Phytotest-based study on the concentration-dependent dynamic interactions of Cd, Pb, and As under multiple exposure conditions in purple soils.

An experimental study on the effects of ethanol and folic acid deficiency, alone or in combination, on pregnant Swiss mice

Editor – We would like to comment on an article published by Doi et al.1 The report was based on a review of studies examining the effectiveness of low and high administered doses of radioiodine for the ablation of thyroid remnant among patients with differentiated thyroid cancer. Their analysis was based on a previously published systematic review conducted by Hackshaw et al2 which concluded that there is currently insufficient evidence to reliably say whether a low dose is associated with a lower ablation success rate than a high dose. Doi et al, however, use the same studies to conclude that a low dose is worse, but there are fundamental problems with their analysis and interpretation. First, they combine studies with very different designs into a single meta-analysis producing a relative risk which appears to be precise and highly statistically significant. The relative risk of having a successful ablation in the low dose group compared to the high dose group was 0.73, 95% confidence interval (CI) 0.61–0.81. The 22 studies, on which this particular result is based, are a mixture of cohort studies, retrospective reviews of patient medical records, and randomized trials. It is inappropriate to combine these studies when the observational studies are likely to be affected by inherent biases and confounding, but the randomized trials are not. Indeed, meta-analyses of observational studies need to be interpreted with great care because the effect of potential confounding in each study could be magnified when the studies are combined, thus producing a spuriously precise effect.3 Sixteen of the 22 studies (73%) were observational, so their results will contribute most to the pooled result. The best evidence must come from randomized clinical trials. Second, when their analysis was restricted to the 6 randomized trials (in which no comparison was based on more than 150 patients in total), the pooled relative risk was 0.68 (95% CI 0.43–1.07), which was not statistically significant (P-value of 0.093). The correct interpretation is that, while there is some evidence of a lower ablation rate when using a low dose, the effect could be due to chance because the CI includes the no-effect value and P >0.05 (i.e., there could be no true difference). However, no comment was made on this. Third, the dose level that defines ‘low’ and ‘high’ differs greatly between these trials. For example, a low dose could be 30 or 50 mCi (a difference of two-thirds), and a high dose could be 50 or 100 mCi (a difference of two-fold). Because of this, it is best to not combine all the trials to produce a single relative risk. Once these considerations have been taken into account, there is no analysis that allows firm conclusions to be made about the comparison of low and high dose radioiodine in treating differentiated thyroid cancer. While some clinicians prefer to administer a high dose at present, it is misleading to rule out the use of a low dose based on current evidence. There are clear potential advantages, such as less time spent in isolation in hospitals and lower risk of future second malignancies.2 What is needed is a large randomized trial, and there are two such trials in progress in the UK and France, each based on several hundred patients.4 These trials will determine with sufficient certainty whether a low dose should be avoided, or could be used instead of a high dose.

Introduction: Clostridium difficile is implicated in 15%–25% of all cases of nosocomial antibiotic-associated diarrhea. Current guidelines recommend oral vancomycin 125 mg every six hours as the drug of choice for severe CDI. The recommendation is based on a retrospective analysis showing vancomycin to be superior to oral metronidazole for the treatment of severe disease, as well as data demonstrating no difference in outcomes between low (125 mg) and high (500 mg) dose vancomycin regimens. Despite this, many clinicians frequently prescribe higher doses (250, 500 mg) of oral vancomycin for severe CDI. While historical literature has suggested no benefit to increased doses of vancomycin, such data do not exist in the age of a more hypervirulent strain. Methods: This study evaluated adult patients admitted to four Detroit Medical Center hospitals hours with CDI confirmed by polymerase chain reaction and meeting severe CDI criteria. Patients received oral vancomycin 125mg every 6 hours (low dose), 250mg or 500mg every 6 hours (considered high dose for study purposes). Patients receiving concomitant CDI therapy were excluded. Exposure to concomitant antimicrobials was also collected. Groups were defined: low dose (LD) vs high dose (HD). P-values < 0.05 were considered significant. Results: From July 2010 to July 2012, this study included 137 CDI patients with a mean age of 67 years. LD group included 95 patients and HD group included 42. Baseline characteristics were similar between groups. Length of stay was 12 ± 9.6 LD v 11.8 ± 10.1 days HD, p=0.33. Duration of diarrhea was 4.2 days LD and 4.1 days HD, p=0.72. ICU admission was required in 28% LD patients and 26% HD, p=0.76. A mean of 2 non-CDI antimicrobials were received in 69% LD and 74% HD while on CDI therapy, p=0.61. Overall clinical cure was achieved in 74% LD and 67% HD, p=0.42. The overall mortality rate was not different between groups, 5.3% LD and 2.4% HD, p=0.67. Conclusions: Clostridium difficile is a very prevalent nosocomial infection. Many patients continue to receive concomitant antimicrobials while on CDI therapy. Increasing the dose of oral vancomycin for patients with severe CDI does not improve efficacy.

Comparison of low and high dose intracoronary adenosine and acetylcholine in women undergoing coronary reactivity testing: Results from the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE)

BackgroundWhile most of the clinical benefits of inhaled corticosteroid (ICS) therapy may occur at low doses, results of dose-ranging studies are inconsistent. Although symptom/lung function response to low and high dose ICS medication is comparable, it is uncertain whether low dose ICSs are as effective as high dose in the treatment of inflammation and remodeling.Methods22 mild or moderate asthmatic adult subjects (corticosteroid free for > 2 months) participated in a randomized, parallel group study to compare effects of fluticasone propionate (FP) 200 mcg/day and 1000 mcg/day. Alveolar macrophage (AM)-derived cytokines and basement membrane thickness (BMT) were measured at baseline and after 7 weeks treatment while symptoms, spirometry, exhaled nitric oxide (eNO) and airway hyperresponsiveness (AHR) to mannitol at baseline and 6 weeks.ResultsFP improved spirometry, eNO, symptoms and AHR with no difference between low and high dose FP. Both high and low dose FP reduced GM-CSF, TNF-alpha and IL-1ra, with no change in BMT and with no differences between low and high dose FP.Conclusions200 μg/day of FP was as effective as 1000 μg/day in improving asthma control, airway inflammation, lung function and AHR in adults in the short term. Future studies should examine potential differential effects between low and high dose combination therapy (ICS/long acting beta agonist) on inflammation and airway remodeling over longer treatment periods.

Comparison of effects of no-, medium-, and high dose dexamethasone in adult cardiac surgery – A post-hoc analysis of the prospective, observational inflacor trial

There is growing evidence that docetaxel, a microtubule-targeting agent like the other taxane paclitaxel, induces dual cytotoxicity mechanism according to dose level. Postgenomics screening technologies are now more and more applied to the elucidation of drug response mechanisms. Proton nuclear magnetic resonance spectroscopy-based pharmacometabolomics was here applied to get further insight into the response of human MCF7 breast carcinoma cells to docetaxel at high (clinical, 5 microM) and low (1 nM) doses. The global response to both doses was evaluated by nuclear morphology and DNA content, the latter as an index of cell proliferation and DNA ploidy. High dose provoked long-lasting cell cycle arrest in mitosis during the first 48 h of exposure to treatment and severe decrease in DNA content followed by significant amount of cell death. In contrast, at low dose, no long-lasting cell cycle arrest was observed on micrographies, and DNA content was decreased but less than at high dose (P < 0.05), without significant cell death. This response was compared to biochemical alteration assessed by pharmacometabolomics. Thirty metabolites were identified and quantified. Metabolite profiling at clinical dose revealed time-dependent disorders in derivatives of glycolysis, lipid metabolism and glutathione metabolism. Comparison between high and low doses was performed at 72 h and showed common traits including the accumulation of cytidinediphosphocholine (x 5.0 and x 6.9, respectively, P < 0.03), the decrease in phosphatidylcholine (x 0.3 and x 0.2, respectively, P < 0.03), and gluthathione (x 0.6 and x 0.6, respectively, P < 0.03). Despite that, significant dose-dependent differences were found in 12 of 30 measured metabolites. Among them, the most discriminant metabolites were polyunsaturated fatty acids (ratio of high-to-low dose of 14.8, P < 0.05), glutamate, myoinositol, and homocysteine (ratio < 0.4, P < 0.05). In addition, the mechanism for glutathione decrease was different. At high dose, it resulted from extensive consumption with precursor starvation (glutamate: -89%, P < 0.05) and increased glutathione S-transferase activity (x 5, P < 0.01), whereas at low dose, it resulted from glutathione biosynthesis blockade with homocysteine accumulation (+144%, P < 0.03) and decreased glutathione S-transferase activity (-70%, P < 0.01). Altogether, this pharmacometabolomics analysis provides further evidence of the varying cellular responses at high and low doses of docetaxel in MCF7 breast cancer cells.

Limb girdle muscular dystrophy (LGMD) 2A/R1, caused by mutations in the CAPN3 gene and CAPN3 loss of function, is known to play a role in disease pathogenicity. In this study, AAVrh74.tMCK.CAPN3 was delivered systemically to two different age groups of CAPN3 knockout (KO) mice; each group included two treatment cohorts receiving low (1.17 × 1014 vg/kg) and high (2.35 × 1014 vg/kg) doses of the vector and untreated controls. Treatment efficacy was tested 20 weeks after gene delivery using functional (treadmill), physiological (in vivo muscle contractility assay), and histopathological outcomes. AAV.CAPN3 gene therapy resulted in significant, robust improvements in functional outcomes and muscle physiology at low and high doses in both age groups. Histological analyses of skeletal muscle showed remodeling of muscle, a switch to fatigue-resistant oxidative fibers in females, and fiber size increases in both sexes. Safety studies revealed no organ tissue abnormalities; specifically, there was no histopathological evidence of cardiotoxicity. These results show that CAPN3 gene replacement therapy improved the phenotype in the CAPN3 KO mouse model at both doses independent of age at the time of vector administration. The improvements were supported by an absence of cardiotoxicity, showing the efficacy and safety of the AAV.CAPN3 vector as a potential gene therapy for LGMDR1.

Morphological and biochemical adaptations to unilateral dopamine denervation of the neostriatum in newborn rats

Female CD-1 mice were treated topically with a low (25-50 nmol) or high (800 nmol) dose of benzo[a]pyrene (BP) or acetone vehicle, followed by 5 nmol 12-O-tetradecanoylphorbol 13-acetate (TPA) twice a week for 26 weeks. Selective UV radiation fractionation followed by PCR methods were used to analyze histologically defined subsets of cells (approximately 100-200 cells) on formalin-fixed, paraffin-embedded and H&E stained microscope sections. DNA samples from normal-appearing, hyperplastic or tumor regions from the skin of animals from each treatment group were isolated and amplified by PCR with c-Ha-ras-specific primers. Single-strand conformation polymorphism (SSCP) analyses were performed on both exon 1 and 2 products from each sample. DNA extracted from each aberrant band of SSCP analyses was amplified by PCR for further sequence analysis. The data indicate that c-Ha-ras mutations can be detected in normal-looking and hyperplastic epidermal cells as well as in tumor cells obtained from mice initiated with BP and promoted with TPA. The frequencies of c-Ha-ras mutations for normal-looking, hyperplastic and tumor samples were 3/20 (15%), 8/17 (47%) and 58/68 (85%), respectively, for the low dose group and 8/18 (44%), 10/20 (50%) and 64/86 (74%), respectively, for the high dose group. These observations indicate that there were no dose dependencies in the mutation frequencies for normal-looking, hyperplastic and tumor samples. For combined high dose and low dose samples, differences in mutation frequencies of the c-Ha-ras gene between the normal-looking, hyperplastic and tumor samples were highly significant (P < 0.0001, Fisher's exact test). All mutations detected were located at codons 12, 13 and 61 of the c-Ha-ras gene. With the numbers in parentheses indicating the nucleotide position in the coding sequence of the c-Ha-ras proto-oncogene, the distributions of mutations for G-->A (35), G-->T (35), G-->C (37), G-->T (38), C-->A (181), A-->T (182) and A-->G (182) in the low dose tumors were 5, 2, 11, 74, 0, 7 and 2%, respectively, and the distribution of mutations in tumors from animals treated with a high dose of BP were 3, 7, 13, 61, 15, 1 and 0%, respectively. Differences in the global mutation spectra (site and kind of all mutations) for the c-Ha-ras gene between the high and low dose group tumors were statistically significant (P < 0.004, Fisher's exact test) and the major difference between these two groups was C-->A (181) base substitutions. In summary, our data indicate that: (i) 79% of the BP/TPA skin tumors in CD-1 mice had c-Ha-ras mutations for the combined data for high dose and low dose tumors; (ii) the major mutations detected in BP/TPA skin tumors were G-->T transversions; (iii) the global mutation profile in the c-Ha-ras proto-oncogene in skin tumors obtained after initiation with a low dose of BP was different from that obtained after initiation with a high dose of BP.

Effects of two different enalapril dosages on clinical, haemodynamic and neurohumoral response of patients with severe congestive heart failure

Ticarcillin and piperacillin adsorption on to polyethersulfone haemodiafilter membranes in an ex-vivo circuit

Introduction: A wide variety in hydrocortisone substitution dose-regimens are considered physiological for patients with secondary adrenal insufficiency. However, it is likely that cognition is negatively influenced by higher cortisol exposure to the brain. So far, no studies have been performed to assess the effects of treatment regimens administered for a substantial period of time with a low physiological hydrocortisone dose in comparison to a high physiological hydrocortisone dose on cognition. Methods: This randomized, double blind cross-over study included 47 patients (mean(SD) age, 51(14) years, range 19-73) with secondary adrenal insufficiency. Patients were randomized to either group 1 (n=22), who first received a low dose during 10 weeks followed by a high dose for another 10 weeks, or group 2 (n=25), who first received a high dose followed by a low dose. All patients received a thrice-daily weight adjusted dose, with a total daily dose of 0.2-0.3 mg/kg body weight in the low dose condition and a total daily dose of 0.4-0.6 mg/kg body weight in the high dose condition. Cognitive performance of patients was measured at baseline and after each treatment period. A battery of 11 standardized cognitive tests which resulted in 37 test scores covering 4 cognitive domains (memory, attention, executive functioning and social cognition) was used. Results: Serum cortisol levels in the high dose condition were significantly higher compared to the serum cortisol levels in the low dose condition for both study periods. No differences in cognitive performance was found between the two dose regimens, except for short term memory (15 Words Test, p = 0.028, Z-score high dose (SD) = -0.03 (1.03), Z-score low dose (SD) = 0.35 (1.01), d = 0.38) and variability of reaction time in the phasic alertness task (Test of Attentional Performance, p = 0.015, Z-score high dose (SD) = -0.42 (0.79), Z-score low dose (SD) = -0.14 (0.82), d= 0.35). Conclusion Overall, no major negative influence on memory, attention, executive functioning and social cognition was observed after 10 weeks of treatment with a higher physiological dose of hydrocortisone in patients with secondary adrenal insufficiency when compared to a lower dose. However, minor effects of high doses of hydrocortisone on aspects of attention and short-term memory are present.

Lively debate continues on the nature of the dose-response relationship for the excess risk of cancer following exposure to ionising radiation at low doses and/or low dose rates. Clearly, these are the exposure conditions of principal importance to radiological protection. Presently, for the purposes of radiological protection, the assumption is made that the underlying dose-response relationship is linear-quadratic with no threshold, and that in the low dose and/or low dose rate region this curve can be approximated by a straight line with a gradient half that of the linear relationship which (for cancers other than leukaemia) is appropriate for moderate to high doses received at high dose rates. This, in essence, is the `linear-nonthreshold (LNT) dose-response model' referred to in the title of NCRP Report No 136.

A population of nearly 30,000 RFM and 11,000 BALB/c mice were exposed to graded radiation doses of ..gamma.. rays at a high (40 to 45 rad/min) or intermediate (8.3 rad/day) dose rate, or to fission neutrons at a high (5 to 25 rad/min) or low (1 rad/day) dose rate. Effects on life shortening are reported. The dose-response curve for ..gamma.. rays in RMF female mice at the high rate showed multiple changes in slope. In the region of 0 to 50 rad, the relationship between life shortening and dose could be described by a dose squared or a linear-dose-squared model with the dose-squared component predominating above approx. 4 rad. For RFM male mice after irradiation at the high dose rate, and for both RFM and BALB/c female mice irradiated at the intermediate dose rate, the curve was linear over the entire range of doses tested. Linear dose-response relationships were also observed with neutrons at both dose rates over the lower end of the dose range. The relative biological effectiveness of neutrons in the 0- to 50-rad range for RFM female mice irradiated at high dose rates was proportional to the -0.5 power of neutron dose, i.e., the RBE increased withmore » decreasing total dose. ..gamma.. rays were less effective in shortening life when delivered at an intermediate dose rate than at a high dose rate. With neutrons, the low dose rate was more effective than the high dose rate at high total doses for both strains. For the RFM, the low-dose rate neutron irradiation at low total doses was less effective than the high dose rate, while no dose-rate effect was observed for BALB/c mice in the low dose range.« less