Dose-response Relationship Curves Research Articles

Preoperative serum selenium predicts acute kidney injury after adult cardiac surgery.

The relationship between serum selenium (Se) and acute kidney injury after adult cardiac surgery (CSA-AKI) remains controversial. This study aimed to investigate the association of preoperative Se level with incident CSA-AKI. A retrospective cohort study was conducted on patients who underwent cardiac surgery. The primary outcome was incident CSA-AKI. Multivariable logistic regression models and natural cubic splines were used to estimate the association of Se levels and primary outcome. A total of 453 patient with a mean age of 62.97 years were included. Among all patients, 159 (35.1%) incident cases of CSA-AKI were identified. The level of preoperative Se concentration in patients with CSA-AKI was significant lower than that in patients without CSA-AKI. The higher preoperative Se level was significantly associated with decreased risk of CSA-AKI (adjusted OR 0.91, 95% CI: 0.87-0.99). Dose-response relationship curve revealed a nearly L-shape correlation between serum Se selenium levels and incident CSA-AKI. Our study suggested that a higher level of serum Se was significantly associated with lower risk of CSA-AKI. Further prospective studies are needed to clarify the causal relationship between serum Se level and incident CSA-AKI.

Association of metal/metalloids exposure with abnormal liver function among occupational population in a mining area of Hunan Province:a prospective study

To investigate the association of metals/metalloids exposure with risk of liver disfunction among occupational population in Hunan Province, and to explore the potential dose-response relationship. In 2017, a mining area in Hunan Province was chosen as the research site, and eligible workers were recruited as study subjects. General demographic characteristics, levels of 23 metals/metalloids in plasma and urine, and liver function index(total bilirubin(TBIL), alanine amino transferase(ALT), globulin(GLB) and γ-glutamyl transferase(GGT)) were obtained by questionnaire, physical examination and laboratory tests. Participants were followed up in 2018, 2019 and 2020 respectively. Cox proportional risk model was used to evaluate the relationship between metal/metalloids exposure and risk of liver disfunction, and dose-response relationship curves were plotted by using the restricted cubic spline function. A total of 891 employees were recruited in the study, 576(65.0%)were aged ≤45 years, 832(93.4%) were male and 530(59.5%) worked as smelters. After adjusting various factors such as age, gender, BMI, type of work, education, smoking, alcohol consumption, diet, stress, medical history, exercise and tea consumption, positive correlations were found between plasma tungsten(HR=4.90, 95%CI 1.17-20.48) and urinary barium(HR=1.07, 95%CI 1.02-1.12) levels with abnormally elevated TBIL levels. Additionally, a significant association was observed between plasma thallium and the risk of elevated ALT levels(HR=11.15, 95%CI 1.97-63.29). Plasma tungsten and thallium, along with barium found in urine, are risk factors for the development of abnormally elevated liver function indices in occupational groups.

Analysis of the short-term noise situation around Bangkok International Airport prior to the second phase of airport expansion begins

Short-term noise measurements carried out around the Bangkok International Airport during 2014-2015 provided baseline datasets of noise levels to illustrate the overview of actual aircraft noise exposure to people living underneath the flight path. The datasets will be useful for social surveys to draw the dose-response relationship curve, validation of noise prediction studies, and noise management plans around the airport before the second phase expansion. This study proposes a post-processing tool for extracting aircraft noise events due to aircraft flyovers from the measurements. The actual noise exposure levels of aircraft fly-over noise events were reported to reflect the existing noise situation around the airport and contribute to the analysis of other studies conducted during the same period.

The association between body mass index and risk of preoperative oxygenation impairment in patients with the acute aortic syndrome.

The study aimed to determine the relationship between body mass index (BMI) and the risk of acute aortic syndrome (AAS) with preoperative oxygenation impairment. A meta-analysis of published observational studies involving BMI and AAS with preoperative oxygenation impairment was conducted. A total of 230 patients with AAS were enrolled for retrospective analysis. All patients were divided into 2 groups (Non-oxygenation impairment group and Oxygenation impairment group). Logistic regression analysis was performed to assess the relation between BMI and the risk of preoperative oxygenation impairment after the onset of AAS. Dose-response relationship curve and subgroup analysis were conducted to test the reliability of BMI as an independent factor of it. For the meta-analysis, the quantitative synthesis indicated that excessive BMI increased the risk of preoperative oxygenation impairment (OR: 1.30, 95% CI: 1.05-1.60, P heterogeneity = 0.001). For the retrospective analysis, a significant association was observed after adjusting for a series of variables. BMI was significantly related to preoperative oxygenation impairment after the onset of AAS (OR: 1.34, 95% CI: 1.15-1.56, p <0.001), and compared with normal weight group (18.5 kg/m2 ≤ BMI < 23.0 kg/m2), the individuals with excessive BMI were at higher risk of preoperative oxygenation impairment for the obese group (BMI ≥ 25 kg/m2) (OR: 17.32, 95% CI: 4.03-74.48, p <0.001). A J-shape curve in dose-response relationship analysis further confirmed their positive correlation. Subgroup analysis showed that diastolic blood pressure (DBP) ≥ 90mmHg carried an excess risk of preoperative oxygenation impairment in obese patients. Excessive BMI was an independent risk factor for AAS with preoperative oxygenation impairment.

Effects of coenzyme Q10 supplementation on glycemic control: A GRADE-assessed systematic review and dose-response meta-analysis of randomized controlled trials.

SummaryBackgroundPrevious reviews reported that the effects of CoQ10 on glycemic control were inconsistent. There is no review exploring the optimal intake of CoQ10 for glycemic control. We aimed to investigate the efficacy of CoQ10 on glycemic control and evaluate the dose–response relationship via integrating the existing evidence from randomized control trials (RCTs).MethodsDatabases (PubMed, Embase, and Cochrane Library) were searched to identify RCTs for investigating the efficacy of CoQ10 on fasting glucose, fasting insulin, HbA1c, and HOMA-IR up to March 12, 2022. We performed a meta-analysis on 40 RCTs of CoQ10. Weighted mean difference (WMD) and 95% confidence intervals (CIs) were calculated for net changes. Evidence certainty was assessed using GRADE. Dose-response relationships were evaluated using 1-stage restricted cubic spline regression model. The protocol was registered in PROSPERO (CRD42021252933).FindingsForty studies (n = 2,424 participants) were included in this meta-analysis. CoQ10 significantly reduced fasting glucose (WMD: -5.22 [95% CI: -8.33, -2.11] mg/dl; P <0.001; I2=95.10%), fasting insulin (-1.32 [-2.06, -0.58] μIU/ml; P < 0.001; I2=78.86%), HbA1c (-0.12% [-0.23, -0.01]; P =0.04; I2=49.10%), and HOMA-IR (-0.69 [-1.00, -0.38]; P <0.001; I2=88.80%). The effect of CoQ10 on outcomes was greater in diabetes with lower heterogeneity. A “U” shape dose-response relationship curve revealed that 100-200 mg/day of CoQ10 largely decreased fasting glucose (χ2 = 12.08, Pnonlinearity =0.002), fasting insulin (χ2 = 9.73, Pnonlinearity =0.008), HbA1c (χ2 = 6.00, Pnonlinearity =0.049), HOMA-IR (χ2 = 25.89, Pnonlinearity <0.001).InterpretationCoQ10 supplementation has beneficial effects on glycemic control, especially in diabetes, and 100-200 mg/day of CoQ10 could achieve the greatest benefit, which could provide a basis for the dietary guidelines of CoQ10 in patients with glycemic disorders.FundingThis work was supported by the National Natural Science Foundation of China (No. 82030098, 81872617 and 81730090), Shenzhen Science, Technology, and Innovation Commission (No. JCYJ20180307153228190), CNS Research Fund for DRI, and National innovation and entrepreneurship training program for undergraduate student (No. 202210558161).

Dietary inflammatory index and depression risk in patients with chronic diseases and comorbidity

BackgroundThe coexistence of depression and chronic diseases can lead to greater disability and increased mortality. The objective of this study was to examine the association between Dietary Inflammatory Index (DII) and depression in patients with chronic diseases and comorbidity. MethodsMultivariable logistic regression analysis was used to investigate the relationship between DII and depression. Dose response relationship was analyzed using a generalized additive model with the smoothing plot. ResultsA total of 7870 chronic diseases patients were enrolled. In multivariate model, the highest quintile of DII was associated with increased risk of depression in patients with diabetes (OR:1.73, 95CI%: 1.17, 2.57), hypertension (OR:1.93, 95CI%: 1.47, 2.52), coronary heart disease (OR:2.65, 95CI%: 1.18, 5.94). The dose response relationship curve suggested the DII tended to be linearly associated with depression in patients with chronic diseases and comorbidity, and the ORs for risk of depression increased with the increase of DII. Furthermore, in patients had at least one chronic comorbidity, the subgroup analysis results showed that those who age<60 years or male participants had higher risk of depression, with ORs (95% CIs) of 2.60 (1.81, 3.74) and 2.51 (1.65, 3.81), respectively. ConclusionThe current study demonstrates that a higher DII is associated with an increased risk of depression in participants with chronic diseases and comorbidity, especially among those less than 60 years and men. Considering diet as a modifiable factor, limiting pro-inflammatory diet or encouraging anti-inflammatory diet may be an effective way to prevent depression and reduce depressive symptoms.

Cumulative noise exposure and the risk of high-frequency hearing loss relationships

Objective: To explore the dose-response relationship between cumulative noise exposure and high-frequency hearing loss, and further to provide a basis for the control of occupational hazards of noise. Methods: A Meta-analysis of dose-response relationships was performed on the data of eligible literatures published in China from January 2000.1 to December 2019.12. Results: The initial combined Odds Ratio (OR) and its 95%CI in the Meta-analysis were 1.10 (1.08-1.12) . As the Begg's funnel plot and Egger's test indicated publication bias (t=5.97, P<0.01) , the Trim-and-Fill Method was used for OR value adjustment. The adjusted-OR was 1.09 (1.07-1.12) ; sensitivity analysis showed that the results of this Meta-analysis have high stability; subgroup analysis indicated that the ORs of the steady-state noise group and the non-steady-state noise group were 1.10 (1.08-1.12) and 1.14 (1.07-1.21) , the ORs of the old standard group and the new standard group were 1.10 (1.08-1.12) and 1.11 (1.00-1.24) , respectively. The nonlinear dose-response relationship curve demonstrated that the risk of high-frequency hearing loss increases rapidly after CNE reaches 95 dB (A) ·years. Conclusion: There is a definite dose-response relationship between CNE and high-frequency hearing loss, which can be used to predict the risk of high-frequency hearing loss in noisy workers.

Relationship of quality and duration of sleep with hypertension among adults in Guangzhou

Objective: To explore the relationship of sleep quality and sleep duration with hypertension among adults aged 30-79 years old in Guangzhou. Methods: According to multi-stage stratified cluster sampling, 12 747 residents aged 30-79 years old were sampled and surveyed in Guangzhou from January 2018 to March 2019. Data on general demographic characteristics, sleep quality, sleep duration and hypertension were collected through questionnaire survey, the Pittsburgh sleep quality index (PSQI) and physical examination. Multivariate logistic regression models were used to analyze the putative association between sleep quality, sleep duration and hypertension. Restrictive cubic spline curve was used to draw the dose-response relationship curve between sleep quality, sleep time and hypertension. Results: The mean age of the subjects was (52.68±12.17) years, the prevalence of hypertension was 36.6% (4 664/12 747), the average score of PSQI was (4.70±2.88), and the average sleep time was (7.00±1.32) hours. The prevalence of hypertension was positively associated with the PSQI score. Compared to the subjects with a score less than 3, OR (95%CI) of hypertension with a PSQI score of 3-5, 5-8, ≥9 were 1.14 (1.02-1.27), 1.17 (1.03-1.34), 1.41 (1.21-1.64), respectively. The relationship between sleep duration and hypertension appeared U-shaped. Compared with 6 to 8 hours sleep duration, both sleep duration<6 hours with OR(95%CI) of 1.27(1.12-1.43) or >8 hours with OR(95%CI) of 1.20(1.05-1.38) was associated with hypertension. Conclusion: Both poor sleep quality, longer or shorter sleep duration were responsible for increased risk of cognitive impairment in older Chinese.

Effects of Anaerobic Exercises on Cardiac Workload, Peripheral Resistance, and Lipid Index in Grade-I Hypertensive Young Adults

Purpose: Hypertension is the leading preventable risk factor for various cardiovascular diseases. With the soaring prevalence globally, there is a need to identify the non-pharmacological management for the maintenance of blood pressure. Hence this study is aimed to determine the impact of an-aerobic exercise in grade-I hypertensive young adults. Methods: A total of 92 participants were recruited from the OPD of a tertiary care hospital between the periods of 11 months (August 2017-June 2018) and were allocated in an anaerobic and aerobic group. The intervention was given based on ACSM, FITT protocol for 8 weeks. The pre- and post-systolic blood pressure, ankle brachial index (ABI), and lipid index were determined. Results: The results obtained from the study showed that eight weeks of prescribed exercises significantly improved systolic blood pressure, ankle brachial index, and lipid index of the hypertensive patients in both groups (CI: 95%, pConclusion: The study concluded that 8 weeks of supervised training programs were found to be effective in improving blood pressure, ABI, and lipid index among grade-I hypertensive young adults. Both exercises regimes were found to be equally effective, however, in term of their impact on the dose-response relationship curve resisted exercises were found to be more potent than aerobic exercises as only 24 sessions of resisted exercises performed for 8 weeks provided an equally effective result as were obtained after 40 sessions of aerobic exercises.

Development of a Model of the Acute and Delayed Effects of High Dose Radiation Exposure in Jackson Diversity Outbred Mice; Comparison to Inbred C57BL/6 Mice

Development of medical countermeasures against radiation relies on robust animal models for efficacy testing. Mouse models have advantages over larger species due to economics, ease of conducting aging studies, existence of historical databases, and research tools allowing for sophisticated mechanistic studies. However, the radiation dose-response relationship of inbred strains is inherently steep and sensitive to experimental variables, and inbred models have been criticized for lacking genetic diversity. Jackson Diversity Outbred (JDO) mice are the most genetically diverse strain available, developed by the Collaborative Cross Consortium using eight founder strains, and may represent a more accurate model of humans than inbred strains. Herein, models of the Hematopoietic-Acute Radiation Syndrome and the Delayed Effects of Acute Radiation Exposure were developed in JDO mice and compared to inbred C57BL/6. The dose response relationship curve in JDO mice mirrored the more shallow curves of primates and humans, characteristic of genetic diversity. JDO mice were more radioresistant than C57BL/6 and differed in sensitivity to antibiotic countermeasures. The model was validated with pegylated-G-CSF, which provided significantly enhanced 30-d survival and accelerated blood recovery. Long-term JDO survivors exhibited increased recovery of blood cells and functional bone marrow hematopoietic progenitors compared to C57BL/6. While JDO hematopoietic stem cells declined more in number, they maintained a greater degree of quiescence compared to C57BL/6, which is essential for maintaining function. These JDO radiation models offer many of the advantages of small animals with the genetic diversity of large animals, providing an attractive alternative to currently available radiation animal models.

Patient-Specific 3-D Image-Based Dose Estimates for Transarterial Radioembolization of Liver Tumors with Yttrium-90 Microspheres

Clinical experience has demonstrated the safety and efficacy of transarterial radioembolization (TARE) with Yttrium (Y-90) in the treatment of liver tumors but only approximate methods exist for estimating dose distribution. Traditional TARE dosimetry takes into account one-dimensional parameters such as treated volume and percent lung shunt to calculate delivery of 120 Gy. Newer 3-D imaging using both anatomical (CT and MRI) and nuclear medicine (SPECT or PET) platforms can provide more accurate activity and dose calculation to tumor, liver, and nearby normal structures. We hypothesized that actual Y-90 dose distribution, as calculated by post-treatment SPECT, is not uniform throughout the GTV and that the mean dose delivered is significantly different than the intended prescribed dose. In this study, 3-D dose calculations were compared against the traditional empirical method in 10 patients undergoing a glass microspheres treatment. The prescription dose was 120 Gy for 9 cases and 85 Gy for one case using the traditional approach. All patients had diagnostic imaging, pre-treatment Tc99m-MAA SPECT/CT scan, and post-treatment Bremsstrahlung SPECT/CT image acquisition. Diagnostic images and SPECT were registered and fused using the deformable registration software system. The gross tumor volume (GTV) and total liver volume were delineated and verified by independent physicians. Based on the activity map from the post-treatment SPECT/CT scan, the dose was generated using medical imaging, which also calculated isodose curves and Dose-Volume Histograms (DVH) using Local Deposition Method or the Voxel S Value approach based on the schema in MIRD. Table 1 lists the range and mean dose to GTV calculated using post-treatment SPECT versus the prescribed dose for the 10 patients. In this sample, the mean dose calculated by post-treatment SPECT was significantly different than the intended prescribed dose, the dose distribution in the GTV was not uniform and had a wide range of distribution, and there were instances where the 3-D dose map revealed under-dose in the GTV. Historically, the empirical method has determined required activity to be administered by TARE using Y-90. With recent advances in high-resolution 3-D image data and computational 3-D treatment planning systems, detailed 3-D dose calculations can be performed before and after treatment. These advances in treatment planning should benefit TARE by establishing a dose-response relationship curve and enabling combined therapy with local ablative techniques such as thermal ablation and stereotactic ablative radiotherapy. Future directions include validating 3-D Y-90 planning software with direct phantom measurements.Abstract 2524; Table 1CaseConventional dosimetry (Gy)SPECT, mean dose GTV (Gy)SPECT, dose range GTV (Gy)1120385[0-1993]212050.5[0-177]3120150[0-399]412018[0-30]5120309[13-694]68584[0-238]7120103[0-257]8120274[0-823]912059[0-290]10120175[78-292] Open table in a new tab

Selection and Evaluation of Indexes Commonly Used to Determine Contamination with T-2 Toxin in Pacific White Shrimp Litopenaeus vannamei by the Grey Relational Method.

The objectives of the present study were to evaluate the effects of different concentrations of the mycotoxin T-2 toxin in feed on muscle performance in the Pacific white shrimp Litopenaeus vannamei, evaluate indexes of physiological variables that indicate T-2 toxin contamination in the shrimp using the grey relational method, and determine the dose-response relationships between T-2 toxin and the indexes. Of the 6 physical, 7 biochemical, and 17 nutritional indexes examined, the values of the grey relational coefficients were highest for the hepatopancreas: body weight ratio (HBR), alanine aminotransferase (ALT) activity, and serine (SER) content (0.83, 0.68, and 0.82, respectively). Therefore, the HBR, ALT activity, and SER content were selected as appropriate indexes for contamination of Pacific white shrimp muscle with T-2 toxin. Based on their dose-response relationship curves, mean effective doses of 1.45, 1.69, and 1.33 mg of T-2 toxin/kg of feed were obtained for the HBR, ALT activity, and SER content, respectively. These results offer technical reference points for the evaluation and control of T-2 toxin in shrimp feed. Received April 28, 2016; accepted April 9, 2017.

Isobolographic Analysis of Interaction for Three-Drug Combination of Carbamazepine, Phenobarbital and Topiramate in the Mouse Maximal Electroshock-Induced Seizure Model

Background/Aims: To characterize the anticonvulsant effects of a combination of 3 antiepileptic drugs (AEDs; i.e. carbamazepine (CBZ), phenobarbital (PB) and topiramate (TPM)) at the fixed-ratio of 1:1:1 in the mouse maximal electroshock (MES)-induced seizure model. Methods: Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25 mA, 500 V, 50 Hz, 0.2 s stimulus duration) delivered via auricular electrodes. Type I isobolographic analysis for parallel dose-response relationship curves (DRRCs) was used to analyze the 3-drug combination. Results: In the mouse MES model, all the studied AEDs (i.e. CBZ, PB and TPM) administered singly had their DRRCs parallel to each other. With type I isobolography for parallel DRRCs, a combination of CBZ, PB and TPM at the fixed-ratio of 1:1:1 exerted supra-additive (synergistic) interaction in the mouse MES model. Conclusions: Synergistic interaction among CBZ, PB and TPM at the fixed-ratio of 1:1:1 against MES-induced seizures is worthy of consideration in further clinical settings. All detailed calculations required to perform type I isobolographic analysis for the 3-drug combination were presented.

Additive interaction of levetiracetam with lamotrigine in the mouse 6 Hz psychomotor seizure model – an isobolographic analysis

The aim of this study was to characterize the anticonvulsant effects of levetiracetam (LEV) in combination with lamotrigine (LTG – a second-generation antiepileptic drug), in the mouse 6 Hz psychomotor seizure model. Limbic (psychomotor) seizure activity was evoked in albino Swiss mice by a current (32 mA, 6 Hz, 3 s stimulus duration) delivered via ocular electrodes and isobolographic analysis for parallel dose-response relationship curves (DRRCs) was used to characterize the consequent anticonvulsant interactions between the drug combinations. Results indicated that LEV administered singly was associated with a DRRC that was parallel to that for LTG. With isobolography for parallel DRRCs, the combination of LEV with LTG at three fixed-ratios of 1:3, 1:1 and 3:1 exerted additive interaction. LEV combined with LTG exerted additive interaction in the mouse 6 Hz psychomotor seizure model.

Additive Interactions between 1-Methyl-1,2,3,4-Tetrahydroisoquinoline and Clobazam in the Mouse Maximal Electroshock-Induced Tonic Seizure Model - An Isobolographic Analysis for Parallel Dose-Response Relationship Curves

Background: The aim of this study was to characterize the anticonvulsant effect of 1-methyl-1,2,3,4-tetrahydroisoquinoline (1-MeTHIQ) in combination with clobazam (CLB) in the mouse maximal electroshock-induced seizure (MES) model. Methods: The anticonvulsant interaction profile between 1-MeTHIQ and CLB in the mouse MES model was determined using an isobolographic analysis for parallel dose-response relationship curves. Results: Electroconvulsions were produced in albino Swiss mice by a current (sine wave, 25 mA, 500 V, 50 Hz, 0.2-second stimulus duration) delivered via auricular electrodes by a Hugo Sachs generator. There was an additive effect of the combination of 1-MeTHIQ with CLB (at the fixed ratios of 1:3, 1:1 and 3:1) in the mouse MES-induced tonic seizure model. Conclusions: The additive interaction of the combination of 1-MeTHIQ with CLB (at fixed-ratios of 1:3, 1:1 and 3:1) in the mouse MES model seems to be pharmacodynamic in nature and worth of considering in further clinical practice.

Combination Therapy of Piperine and Phenytoin in Maximal Electroshock Induced Seizures in Mice: Isobolographic and Biochemical Analysis

The present study was aimed to characterize the anticonvulsant effects of piperine in combination with well established antiepileptic drug (AED) phenytoin, in the mouse maximal electroshock (MES)-induced seizure model by using the type I isobolographic analysis for non-parallel dose-response relationship curves (DRRCs). Potential adverse-effect profiles of interactions of phenytoin with piperine at the fixed-ratio of 1:1 from the MES test with respect to long-term memory and skeletal muscular strength were evaluated along with free plasma concentration of piperine and phenytoin. Parameters of oxidative stress (glutathione, malondialdehyde), brain serotonin and serum calcium levels were also determined to probe the mechanism involved in the interaction. Test of parallelism revealed that 2 drugs were associated with non-parallel dose response effects, hence only one fixed ratio combination (1:1) was evaluated which displayed additive interaction between the 2 drugs with a slight tendency towards superadditivity. Free plasma concentrations of piperine and phenytoin revealed no significant changes in their concentrations when the drugs were combined at the fixed-ratio of 1:1. In combination, neither long-term memory nor skeletal muscular strength was impaired. Analysis of biochemical parameters showed that the piperine alone or in combination with phenytoin successfully reversed the parameters of oxidative stress and increased brain serotonin levels as compared to MES group. However, no significant alteration in the serum calcium levels was observed by any treatment. In conclusion, the combination displayed additive interaction and slight tendency towards synergistic potential with protection towards side effects associated with AED therapy and is worthy of consideration for further investigations.

Fasting glucose cutoff point: where does the risk terminate? Tehran lipid and glucose study

The aim of this study is to determine safe fasting plasma glucose (FPG) levels. We included data on 5,960 individuals aged ≥20 years at baseline with at least one follow-up examination. Diabetes was ascertained in accordance with American Diabetes Association criteria, using standard 2-h post-challenge plasma glucose test. Multivariate restricted cubic splines Weibull regression was implemented for interval-censored survival data on incident diabetes. We used Harrell's C statistic for discrimination, Nam-D'Agostino χ(2) for calibration, and Royston's R(2) for variations in the outcome explained by models. During a 6-year median follow-up, 369 incident cases of diabetes were ascertained. Family history of diabetes, systolic blood pressure, waist-to-height ratio, and triglyceride-to-high-density lipoprotein cholesterol ratio, independent of FPG and each other remained associated with incident diabetes. The cubic splines model achieved good calibration (χ(2) = 12.1) and discrimination (C = 0.828) and explained 75% of variation in the time until incident diabetes. A J-shaped FPG-diabetes relationship was observed. Descending arm of the dose-response relationship curve corresponded to increasing FPG levels up to 4.0 mmol l(-1), where it started increasing. The risk of incident diabetes decreased with decreasing levels of FPG down to 4.0 mmol l(-1), where the risk stopped decreasing. Multivariate-adjusted risk of incident diabetes was zero at FPG = 5.05 mmol l(-1). Although currently there is no firm evidence to show that early intervention among individuals with the elevated FPG levels could prevent or delay onset of diabetes, individuals with FPG levels below 5.05 mmol l(-1) could be safely reassured about their near-term risk of developing incident diabetes and screened on a less frequent basis.

Additive interactions of pregabalin with lamotrigine, oxcarbazepine and topiramate in the mouse maximal electroshock-induced seizure model: A type I isobolographic analysis for non-parallel dose–response relationship curves

The aim of this study was to characterize the anticonvulsant effects of pregabalin (PGB-a third-generation antiepileptic drug) in combination with three second-generation antiepileptic drugs (i.e., lamotrigine [LTG], oxcarbazepine [OXC] and topiramate [TPM]) in the mouse maximal electroshock (MES)-induced seizure model by using the type I isobolographic analysis for non-parallel dose-response relationship curves (DRRCs). Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25mA, 500V, 50Hz, 0.2s stimulus duration) delivered via auricular electrodes. Potential adverse-effect profiles of interactions of PGB with LTG, OXC and TPM at the fixed-ratio of 1:1 in the MES test with respect to motor performance, long-term memory and skeletal muscular strength were measured. In the mouse MES model, PGB administered singly had its DRRC non-parallel to that for LTG, OXC and TPM. With type I isobolography for non-parallel DRRCs, the combinations of PGB with LTG, OXC and TPM at the fixed-ratio of 1:1 exerted additive interaction. In all combinations, neither motor coordination, long-term memory nor muscular strength were affected. In conclusion, the additive interactions between PGB and LTG, OXC and TPM are worthy of consideration while extrapolating the results from this study to clinical settings.

Interactions of stiripentol with clobazam and valproate in the mouse maximal electroshock-induced seizure model

The aim of this study was to characterize the anticonvulsant effects of stiripentol (STP) in combination with clobazam [CLB], and valproate [VPA]) in the mouse maximal electroshock (MES)-induced seizure model using the type I isobolographic analysis for parallel and non-parallel dose-response relationship curves (DRRCs). Potential adverse-effect profiles of interactions of STP with CLB and VPA at the fixed-ratio of 1:1 in the MES test with respect to motor performance, long-term memory and skeletal muscular strength were measured along with total brain antiepileptic drug concentrations. In the mouse MES model, STP administered singly had its DRRC non-parallel to that for CLB and, simultaneously, parallel to that for VPA. With type I isobolography for parallel DRRCs, the combinations of STP with VPA at three fixed-ratios of 1:3, 1:1 and 3:1 exerted sub-additive (antagonistic) interaction. Isobolography for non-parallel DRRCs revealed that the combination of STP with CLB at the fixed-ratio of 1:1 produced additive interaction. For all combinations, neither motor coordination, long-term memory nor muscular strength was affected. Total brain antiepileptic drug concentrations revealed bi-direction changes with the most profound being an 18.6-fold increase in CLB by STP and a 2.3-fold increase in STP by VPA. In conclusion, the additive interaction between STP and CLB was associated with a concurrent pharmacokinetic interaction and these data may explain the clinical efficacy seen with this combination. In contrast, the antagonism between STP and VPA was surprising since synergism is observed clinically.

Interactions of 1-methyl-1,2,3,4-tetrahydroisoquinoline with lamotrigine, oxcarbazepine, pregabalin, and topiramate in the mouse maximal electroshock-induced seizure model: A type I isobolographic analysis

The aim of this study was to characterize the anticonvulsant effects of 1-methyl-1,2,3,4-tetrahydroisoquinoline (MeTHIQ--an endogenous parkinsonism-preventing substance) in combination with four second-generation antiepileptic drugs (AEDs: lamotrigine [LTG], oxcarbazepine [OXC], pregabalin [PGB], and topiramate [TPM]) in the mouse maximal electroshock (MES)-induced seizure model by using the type I isobolographic analysis for parallel and non-parallel dose-response relationship curves (DRRCs). Potential adverse-effect profiles of interactions of MeTHIQ with LTG, OXC, PGB and TPM at the fixed-ratio of 1:1 from the MES test with respect to motor performance, long-term memory and skeletal muscular strength were measured along with total brain concentrations of MeTHIQ and TPM. In the mouse MES model, MeTHIQ administered singly had its DRRC parallel to those for OXC and TPM, and simultaneously, non-parallel to those for LTG and PGB. With type I isobolography for parallel DRRCs, the combination of MeTHIQ with TPM at three fixed-ratios of 1:3, 1:1 and 3:1 exerted supra-additive (synergistic) interaction, whereas the combination of MeTHIQ with OXC at the fixed-ratios of 1:3, 1:1 and 3:1 produced additive interaction. Similarly, the type I isobolography for non-parallel DRRCs revealed that the combination of MeTHIQ with LTG and PGB at the fixed-ratio of 1:1 produced additive interaction. For all combinations, neither motor coordination, long-term memory nor muscular strength were affected. Total brain concentrations of MeTHIQ and TPM revealed no significant changes in their concentrations when the drugs were combined at the fixed-ratios of 1:3, 1:1 and 3:1. In conclusion, the synergistic interaction of MeTHIQ with TPM at the fixed-ratios of 1:3, 1:1 and 3:1 against MES-induced seizures was pharmacodynamic in nature and thus, it is worthy of consideration in further clinical settings. The combinations of MeTHIQ with LTG, OXC and PGB were neutral in the mouse MES model.