01

    The objective of this study was to examine whether genetically determined differences in the guanylyl cyclase/natriuretic peptide receptor-A gene (Npr1) affect cardiac expression of proinflammatory cytokines, hypertrophic markers, nuclear factor-κB (NF-κB), and activating protein-1 (AP-1) in am Npr1 gene-dose–dependent manner. In the present studies, adult male Npr1 gene-disrupted (Npr1−/−), wild-type (Npr1+/+), and gene-duplicated (Npr1++/++) mice were used. The Npr1−/− mice showed 41 mm Hg higher systolic blood pressure and 60% greater heart weight to body weight (HW/BW) ratio; however, Npr1++/++ mice exhibited 15 mm Hg lower systolic blood pressure and 12% reduced HW/BW ratio compared with Npr1+/+ mice. Significant upregulation of gene expression of proinflammatory cytokines and hypertrophic markers along with enhanced NF-κB/AP-1 binding activities were observed in the Npr1−/− mouse hearts. Conversely, hypertrophic markers and proinflammatory cytokines gene expression as well as NF-κB/AP-1 binding activities were markedly decreased in Npr1++/++ mouse hearts compared with wild-type mice. The ventricular guanylyl cyclase activity and cGMP levels were reduced by 96% and 87%, respectively, in Npr1−/− mice; however, these parameters were amplified by 2.8-fold and 3.8-fold, respectively, in Npr1++/++ mice. Echocardiographic analysis revealed significantly increased fractional shortening in Npr1++/++ mice (P < .05) but greatly decreased in Npr1−/− mice (P < .01) hearts compared with Npr1+/+ mice. The present findings suggest that Npr1 represses the expression of cardiac proinflammatory mediators, hypertrophic markers, and NF-κB/AP-1–mediated mechanisms, which seem to be associated in an Npr1 gene-dose–dependent manner. PMID:24424043

  6. Dose-Dependent Induction of an Idiotypic Cascade by Anti-Glycosaminoglycan Monoclonal Antibody in apoE−/− Mice: Association with Atheroprotection

    PubMed Central

    Sarduy, Roger; Brito, Victor; Castillo, Adriana; Soto, Yosdel; Griñán, Tania; Marleau, Sylvie; Vázquez, Ana María

    2017-01-01

    Atherosclerosis, the underlying pathology of most cardiovascular diseases, is triggered by the retention of apolipoprotein B (apoB)-containing lipoproteins in the arterial wall through electrostatic interactions with glycosaminoglycan (GAG) side chains of proteoglycans. Previously, we reported the antiatherogenic properties of the chimeric monoclonal antibody (mAb) chP3R99-LALA, which binds sulfated GAGs, inhibits low-density lipoprotein (LDL)–chondroitin sulfate (CS) association, and abrogates LDL oxidation and foam cell formation. In preventive and therapeutic settings, apoE-deficient (apoE−/−) mice immunized with 50 μg of this mAb showed reduced atherosclerotic lesions related with the induction of autologous anti-GAG antibodies. Knowing that age and sex are major non-modifiable risk factors in the development of atherosclerosis, the present study aimed to assess the influence of these variables on the capacity of chP3R99-LALA mAb to generate an anti-CS antibody response. Also, we aimed at defining the impact of the dose of chP3R99-LALA on the anti-CS antibody induction and the atheroprotective effect of this mAb in apoE−/− mice. Neither age nor sex had an impact in the IgG anti-CS antibody response induced by s.c. immunization with this mAb. Moreover, chP3R99-LALA mAb reduced atherosclerotic lesions to a similar extent in both young male and female apoE−/− mice fed a hypercholesterolemic diet and, in middle-aged female apoE−/− mice, with spontaneous lesions. On the other hand, increasing the dose of chP3R99-LALA (200 vs. 50 μg) elicited an anti-idiotype antibody cascade characterized by higher levels of anti-idiotype (Ab2), anti-anti-idiotype (Ab3), and anti-CS antibody responses. Moreover, this dose increment resulted in a striking reduction of aortic atherosclerotic lesions in immunized mice. PMID:28316603

  7. 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

  8. Pretreatment of mice with lipopolysaccharide (LPS) or IL-1β exerts dose-dependent opposite effects on Shiga toxin-2 lethality

    PubMed Central

    Palermo, M; Alves-Rosa, F; Rubel, C; Fernández, G C; Fernández-Alonso, G; Alberto, F; Rivas, M; Isturiz, M

    2000-01-01

    Haemolytic uraemic syndrome (HUS) has been closely associated with infection with a group of Shiga toxin-producing enterohaemorrhagic Eschericchia coli in young children. Shiga toxins (Stx) have been implicated as pathogenic agents of HUS by binding to the surface receptor of endothelial cells. LPS is a central product of the Gram-negative bacteria and several reports have documented that both LPS and Stx are important for disease development. In this study the reciprocal interactions between LPS and Stx2 are analysed in a mouse model. The results demonstrated that LPS was able to reduce or enhance Stx2 toxicity, depending on the dose and the timing of the injection. The involvement of the main early cytokines induced by LPS, tumour necrosis factor alpha (TNF-α) and IL-1β, in those LPS opposite effects on Stx2 toxicity was evaluated. Stx2 toxicity was enhanced by in vivo injection of murine TNF-α and low doses of murine IL-1β. However, at higher doses of IL-1β which induced corticosteroid increase in serum, Stx2 lethality was decreased. Considering that dexamethasone and IL-1β reproduce the LPS protective effects, it is suggested that endogenous corticosteroids secondary to the inflammatory response induced by LPS, mediate the protection against Stx2. It can be concluded that the fine equilibrium between proinflammatory and anti-inflammatory activities strongly influences Stx2 toxicity. PMID:10606967

  9. Differentiation of human embryonic stem cells into osteogenic or hematopoietic lineages: a dose-dependent effect of osterix over-expression.

    PubMed

    Kärner, Elerin; Unger, Christian; Cerny, Radim; Ahrlund-Richter, Lars; Ganss, Bernhard; Dilber, M Sirac; Wendel, Mikael

    2009-02-01

    Enhanced differentiation of human embryonic stem cells (HESCs), induced by genetic modification could potentially generate a vast number of diverse cell types. Such genetic modifications have frequently been achieved by over-expression of individual regulatory proteins. However, careful evaluation of the expression levels is critical, since this might have important implications for the differentiation potential of HESCs. To date, attempts to promote osteogenesis by means of gene transfer into HESCs using the early bone "master" transcription factor osterix (Osx) have not been reported. In this study, we attained HESC subpopulations expressing two significantly different levels of Osx, following lentiviral gene transfer. Both subpopulations exhibited spontaneous differentiation and reduced expression of markers characteristic of the pluripotent phenotype, such as SSEA3, Tra1-60, and Nanog, In order to promote bone differentiation, the cells were treated with ascorbic acid, beta-glycerophosphate and dexamethasone. The high level of Osx, compared to endogenous levels found in primary human osteoblasts, did not enhance osteogenic differentiation, and did not up-regulate collagen I expression. We show that the high Osx levels instead induced the commitment towards the hematopoietic-endothelial lineage-by up-regulating the expression of CD34 and Gata1. However, low levels of Osx up-regulated collagen I, bone sialoprotein and osteocalcin. Conversely, forced high level expression of the homeobox transcription factor HoxB4, a known regulator for early hematopoiesis, promoted osteogenesis in HESCs, while low levels of HoxB4 lead to hematopoietic gene expression.

  10. Dose-dependent effect of oregano (Origanum vulgare L.) on lipid peroxidation and antioxidant status in 1,2-dimethylhydrazine-induced rat colon carcinogenesis.

    PubMed

    Srihari, Thummala; Sengottuvelan, Murugan; Nalini, Namasivayam

    2008-06-01

    Colon cancer is a major cause of morbidity and mortality in developed and developing countries. Diet and dietary constituents play a major role in the aetiology of colon cancer. We have investigated the effect of an aqueous extract of oregano (Origanum vulgare. L.) on lipid peroxidation and anti-oxidant status in 1,2-dimethylhydrazine (DMH)-induced rat colon carcinogenesis. We aimed to identify the important antioxidants present in Indian oregano using RP-HPLC. DMH (20 mgkg(-1)) was administered subcutaneously once a week for the first four weeks and then discontinued. Oregano was supplemented every day orally at a dose of 20, 40 or 60 mgkg(-1) to different groups of rats for 15 weeks. After this time the rats were killed and the colons were examined visually and evaluated biochemically. The levels of lipid peroxidation products, such as thiobarbituric acid reactive substances and conjugated dienes were significantly higher in the liver whereas in caecum and colon the levels were lower in DMH-treated animals as compared with control rats. The levels of the anti-oxidants superoxide dismutase, catalase, reduced glutathione, glutathione reductase, glutathione peroxidase and glutathione-S-transferase were decreased in DMH-treated rats, but were significantly reversed on oregano supplementation. Oregano supplementation (40 mgkg(-1)) had a modulatory role on tissue lipid peroxidation and antioxidant profile in colon cancer-bearing rats, which suggested a possible anti-cancer property of oregano.

  11. [Dose-dependent effect of locally administered sulprostone gel on serum luteal and placental hormones in cervix priming in the 1st trimester].

    PubMed

    Rath, W; Pitzel, L; Hilgers, R; Kuhn, W

    1989-01-01

    In a prospective, randomised study 30 primigravidae were treated with 25 micrograms, 50 mu, or 100 micrograms sulprostone gel in order to soften the cervix prior to first trimester termination of pregnancy. 10 multigravidae received only the gel vehicle tylose. For objective demonstration of the priming effect, the force required for dilatation of the cervical canal was measured in Newton by a special tonometer before prostaglandin (PG) application and before operation. Serum progesterone, 17-beta-estradiol and hP1 levels were determined radioimmunologically prior to PG application and at two-hours intervals until curettage. A sonographic examination for determing the vitality of the pregnancy was performed before PG administration and immediately before the surgical intervention. There were no significant differences in the primig effect between the 50 micrograms and 100 micrograms sulprostone-treated group; the application of 25 micrograms sulprostone was significantly less effective. After 100 micrograms sulprostone gel abortion occurred in 2 patients, 6 women showed a marked decrease in hPl concentrations, progesterone levels were found to be reduced to 31.6-78.7% and 17-beta-estradiol to 10-40% of the initial values before PG application. We found a close time correlation between the occurrence of contraction-induced lower abdominal pain and the fall in hormone concentrations. No abortions occurred in any of the patients treated with 50 micrograms sulprostone gel; in 9 women without clinical symptoms no significant changes of the hormone concentrations were observed. In contrast to the previously published literature our results indicate that effective cervical ripening can be achieved by this method without disturbance of the feto-placental unit and the trophoblast respectively.

  12. Quercetin Induces Dose-Dependent Differential Morphological and Proliferative Changes in Rat Uteri in the Presence and in the Absence of Estrogen

    PubMed Central

    Shahzad, Huma; Giribabu, Nelli; Sekaran, Muniandy

    2015-01-01

    Abstract Quercetin could have profound effects on uterine morphology and proliferation, which are known to be influenced by estrogen. This study investigated the effect of quercetin on these uterine parameters in the presence and in the absence of estrogen. Ovariectomized adult female rats received peanut oil, quercetin (10, 50, and 100 mg/kg/day), estrogen, or estrogen+quercetin (10, 50, or 100 mg/kg/day) treatment for 7 consecutive days. At the end of the treatment, uteri were harvested for histological and molecular biological analyses. Distribution of proliferative cell nuclear antigen (PCNA) protein in the uterus was observed by immunohistochemistry. Levels of expression of PCNA protein and mRNA in uterine tissue homogenates were determined by Western blotting and real-time polymerase chain reaction, respectively. Our findings indicated that administration of 10 mg/kg/day of quercetin either alone or with estrogen resulted in decreased uterine expression of PCNA protein and mRNA with the percentage of PCNA-positive cells in uterine luminal and glandular epithelia markedly reduced compared with estrogen-only treatment. Changes in uterine morphology were the opposite of changes observed following estrogen treatment. Treatment with 100 mg/kg/day of quercetin either alone or with estrogen resulted in elevated PCNA protein and mRNA expression. In addition, the percentages of PCNA-positive cells in the epithelia, which line the lumen and glands, were increased with morphological features mimicking changes that occur following estrogen treatment. Following 50 mg/kg/day quercetin treatment, the changes observed were in between those changes that occur following 10 and 100 mg/kg/day quercetin treatment. In conclusion, changes in uterine morphology and proliferation following 10 mg/kg/day quercetin treatment could be attributed to quercetin's antiestrogenic properties, while changes that occur following 100 mg/kg/day quercetin treatment could be

  13. 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.

  14. Quercetin Induces Dose-Dependent Differential Morphological and Proliferative Changes in Rat Uteri in the Presence and in the Absence of Estrogen.

    PubMed

    Shahzad, Huma; Giribabu, Nelli; Sekaran, Muniandy; Salleh, Naguib

    2015-12-01

    Quercetin could have profound effects on uterine morphology and proliferation, which are known to be influenced by estrogen. This study investigated the effect of quercetin on these uterine parameters in the presence and in the absence of estrogen. Ovariectomized adult female rats received peanut oil, quercetin (10, 50, and 100 mg/kg/day), estrogen, or estrogen+quercetin (10, 50, or 100 mg/kg/day) treatment for 7 consecutive days. At the end of the treatment, uteri were harvested for histological and molecular biological analyses. Distribution of proliferative cell nuclear antigen (PCNA) protein in the uterus was observed by immunohistochemistry. L