Impacts of methyl jasmonate on Selaginella martensii: volatiles, transcriptomics, phytohormones, and gas exchange.

Methyl jasmonate (MeJA) induces various defence responses in seed plants, but for early plant lineages, information on the potential of jasmonates to elicit stress signalling and trigger physiological modifications is limited. The spikemoss Selaginella martensii was exposed to a range of MeJA concentrations (0, 10, 25, and 50 mM), and biogenic volatile organic compound (BVOC) emissions, photosynthetic rate (A), and stomatal conductance (gs) were continuously measured. In addition, changes in phytohormone concentrations and gene expression were studied. Enhancement of methanol, lipoxygenase pathway volatiles and linalool emissions, and reductions in A and gs, were MeJA dose-dependent. Before MeJA treatment, the concentration of 12-oxo-phytodienoic acid (OPDA) was 7-fold higher than jasmonic acid (JA). MeJA treatment rapidly increased OPDA and JA concentrations (within 30 min), with the latter more responsive. Some genes involved in BVOC biosynthesis and OPDA-specific response were up-regulated at 30 min after MeJA spraying, whereas those in the JA signalling pathway were not affected. Although JA was synthesized in S. martensii, OPDA was prioritized as a signalling molecule upon MeJA application. MeJA inhibited primary and enhanced secondary metabolism; we propose that fast-emitted linalool could serve as a marker of elicitation of stress-induced metabolism in lycophytes.

Effects of Leucine Ingestion and Contraction on the Sestrin/GATOR2 Pathway and mTORC1 Activation in Rat Fast-Twitch muscle.

BACKGROUND: Leucine activates the mechanistic/mammalian target of rapamycin complex 1 (mTORC1) in mammalian skeletal muscle. Recent studies have shown that Sestrin, a leucine sensor, might play a role in this process. However, it remains unknown whether Sestrin dissociates from GATOR2 in a dose- and time-dependent manner and whether an acute bout of muscle contraction augments this dissociation. OBJECTIVE: This study aimed to examine the effects of leucine ingestion and muscle contraction on the interaction between Sestrin1/2 and GATOR2 and on mTORC1 activation. METHODS: Male Wistar rats were randomly assigned to control (C), leucine 3 (L3), or leucine 10 (L10) groups. Intact gastrocnemius muscles were subjected to 30 repetitive unilateral contractions. The L3 and L10 groups were then orally administered 3 and 10 mmol/kg body weight of L-leucine 2 h after the end of the contractions, respectively. Blood and muscle samples were collected 30, 60, or 120 min after the administration. RESULTS: The blood and muscle leucine concentrations increased in a dose-dependent manner. The ratio of phosphorylated ribosomal protein S6 kinase (S6K) to total S6K (which indicates mTORC1 signaling activation) was markedly increased by muscle contraction and increased in a dose-dependent manner only in rested muscle. Leucine ingestion but not muscle contraction increased Sestrin1 dissociation from GATOR2 and Sestrin2 association with GATOR2. A negative relationship was observed between the blood and muscle leucine concentrations and the Sestrin1 association with GATOR2. CONCLUSIONS: The results suggest that Sestrin1, but not Sestrin2, regulates leucine-related mTORC1 activation via its dissociation from GATOR2 and that acute exercise-induced mTORC1 activation involves pathways other than the leucine-related Sestrin1/GATOR2 pathway.

Dose-dependent efficacy of bevacizumab in recurrent glioblastoma.

BACKGROUND: Bevacizumab (BEV), at a standard dose of 10 mg/kg every 2 weeks is associated with prolonged progression-free survival (PFS) but no improvement in overall survival (OS) in recurrent glioblastoma (rGBM). Few studies have examined the potential dose-dependent efficacy of BEV. In Ontario, reimbursement for the costs of BEV varies, and as a result, our practice began to routinely use lower dose regimens. The main aim of this study was to ensure that there was no harm to patients who received the low dose protocol. METHODS: A single-center retrospective study of patients given BEV for rGBM between 2015 and 2020 was performed. Clinical and treatment data including BEV dose regimen [SD (10 mg/kg every 2 weeks) vs. LD (5 mg/kg every 2-3 weeks or 10 mg/kg every 3 weeks)] received at the time of rGBM diagnosis were captured. Overall survival (OS) and progression-free survival (PFS) on BEV were compared using the Kaplan-Meier product-limit method. Log-rank test was used to compare potential predictive factors. Cox regression model was performed for multivariable analysis of OS and PFS. RESULTS: A total of 96 patients were included with a median follow-up duration of 6.84 months (range 1.12-50.63 months) from the date of the first infusion. The LD group consisted of 55 of the 96 patients. By virtue of funding mechanisms for BEV, the median age in the LD group was significantly higher (62 vs. 54 years p = 0.009). There was no difference in MGMT status between the two groups (p = 0.60). The LD group had prolonged median PFS (5.89 months versus 3.22 months; p = 0.0112) and OS (10.23 months versus 6.28 months; p = 0.0010). Multivariable analysis including the dose of BEV, the extent of resection, gender, and age revealed that standard dose of BEV, subtotal resection, and female sex were associated with worse overall survival. Nine patients in the SD group vs. 18 patients in the LD group reported an adverse event related to BEV. CONCLUSION: For patients with recurrent GBM, we found that a low dose regimen of BEV was associated with prolonged OS and PFS compared to the standard dose regimen. Lower dose schedules may be a better and more cost-effective option for patients with rGBM. Lower costs might provide more equitable access to this very important palliative drug.

New insight into the perplexing toxic features of PCBs: A study of nephrotoxicity in an animal model.

The present study investigated the effects of PCBs on the rat kidneys with attention given to the determination critical effect dose (CED) using the Benchmark dose (BMD) approach. Male albino Wistar rats (7 animals per group) were given by oral gavage Aroclor 1254 dissolved in corn oil at doses of 0.0, 0.5, 1, 2, 4, 8, or 16 mg/kg b.w./day for 28 days. The PCB nephrotoxicity was manifested by a dose-dependent changes in serum urea levels. The study has also revealed PCB-induced oxidative stress induction in kidneys. The observed nephrotoxic effects can be partly explained by oxidative damage of lipids and proteins in the kidneys due to observed reduced CuZnSOD activity and disturbances in antioxidant protection. Аll the renal oxidative stress parameters showed dependence on PCB oral doses as well as internal, measure kidney PCB levels. Calculated BMDL values were lower than estimated no observed adverse effect levels (NOAEL) based on the study, suggesting the importance of BMD approach use in future risk assessment.

An all-organic conditioning method to achieve deep dewatering of waste activated sludge and the underlying mechanism.

Among the common treatment/disposal routes of excessive activated sludge from municipal wastewater treatment plant, dewatering process functions as an essential pre-/post-treatment for volume minimization and transportation facilitation. Since inorganic coagulants have long been criticized for their high dosage and solid residue in sludge cake, there is an urgent need for investigations regarding the potential of applying organic chemicals as the conditioner. In this study, combined use of poly dimethyldiallylammonium chloride (PDMD) and tannic acid (TA) were investigated as an all-organic co-conditioning method for sewage sludge pre-treatment. Results showed that this all-organic conditioning strategy can effectively improve the dewaterability of sewage sludge. The capillary suction time reduced from 128.8 s to 23.1 s, and the filtration resistance reduced from 1.24 × 1012 cm/g to 7.38 × 1010 cm/g. The moisture content of dewatered sludge cake decreased to as low as 55.83%, showing the highest dewatering efficiency reported so far. In addition, the combination of PDMD and TA maximized the treating efficiency with very limited consumption of conditioners (added up to 4% of total solid). Based on the physic-chemical and rheological property investigation, it was proposed that the intermediate molecular weight polymer-based flocculation process and the TA agent-based protein precipitation process, could remarkably strengthen the compactness and structure robustness of sludge. In all, this PDMD-TA-based conditioning method suggested practical significance in consideration of its cost-effectiveness and disposal convenience of sludge cake.

Exposure to nanoparticles of magnetite Fe3O4 in three different doses and their influence on selected respiratory parameters of bronchoalveolar lavage after intravenous instillation.

OBJECTIVES: Due to nano-dimensions (less than 100 nm), can nanoparticles probably penetrate through various membranes and travel from the bloodstream to other organs in the body. The aim of our study was to find out whether NPs Fe3O4 (coated with sodium oleate) injected into the tail vein of laboratory Wistar rats pass through the bloodstream to the respiratory tract (in comparison with a control group); and if so whether increasing doses of NPs Fe3O4 have an escalating harmful effect on selected bronchoalveolar lavage (BAL) parameters. METHODS: Wistar rats were intravenously given 3 doses of the suspension of NPs Fe3O4 (0.1% LD50 = 0.0364, 1.0% = 0.364 and 10.0% = 3.64 mg/kg animal body weight). Seven days later, we sacrificed the animals under anaesthesia, performed bronchoalveolar lavage (BAL), and isolated the collected cells. Many inflammatory and cytotoxic BAL parameters were examined. RESULTS: Both inflammatory and cytotoxic BAL parameters affected by Fe3O4 suspension were changed compared to control results, but not all were statistically significant. Thus, the NPs Fe3O4 passed through the bloodstream to the respiratory tract and affected it. The highest concentration of NPs Fe3O4 (10%) had the most influence on BAL parameters (7 of 12 parameters). Only 3 parameters showed a pure dose dependence. CONCLUSION: We assume that the adverse effect of Fe3O4 NPs in our study is probably not correlated with the dose, but rather with the size of the particles or with their surface area.

DOSE DEPENDENCE OF SUBCHRONIC INFLUENCING OF ACETAMIPRID ON THE ORGANISM OF RATS FROM DATA OF MORPHOLOGICAL RESEARCHES.

OBJECTIVE: The aim: To determine the dose dependence of the subchronic effect of acetamiprid on the body of rats based on the data of morphological studies of internal organs. PATIENTS AND METHODS: Materials and methods: The experiment was performed on Wistar Han rats, which were orally administered acetamiprid in doses of 6, 12 and 60 mg/kg for 13 weeks. During the experiment, clinical studies were carried out, the general condition of the animals, body weight were assessed. After necropsy, the absolute and relative weight of internal organs was determined, and morphological studies of the brain, liver, kidneys, and spleen were performed with using an Olympus BX 54 light microscope and an Olympus C-5050 ZOOM camera with software Olympus DP-Soft. The research results were subjected to statistical processing using the Microsoft Excel 2010 computer program package. RESULTS: Results: The most pronounced manifestations of the toxic effect of acetamiprid were observed at a dose of 60 mg/kg, which indicated its hepatotoxic and nephrotoxic effects, as well as neurotoxic effects with signs of irreversible neurocyte damage. CONCLUSION: Conclusions: Morphological studies showed a dose-dependent nature and degree of expressiveness of the toxic effect of acetamiprid. According to the totality and nature of the changes revealed in the conditions of the conducted subchronic experiment on rats, no observed adverse effect level (NOAEL) was determined at the level of 12 mg/kg, no observed effect level (NOEL) - 6 mg/kg.

Comparative analysis of helminth infectivity: growth in intermediate hosts increases establishment rates in the next host.

Parasitic worms (i.e. helminths) commonly infect multiple hosts in succession before reproducing. At each life cycle step, worms may fail to infect the next host, and this risk accumulates as life cycles include more successive hosts. Risk accumulation can be minimized by having high establishment success in the next host, but comparisons of establishment probabilities across parasite life stages are lacking. We compiled recovery rates (i.e. the proportion of parasites recovered from an administered dose) from experimental infections with acanthocephalans, cestodes and nematodes. Our data covered 127 helminth species and 16 913 exposed hosts. Recovery rates increased with life cycle progression (11%, 29% and 46% in first, second and third hosts, respectively), because larger worm larvae had higher recovery, both within and across life stages. Recovery declined in bigger hosts but less than it increased with worm size. Higher doses were used in systems with lower recovery, suggesting that high doses are chosen when few worms are expected to establish infection. Our results indicate that growing in the small and short-lived hosts at the start of a complex life cycle, though dangerous, may substantially improve parasites' chances of completing their life cycles.

Evaluating Sacubitril/Valsartan Dose Dependence on Clinical Outcomes in Patients With Heart Failure With Reduced Ejection Fraction.

BACKGROUND: Limited evidence is available regarding low (24/26 mg) and middle (49/51 mg) doses of sacubitril/valsartan. OBJECTIVES: The purpose of this study was to investigate the effect of sacubitril/valsartan dose on heart failure (HF) hospitalization and mortality in patients with HF with reduced ejection fraction (HFrEF). METHODS: A retrospective multicenter cohort study compared 3 doses of sacubitril/valsartan in patients with HFrEF. The coprimary outcomes were all-cause mortality and rehospitalization for HF. Propensity matching analysis was performed. RESULTS: Of 721 eligible patients, propensity matching created a cohort with an effective sample size of 652 (24/26-mg group [n = 326], 49/51-mg group [n = 147], 97/103-mg group [n = 179]). The HF hospitalization rates were 29.14% in the 24/26-mg group, 19.51% in the 49/51-mg group, and 16.10% in the 97/103-mg group (24/26 vs 49/51 mg: HR = 1.56, 95% CI = 1.04-2.34; 24/26 vs 97/103 mg: HR = 1.79, 95% CI = 1.18-2.73; 49/51 vs 97/103 mg: HR = 1.15, 95% CI = 0.70-1.89). All-cause mortality rates were 29.63% in the 24/26-mg group, 17.58% in the 49/51-mg group, and 9.27% in the 97/103-mg group (24/26 vs 49/51 mg: HR = 1.67, 95% CI = 1.07-2.59; 24/26 vs 97/103 mg: HR = 2.56, 95% CI = 1.54-4.24; 49/51 vs 97/103 mg: HR = 1.54, 95% CI = 0.84-2.82). CONCLUSION AND RELEVANCE: Sacubitril/valsartan 97/103- or 49/51-mg dose is associated with a lower mortality or hospitalization rate for HF in patients receiving sacubitril/valsartan compared with the 24/26-mg dose group.

Differential drivers of intraspecific and interspecific competition during malaria-helminth co-infection.

Various host and parasite factors interact to determine the outcome of infection. We investigated the effects of two factors on the within-host dynamics of malaria in mice: initial infectious dose and co-infection with a helminth that limits the availability of red blood cells (RBCs). Using a statistical, time-series approach to model the within-host 'epidemiology' of malaria, we found that increasing initial dose reduced the time to peak cell-to-cell parasite propagation, but also reduced its magnitude, while helminth co-infection delayed peak cell-to-cell propagation, except at the highest malaria doses. Using a mechanistic model of within-host infection dynamics, we identified dose-dependence in parameters describing host responses to malaria infection and uncovered a plausible explanation of the observed differences in single vs co-infections. Specifically, in co-infections, our model predicted a higher background death rate of RBCs. However, at the highest dose, when intraspecific competition between malaria parasites would be highest, these effects of co-infection were not observed. Such interactions between initial dose and co-infection, although difficult to predict a priori, are key to understanding variation in the severity of disease experienced by hosts and could inform studies of malaria transmission dynamics in nature, where co-infection and low doses are the norm.

Dose-Dependent Effect of Bacillus sp. Metabolites from Permafrost on Lymphocyte Differentiation in the Thymus.

We studied the effect of a single intraperitoneal injection of metabolites from Bacillus sp. M3 strain isolated from permafrost (from 5×103 to 50×103 microbial bodies) on differentiation of T cells in the thymus of F1(CBA/Black-6) mice. On day 21 after the injection of metabolites, a dose-dependent decrease in the level of CD34+CD44+ and an increase in the number of CD34+CD44-, CD25-TCR+, CD25+TCR+max, CD4+CD8-, CD4-CD8+, and CD44+TCR+ lymphocytes were observed in the thymus. The increase in thymus level of mature (CD25+TCR+max) and migration-ready (CD44+TCR+) T cells in combination with a moderate decrease in the level of T cell precursors entering the thymus from the bone marrow (CD34+CD44+) can indicate a modulating influence of Bacillus sp. metabolites on functional activity of the thymus aimed at maintenance of the T cell balance in the body.

Energy and dose dependence of GafChromic EBT3-V3 film across a wide energy range.

AIM: To determine the energy and dose dependence of GafChromic EBT3-V3 film over an energy range 0.2 mm Al HVL to 6 MV. BACKGROUND: The decay scheme of a brachytherapy source may be complex and the spectrum of energy can be wide. LiF TLDs are the golden standard recommended for dosimetric measures in brachytherapy, for their energy independence, but TLDs could be not available in some centres. An alternative way to perform dose measurements is to use GafChromic films, but they show energy dependence. METHODS AND MATERIALS: Films have been irradiated at increasing dose with three different beams: 6 MV beam, TPR20, 10 = (0.684 ±â€¯0.01), HVL = (2.00 ±â€¯0.01)mmAl and HVL = (0.20 ±â€¯0.01)mmAl. Calibration curves were generated using the same dose range (0cGy to 850cGy) for the three energies. Using the 6 MV calibration curve as reference, the film response in terms of net optical density (OD) was evaluated. RESULTS: The difference in the calibration curve obtained by irradiating the film with 6 MV and 2 mm Al HVL energy beams is less than 3 %, within the calibration uncertainty, in the dose range 500-850cGy. The OD of EBT3-V3 film is significantly lower at 0.2 mmAl HVL compared to 6 MV, showing differences up to 25 %. CONCLUSION: Within the range 6 MV-2 mm Al HVL and dose higher than 500cGy, GafChromic EBT3-V3 films are energy independent. In this dose range, films can be calibrated in a simple geometry, using a 6 MV Linac beam, and can be used for brachytherapy sources dose measures. The use of EBT3 films can be extended to reference dosimetry in Ir-192 clinical brachytherapy.

Wave-Like Dose-Dependence of the Stimulating Effects of Dimebon on Cognition in a Wide Dose Range.

Comparison of the cognition-stimulating effects of Dimebon in a wide dose range revealed a non-monotonic and nontrivial wave-like dose-dependence of its activity. Positive results were obtained at low (0.02-0.05 mg/kg) or high (5-10 mg/kg) doses of Dimebon, while intermediate doses were ineffective. This type of the dose dependence of the pharmacological effect can indicate that the substance has several targets. This fact should be taken into consideration when selecting the doses and concentrations of the substance and its analogues for further studies, and for planning treatment schemes and administration doses in clinical studies.

Dose-dependence of transient respiratory motion artifacts on gadoxetic acid-enhanced arterial phase MR images.

PURPOSE: To compare the occurrence of transient respiratory motion (TM) artifacts between 0.05 mmol/kg and 0.025 mmol/kg gadoxetic-acid on arterial phase MRI intra-individually for evaluating dose-dependence of gadoxetic acid. MATERIALS AND METHODS: This retrospective study involved 91 patients who underwent dynamic MRI at 1.5T at different times, one time with 0.05 mmol/kg and the other 0.025 mmol/kg gadoxetic-acid. Examinations with 0.05 mmol/kg totaled 91 scans, and examinations with 0.025 mmol/kg totaled 375 scans (due to multiple exams for several patients). The scan with 0.025 mmol/kg closest in time to the 0.05 mmol/kg scan was selected to minimize temporal effects. Two radiologists graded TM artifacts in the arterial phase images using a four-point scale: no, mild, moderate, and severe artifacts. Results were compared between the two protocols (0.05 mmol/kg versus all 0.025 mmol/kg and 0.05 mmol/kg versus selected 0.025 mmol/kg), and the odds ratio for moderate-to-severe artifacts was calculated. RESULTS: Significantly more TM artifacts were observed in the double dose (16/91 [17%]) scans compared with either all (17/375 [4%]; P < 0.01) or selected (3/91 [3%]; P = 0.01) standard dose scans. The odds ratio of the moderate-to-severe artifacts with the higher dose was 4.99-5.33. CONCLUSION: There appears to be dose-dependence of gadoxetic-acid and the occurrence of TM artifacts. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:433-438.

Coated platelets introduce significant delay in onset of peak thrombin production: Theoretical predictions.

Platelets play a crucial role in the initiation, progress, termination as well as regulation of blood coagulation. Recent studies have confirmed that not all but only a small percentage of thrombin-activated platelets ("coated" platelets) exhibit procoagulant properties (namely the expression of phosphatidylserine binding sites) required for the acceleration and progress of coagulation. A mechanistic model is developed for in vitro coagulation whose key features are distinct equations for coated platelets, thrombin dose-dependence for coated platelets, and competitive binding of coagulation factors to platelet membrane. Model predictions show significant delay in the onset of peak Va production, and peak thrombin production when dose-dependence is incorporated instead of a fixed theoretical maximum percentage of coated platelets. Further, peak thrombin concentration is significantly overestimated when either fractional presence of coated platelets is ignored (by 299.4%) or when dose-dependence on thrombin is ignored (by 24.7%).

Acupuncture for chronic low back pain: a randomized controlled feasibility trial comparing treatment session numbers.

OBJECTIVE: To evaluate the feasibility of a randomized controlled trial investigating the optimal number of treatment sessions of acupuncture, used as an adjunct to usual care, for managing chronic low back pain. METHODS: In total, 45 participants with chronic low back pain were recruited and randomly allocated to receive usual care plus 4, 7, or 10 sessions of acupuncture (15/group). Primary outcomes were recruitment rate, randomization rate, treatment compliance, completion of the outcome measures, and retention rates. Secondary outcomes included back function, pain intensity and bothersomeness, generic health status, activity disability, and participant satisfaction. Data were collected at baseline and discharge, and at 6 and 12 weeks post randomization. RESULTS: The recruitment method was demonstrated to be successful: recruitment rate was 43.7%, and randomization rate was 100%. Compliance with treatment was high among participants (86.7%, 86.7%, and 100% for the 4-, 7-, and 10-session group, respectively). Outcome questionnaires used in this study were found to be appropriate for a future randomized controlled trial. Participant retention rates were 88.9% at discharge and at 6 weeks post randomization and 84.4% at 12 weeks post randomization. Secondary outcomes (except for pain intensity) favored the 10-session acupuncture group at 12 weeks post randomization. Over 90% of participants indicated that they were "very satisfied" and/or "extremely satisfied" with the acupuncture treatment. CONCLUSION: This study demonstrated that a full-scale randomized controlled trial using the methodology described above is feasible, and such a trial is essential to test the dose dependence of acupuncture.

Effect of dose and frequency of exposure to infectious stages on trematode infection intensity and success in mussels.

Marine parasites such as trematodes often compromise the fitness of their hosts. Such effects are generally considered to be density-dependent, i.e. the greater the infection intensity in the host, the greater the detrimental impact on host fitness. However, the mechanisms determining infection in marine hosts are still poorly understood. Here, we investigated the effect of cercarial dose and exposure frequency (single vs. trickle infections) of a marine trematode parasite, Himasthla elongata (Trematoda: Echinostomatidae), on infection intensity and success in its second intermediate host, the blue mussel Mytilus edulis, an abundant and widely distributed bivalve in European coastal waters. In our laboratory experiment, we tested 4 levels of parasite doses and showed that mussels faced higher parasite infection intensity at higher doses of cercarial exposure and that they acquired more infections when repeatedly exposed to smaller doses compared to a single high dose. However, the infection success of cercariae did not differ among 4 dose levels but was only significantly different between trickle and single exposures. This indicates that cercariae were not subjected to a dose-dependent regulation of their infectivity, suggesting that infection intensity in mussels is largely driven by factors mediating the abundance of infective stages. With the combined investigation of the effect of cercarial dose and exposure frequency at realistic dose levels, our study contributes to our currently very limited understanding of the determinants of infection intensity in marine hosts and highlights the usefulness of experimental studies in advancing our knowledge in this field.

Population pharmacokinetics of gabapentin in healthy Korean subjects with influence of genetic polymorphisms of ABCB1.

The objective of this study was to perform population pharmacokinetic (PK) analysis of gabapentin in healthy Korean subjects and to investigate the possible effect of genetic polymorphisms (1236C > T, 2677G > T/A, and 3435C > T) of ABCB1 gene on PK parameters of gabapentin. Data were collected from bioequivalence studies, in which 173 subjects orally received three different doses of gabapentin (300, 400, and 800 mg). Only data from reference formulation were used. Population pharmacokinetics (PKs) of gabapentin was estimated using a nonlinear mixed-effects model (NONMEM). Gabapentin showed considerable inter-individual variability (from 5.2- to 8.7-fold) in PK parameters. Serum concentration of gabapentin was well fitted by a one-compartment model with first-order absorption and lag time. An inhibitory Emax model was applied to describe the effect of dose on bioavailability. The oral clearance was estimated to be 11.1 L/h. The volume of distribution was characterized as 81.0 L. The absorption rate constant was estimated at 0.860 h-1, and the lag time was predicted at 0.311 h. Oral bioavailability was estimated to be 68.8% at dose of 300 mg, 62.7% at dose of 400 mg, and 47.1% at dose of 800 mg. The creatinine clearance significantly influenced on the oral clearance (P < 0.005) and ABCB1 2677G > T/A genotypes significantly influenced on the absorption rate constant (P < 0.05) of gabapentin. However, ABCB1 1236C > T and 3435C > T genotypes showed no significant effect on gabapentin PK parameters. The results of the present study indicate that the oral bioavailability of gabapentin is decreased when its dosage is increased. In addition, ABCB1 2677G > T/A polymorphism can explain the substantial inter-individual variability in the absorption of gabapentin.

Body temperature changes during simulated bacterial infection in a songbird: fever at night and hypothermia during the day.

Although fever (a closely regulated increase in body temperature in response to infection) typically is beneficial, it is energetically costly and may induce detrimentally high body temperatures. This can increase the susceptibility to energetic bottlenecks and risks of overheating in some organisms. Accordingly, it could be particularly interesting to study fever in small birds, which have comparatively high metabolic rates and high, variable body temperatures. We therefore investigated two aspects of fever and other sickness behaviours (circadian variation, dose dependence) in a small songbird, the zebra finch. We injected lipopolysaccharide (LPS) at the beginning of either the day or the night, and subsequently monitored body temperature, body mass change and food intake for the duration of the response. We found pronounced circadian variation in the body temperature response to LPS injection, manifested by (dose-dependent) hypothermia during the day but fever at night. This resulted in body temperature during the peak response being relatively similar during the day and night. Day-to-night differences might be explained in the context of circadian variation in body temperature: songbirds have a high daytime body temperature that is augmented by substantial heat production peaks during activity. This might require a trade-off between the benefit of fever and the risk of overheating. In contrast, at night, when body temperature is typically lower and less variable, fever can be used to mitigate infection. We suggest that the change in body temperature during infection in small songbirds is context dependent and regulated to promote survival according to individual demands at the time of infection.

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

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.