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5‐Aminolevulinic acid (ALA) is a prodrug for protoporphyrin IX (PpIX)‐mediated photodynamic therapy (PDT) and fluorescence‐guided tumor surgery. We previously reported that lapatinib, a repurposed ABCG2 inhibitor, enhanced ALA‐induced PpIX fluorescence and PDT by blocking ABCG2‐mediated PpIX efflux. In the present study, we evaluated how the variation in ABCG2 activities/protein levels affected tumor cell response to the enhancement of PpIX/PDT by lapatinib and Ko143, an ABCG2 tool inhibitor. ABCG2 activities and protein levels were determined in a panel of human cancer cell lines. Effects of lapatinib and Ko143 on enhancing ALA‐PpIX fluorescence and PDT were evaluated and correlated with tumor cell ABCG2 activities. We found that both lapatinib and Ko143 enhanced ALA‐PpIX fluorescence and PDT in a dose‐dependent manner, although lapatinib exhibited lower efficacy and potency than Ko143 in nearly all cancer cell lines. The EC50 of ABCG2 inhibitors for enhancing ALA‐PpIX and PDT had a positive correlation with tumor cell ABCG2 activities, indicating that tumor cell lines with lower ABCG2 activities were more sensitive to ABCG2 inhibitors for PpIX/PDT enhancement. Our results suggest that, for optimal therapeutic enhancement, the dose of ABCG2 inhibitors needs to be tailored based on the ABCG2 expression/activity in tumors. [ABSTRACT FROM AUTHOR]

Grapholita molesta (Busck) is an important pest of pear trees. Numerous esters accumulate consistently in mature pear fruits. However, little is known about the effects of single esters from pear fruits at different concentrations on the responses of male and female G. molesta. In this study, the responses of virgin males, virgin females, and gravid females to five esters (3‐methylbutyl acetate, ethyl hexanoate, ethyl butanoate, butyl acetate, and hexyl acetate) of pear fruits at three dosage levels (1, 5 and 10 μg/μL) were investigated using electroantennography (EAG), wind tunnel experiments, and field tests. Our results showed that ethyl butanoate (5 μg/μL) elicited higher EAG responses in virgin females and males than a mixture of all five volatiles, and elicited an equal EAG response to that for the mixture in gravid females, with all responses to ethyl butanoate and the mixture being higher than the response to hexane alone. For upwind flight, ethyl butanoate (5 μg/μL) excited equal moth flight–location behavior in virgin and gravid females to that for the mixture, which were both higher than the response to hexane. For close flight, ethyl hexanoate (5 μg/μL) and 3‐methylbutyl acetate (10 μg/μL) appeared to be the activating compounds, eliciting equal responses from virgin females to that of the mixture, and higher responses of gravid females to that of the mixture, both of which were higher than the responses to hexane. Upwind and close flight responses of virgin males were lower than those of virgin and gravid females. In field trials, we verified that traps baited with ethyl butanoate (5 μg/μL) captured more moths than the other esters. Therefore, from the esters and concentrations tested, we recommend ethyl butanoate (5 μg/μL) for potential use as an attractant for G. molesta in orchards. [ABSTRACT FROM AUTHOR]

Bone defects are difficult to heal, which conveys a heavy burden to patients' lives and their economy. The total flavonoids of Rhizoma drynariae (TFRD) can promote the osteogenesis of distraction osteogenesis. However, the dose effect is not clear, the treatment period is short, and the quality of bone formation is poor. In our study, we observed the long‐term effects and dose effects of TFRD on bone defects, verified the main ingredients of TFRD in combination with network pharmacology for the first time, explored its potential mechanism, and verified these findings. We found that TFRD management for 12 weeks regulated osteogenesis and angiogenesis in rats with 4‐mm tibial bone defects through the PI3K/AKT/HIF‐1α/VEGF signaling pathway, especially at high doses (135 mg kg−1 d−1). The vascularization effect of TFRD in promoting human umbilical vein endothelial cells was inhibited by PI3K inhibitors. These results provide a reference for the clinical application of TFRD. [ABSTRACT FROM AUTHOR]

This study aimed to quantitatively compare the efficacy of fluticasone furoate (FF) and fluticasone propionate (FP) in adolescents and adults with asthma. We searched the PubMed and EMBASE databases for placebo‐controlled trials that met the inclusion criteria. Pharmacodynamic models were established to describe the time–course of the primary outcome (trough forced expiratory volume in the first second [FEV1]). Secondary outcomes (asthma symptoms, quality of life and exacerbations) were also compared via a meta‐analysis. A total of 14 articles were included in the analysis, involving 6640 subjects. The efficacy plateau of the two drugs could be reached in 2 weeks. The changes from the baseline in trough FEV1 (95% CI) at week 2 of FF at 200 and 100 μg/day were 0.168 L (0.064–0.199) and 0.127 L (0.048–0.163), respectively. The changes from the baseline in trough FEV1 (95% CI) at week 2 of FP at 1000, 500, 250 and 100 μg/day were 0.133 L (0.049–0.171), 0.127 L (0.043–0.163), 0.117 L (0.039–0.150) and 0.093 L (0.032–0.129), respectively. The efficacy of FP had reached a plateau at the maximum evaluated dose (1000 μg/day), while a plateau effect was not seen at the maximum evaluated dose of FF (200 μg/day). In terms of secondary outcomes, the relative effects of the two drugs relative to the placebo were similar and did not show obvious dose–effect relationships. In this study, the time–course and dose–effect characteristics of FP, FF and placebo were quantitatively evaluated, providing necessary quantitative information for asthma‐related guidelines. [ABSTRACT FROM AUTHOR]

Grapholita molesta (Busck) is a menacing pest of fruit trees worldwide. A mixture of glucose, acetic acid, ethanol, and water (GAEWM) has been widely used for monitoring or trapping G. molesta adults. Previous research has shown that acetic acid captures more moths compared to ethanol; however, the respective roles of acetic acid and ethanol in bisexual attraction remain unknown. This study investigated the olfactory behaviours of virgin females, virgin males, and gravid females to variations in nine concentration levels of acetic acid (A) and ethanol (E) for GAEWM using electroantennography, a wind tunnel experiment, and a field test. There was a significant dose‐dependent response by moths to the GAEWM lure variations that affected the range of lure detection and the probability of a moth being trapped. In contrast, adult sex and mating status had the strongest effect on the behaviours associated with flying close to the trap. For medium level dosages of A and E, one combination with acetic acid exceeding ethanol content (A > E; #3, A:E = 3:1) elicited antennal detection by the test adults, and upwind flight of the females. In another combination with ethanol predominating (E > A; #7, A:E = 1:3), the lured traps caught more males than control groups. For low dosages, with the acetic acid level equal to ethanol (A = E; #1, A:E = 1:1), females flew upwind, and virgin females flew around the lure. For high level dosages, with A > E (#6, A:E = 3:2), the antennae of gravid females and virgin males reacted to the lure. These results concluded that the acetic acid to ethanol ratios of either 3:1 or 1:3 in GAEWM has the potential to improve the attraction of both G. molesta sexes to traps. [ABSTRACT FROM AUTHOR]

Human exposure to bisphenols has rarely been reported. The most important challenges in this regard are the sensitivity and accuracy of the analytical methods employed. Dansyl chloride derivatization prior to high‐performance liquid chromatography–tandem mass spectrometry has been prevalently employed to improve sensitivity. However, the dose effect of the derivatization reagent on the reaction products is not well understood, especially for reactants with two or more active groups. This study investigated the mass ratio of dansyl chloride to bisphenols and found the mass ratio played a vital role in changing the composition of derivatives; further, the optimal ratio for obtaining di‐substituted derivatives was confirmed. Under optimal conditions, solid‐phase extraction followed by dansyl chloride derivatization coupled with high‐performance liquid chromatography–tandem mass spectrometry was used to detect eight bisphenols in human serum samples. The method detection limits of the eight bisphenols were 0.025‒0.28 ng/mL, and the recoveries were 72.9‒121.7% by spiking bisphenols (2, 5, and 20 ng/mL) into bovine serum. The detection frequencies of bisphenol A and bisphenol F in 73 serum samples obtained from children from Guangzhou were 41.1% and 71.2%, respectively, while the detection frequencies of other bisphenols were below 20%. The concentrations of bisphenol A and bisphenol F were < 0.28‒8.0 ng/mL and < 0.028‒7.6 ng/mL, respectively. [ABSTRACT FROM AUTHOR]

Background: We studied the relationship between trismus (maximum interincisor opening [MIO] ≤35 mm) and the dose to the ipsilateral masseter muscle (iMM) and ipsilateral medial pterygoid muscle (iMPM). Methods: Pretreatment and post‐treatment measurement of MIO at 13 weeks revealed 17% of trismus cases in 83 patients treated with chemoradiation and intensity‐modulated radiation therapy. Logistic regression models were fitted with dose parameters of the iMM and iMPM and baseline MIO (bMIO). A risk classification tree was generated to obtain optimal cut‐off values and risk groups. Results: Dose levels of iMM and iMPM were highly correlated due to proximity. Both iMPM and iMM dose parameters were predictive for trismus, especially mean dose and intermediate dose volume parameters. Adding bMIO, significantly improved Normal Tissue Complication Probability (NTCP) models. Optimal cutoffs were 58 Gy (mean dose iMPM), 22 Gy (mean dose iMM) and 46 mm (bMIO). Conclusions: Both iMPM and iMM doses, as well as bMIO, are clinically relevant parameters for trismus prediction. [ABSTRACT FROM AUTHOR]

Empirical evidence for the effectiveness of long-term psychodynamic psychotherapy (LTPP) in patients with mood disorders is growing. However, it is unclear whether the effectiveness of LTPP is due to distinctive features of psychodynamic/psychoanalytic techniques or to a higher number of sessions. We tested these rival hypotheses in a quasi-experimental study comparing psychoanalytic therapy (i.e., high-dose LTPP) with psychodynamic therapy (i.e., low-dose LTPP) and cognitive-behavioural therapy (CBT) for depression. Analyses were based on a subsample of 77 subjects, with 27 receiving psychoanalytic therapy, 26 receiving psychodynamic therapy and 24 receiving CBT. Depressive symptoms, interpersonal problems and introject affiliation were assessed prior to treatment, after treatment and at the 1-, 2- and 3-year follow-ups. Psychoanalytic techniques were assessed from three audiotaped middle sessions per treatment using the Psychotherapy Process Q-Set. Subjects receiving psychoanalytic therapy reported having fewer interpersonal problems, treated themselves in a more affiliative way directly after treatment and tended to improve in depressive symptoms and interpersonal problems during follow-up as compared with patients receiving psychodynamic therapy and/or CBT. Multilevel mediation analyses suggested that post-treatment differences in interpersonal problems and introject affiliation were mediated by the higher number of sessions, and follow-up differences in depressive symptoms were mediated by the more pronounced application of psychoanalytic techniques. We also found some evidence for indirect treatment effects via psychoanalytic techniques on changes in introject affiliation during follow-up. These results provide support for the prediction that both a high dose and the application of psychoanalytic techniques facilitate therapeutic change in patients with major depression. [ABSTRACT FROM AUTHOR]

Objective The current study used multilevel growth mixture modeling to ascertain groups of patients who had similar trajectories in their psychological functioning over the course of short-term treatment. Method A total of 10,854 clients completed a measure of psychological functioning before each session. Psychological functioning was measured by the Behavioral Health Measure, which is an index of well-being, symptoms, and life-functioning. Clients who attended 5 to 25 sessions at 46 different university/college counseling centers and one community mental health center were included in this study. Client diagnoses and the specific treatment approaches were not known. Results A 3-class solution was a good fit to the data. Clients in classes 1 and 3 had moderate severity in their initial psychological functioning scores, and clients in class 2 had more distressed psychological functioning scores. The trajectory for clients in class 1 was typified by early initial change, followed by a plateau, and then another gain in psychological functioning later in treatment. The trajectory for clients in class 2 demonstrated an initial decrease in functioning, followed by a rapid increase, and then a plateau. Last, the clients in class 3 had a steady increase of psychological functioning, in a more linear manner. Conclusion The trajectories of change for clients are diverse, and they can ebb and flow more than traditional dose-effect and good-enough level models may suggest. [ABSTRACT FROM AUTHOR]

ABSTRACT Over one hundred VPS13B mutations are reported in Cohen syndrome (CS). Most cases exhibit a homogeneous phenotype that includes intellectual deficiency (ID), microcephaly, facial dysmorphism, slender extremities, truncal obesity, progressive chorioretinal dystrophy, and neutropenia. We report on a patient carrying two VPS13B splicing mutations with an atypical phenotype that included microcephaly, retinopathy, and congenital neutropenia, but neither obesity nor ID. RNA analysis of the IVS34+2T_+3AinsT mutation did not reveal any abnormal splice fragments but mRNA quantification showed a significant decrease in VPS13B expression. RNA sequencing analysis up- and downstream from the IVS57+2T>C mutation showed abnormal splice isoforms. In contrast to patients with typical CS, who express only abnormal VPS13B mRNA and truncated protein, a dose effect of residual normal VPS13B protein possibly explains the incomplete phenotype in the patient. This observation emphasizes that VPS13B analysis should be performed in cases of congenital neutropenia associated with retinopathy, even in the absence of ID, therefore extending the VPS13B phenotype spectrum. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Study Objective To explore the effects of metformin dose on cancer risk reduction in patients with type 2 diabetes. Design Population-based cohort study. Data Source National Health Insurance program Longitudinal Health Insurance Database. Patients A total of 65,754 age- and gender-matched patients without diabetes and no previous cancer diagnosis were extracted from the database. Measurements and Main Results We compared cancer risk among the subjects who had no diabetes, had type 2 diabetes but were not on diabetes drugs, used metformin only, used antidiabetic drugs other than metformin, or used metformin in combination with other antidiabetic drugs. Our results revealed dose-dependent effects of metformin on cancer risk and cancer onset times. A significant decrease in cancer risk was found in the monotherapy group who received more than 360 defined daily doses ( DDDs) of metformin (hazard ratio [ HR] 0.40, 95% confidence interval [ CI] 0.24-0.66). The greatest decrease in cancer risk was observed in patients who took more than 1080 DDDs ( HR 0.27, 95% CI 0.09-0.84). Significantly greater dose-dependent effects were seen in patients who used metformin in combination with other antidiabetic drugs. Conclusion The magnitude of cancer risk reduction and prolonged cancer onset times produced by metformin in patients with type 2 diabetes depended on the dose of metformin, regardless of whether metformin was used alone or combined with other antidiabetic drugs. [ABSTRACT FROM AUTHOR]

Abstract: Low molecular weight heparins (LMWHs) are used for prevention of clotting in the dialysis circuit. The aim of this trial was to define the optimal dose of a new LMWH and to test the efficiency of a single dose at the start of the session. Fifteen patients were treated according to a double blind and crossover design during 4 blocks of 5 consecutive reviparin doses assigned randomly as 50, 60, 70, 85, and 100 IU anti-Xa/kg. Assessment was carried out on screening of fibrin rings or clots in the arterial and venous air traps and on visual detection of fiber in the dialyzer after rinsing. These clinical results were compared to plasmatic anti-Xa activity and thrombin-antithrombin (TAT) complex generation. A standard dose of 70 IU anti-Xa/kg of nadroparin was used as the control. After a bolus of 50 to 100 IU anti-Xa/kg, the occurrence of fibrin rings and clots in the air traps was dependent on three factors: dose of LMWH, time of the session, and patient status. A bolus of 85 IU anti-Xa/kg of reviparin was effective and safe for sessions of 4 h. For this dose, plasmatic anti-Xa activity was 0.96 ± 0.28 IU/ml at Hour 2 and 0.82 ± 0.22 IU/ml at Hour 4. TAT complexes are good markers of the activation of the coagulation. They did not increase during a 4 h session after a reviparin bolus of 100 IU/kg. For the same LMWH dose, the trial shows a great variability of the clinical effect and anti-Xa activities from one patient to another. A single dose of 85 IU anti-Xa/kg of reviparin can be used at the start of the dialysis session as a loading dose. We advise adapting the dose during the subsequent sessions according to the appearance of the blood circuit. The benefit of monitoring anti-Xa activity and TAT complexes could be tested in a further trial. [ABSTRACT FROM AUTHOR]

Over one hundred VPS13B mutations are reported in Cohen syndrome (CS). Most cases exhibit a homogeneous phenotype that includes intellectual deficiency (ID), microcephaly, facial dysmorphism, slender extremities, truncal obesity, progressive chorioretinal dystrophy, and neutropenia. We report on a patient carrying two VPS13B splicing mutations with an atypical phenotype that included microcephaly, retinopathy, and congenital neutropenia, but neither obesity nor ID. RNA analysis of the IVS34+2T&#95;+3AinsT mutation did not reveal any abnormal splice fragments but mRNA quantification showed a significant decrease in VPS13B expression. RNA sequencing analysis up- and downstream from the IVS57+2T>C mutation showed abnormal splice isoforms. In contrast to patients with typical CS, who express only abnormal VPS13B mRNA and truncated protein, a dose effect of residual normal VPS13B protein possibly explains the incomplete phenotype in the patient. This observation emphasizes that VPS13B analysis should be performed in cases of congenital neutropenia associated with retinopathy, even in the absence of ID, therefore extending the VPS13B phenotype spectrum., (© 2013 Wiley Periodicals, Inc.)