Giardia intestinalis extracellular vesicles induce changes in gene expression in human intestinal epithelial cells in vitro.

Giardiasis is a common waterborne zoonotic disease caused by Giardia intestinalis. Upon infection, Giardia releases excretory and secretory products (ESPs) including secreted proteins (SPs) and extracellular vesicles (EVs). Although the interplay between ESPs and intestinal epithelial cells (IECs) has been previously described, the functions of EVs in these interactions and their differences from those of SPs require further exploration. In the present study, EVs and EV-depleted SPs were isolated from Giardia ESPs. Proteomic analyses of isolated SPs and EVs showed 146 and 91 proteins, respectively. Certain unique and enriched proteins have been identified in SPs and EVs. Transcriptome analysis of Caco-2 cells exposed to EVs showed 96 differentially expressed genes (DEGs), with 56 upregulated and 40 downregulated genes. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) indicated that Caco-2 genes related to metabolic processes, the HIF-1 signaling pathway, and the cAMP signaling pathway were affected. This study provides new insights into host-parasite interactions, highlighting the potential significance of EVs on IECs during infections.

Air-Assisted Electrospinning of Dihydromyricetin-Loaded Dextran/Zein/Xylose Nanofibers and Effects of the Maillard Reaction on Fiber Properties.

Dihydromyricetin (DMY) has been encapsulated in delivery systems to address the solubility limitations of DMY in water and improve its bioavailability. Air-assisted electrospinning has been used as a novel technology to load DMY. To evaluate the impact of adding DMY to dextran/zein nanofibers and understand the effects of the Maillard reaction (MR) on the physical and functional properties of DMY-loaded nanofibers, dextran/zein/xylose nanofibers with 0%, 1%, 2%, 3%, and 4% DMY were fabricated, followed by MR crosslinking. Scanning electron microscopy (SEM) observations indicated that the addition of DMY and the MR did not affect the morphology of the nanofibers. X-ray diffraction (XRD) results indicated amorphous dispersion of DMY within the nanofibers and a decreased crystalline structure within the nanofibers following the MR, which might improve their molecular flexibility. The nanofibrous film formed after the MR exhibited both increased tensile strength and elastic modulus due to hydrogen bonding within the nanofibers and increased elongation at break attributed to the increased amorphization of the structure after crosslinking. The nanofibers were also found to exhibit improved heat stability after the MR. The antioxidant activity of the nanofibers indicated a dose-dependent effect of DMY on radical scavenging activity and reducing power. The maintenance of antioxidant activity of the nanofibers after the MR suggested heat stability of DMY during heat treatment. Overall, dextran/zein nanofibers with various DMY contents exhibited tunable physical properties and effective antioxidant activities, indicating that dextran/zein nanofibers offer a successful DMY delivery system, which can be further applied as an active package.

Efficacy and safety of low-dose cyclophosphamide combined with lenvatinib, pembrolizumab and TACE for unresectable hepatocellular carcinoma: A single-center, prospective, single-arm clinical trial.

Objective: Unresectable hepatocellular carcinoma (uHCC) continues to pose effective treatment options. The objective of this study was to assess the efficacy and safety of combining low-dose cyclophosphamide with lenvatinib, pembrolizumab and transarterial chemoembolization (TACE) for the treatment of uHCC. Methods: From February 2022 to November 2023, a total of 40 patients diagnosed with uHCC were enrolled in this small-dose, single-center, single-arm, prospective study. They received a combined treatment of low-dose cyclophosphamide with lenvatinib, pembrolizumab, and TACE. Study endpoints included progression-free survival (PFS), objective response rate (ORR), and safety assessment. Tumor response was assessed using the modified Response Evaluation Criteria in Solid Tumors (mRECIST), while survival analysis was conducted through Kaplan-Meier curve analysis for overall survival (OS) and PFS. Adverse events (AEs) were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). Results: A total of 34 patients were included in the study. The median follow-up duration was 11.2 [95% confidence interval (95% CI), 5.3-14.6] months, and the median PFS (mPFS) was 15.5 (95% CI, 5.4-NA) months. Median OS (mOS) was not attained during the study period. The ORR was 55.9%, and the disease control rate (DCR) was 70.6%. AEs were reported in 27 (79.4%) patients. The most frequently reported AEs (with an incidence rate >10%) included abnormal liver function (52.9%), abdominal pain (44.1%), abdominal distension and constipation (29.4%), hypertension (20.6%), leukopenia (17.6%), constipation (17.6%), ascites (14.7%), and insomnia (14.7%). Abnormal liver function (14.7%) had the most common grade 3 or higher AEs. Conclusions: A combination of low-dose cyclophosphamide with lenvatinib, pembrolizumab, and TACE is safe and effective for uHCC, showcasing a promising therapeutic strategy for managing uHCC.

Advancements in understanding mechanisms of hepatocellular carcinoma radiosensitivity: A comprehensive review.

Primary liver cancer is a significant health problem worldwide. Hepatocellular carcinoma (HCC) is the main pathological type of primary liver cancer, accounting for 75%-85% of cases. In recent years, radiotherapy has become an emerging treatment for HCC and is effective for various stages of HCC. However, radiosensitivity of liver cancer cells has a significant effect on the efficacy of radiotherapy and is regulated by various factors. How to increase radiosensitivity and improve the therapeutic effects of radiotherapy require further exploration. This review summarizes the recent research progress on the mechanisms affecting sensitivity to radiotherapy, including epigenetics, transportation and metabolism, regulated cell death pathways, the microenvironment, and redox status, as well as the effect of nanoparticles on the radiosensitivity of liver cancer. It is expected to provide more effective strategies and methods for clinical treatment of liver cancer by radiotherapy.

HABP4 overexpression promotes apoptosis in goat turbinate bone cells.

Hyaluronic acid-binding protein (HABP4) plays important roles in regulating cell cycle and apoptosis. However, its functions in regulating cell apoptosis remain unclear. To reveal the effects of HABP4 on cell proliferation, cell cycle and apoptosis, the HABP4 sequence was cloned, and we investigated the gain and loss functions of HABP4 in goat turbinate bone cells. Our results showed that a 1,496-bp HABP4 sequence was cloned successfully. The interference effect of siRNA1 on HABP4 was the strongest, reducing its mRNA expression level by 83%, decreasing the cells in the G0/G1 and S phases of the cell cycle and inhibiting cell growth and apoptosis. The overexpression of HABP4 produced contrasting results. Furthermore, an HABP4 knockdown caused the up-regulated expression of genes associated with apoptosis, including Bcl-2 and BCL2L11, but the down-regulation of Caspase3, Caspase7, Bax, PARP1, SOCS2 and P53 mRNA levels. Additionally, HABP4 overexpression significantly up-regulated the expression levels of Bax, Caspase3, Caspase7, BCL2L11, P53, SOCS2 and PARP1. However, the expression of Bcl-2 was down-regulated. These data provide an important foundation for further in-depth studies of HABP4 functions.

Is adjuvant chemotherapy necessary for locally advanced rectal cancer patients with pathological complete response after neoadjuvant chemoradiotherapy and radical surgery? A systematic review and meta-analysis.

PURPOSE: Current clinical guidelines recommended the routine use of adjuvant chemotherapy for locally advanced rectal cancer (LARC) patients. However, the effects of adjuvant chemotherapy in patients with pathological complete response (pCR) after neoadjuvant chemoradiotherapy and radical surgery showed discrepancies in different investigations. METHODS: A systematic review and meta-analysis were conducted using PubMed, Embase and Web of Science databases. All original comparative studies published in English that were related to adjuvant versus non-adjuvant chemotherapy for LARC patients with pCR were included. RESULTS: A total of 6 studies based on 18 centres or databases involving 2948 rectal cancer patients with pCR (adjuvant group = 1324, non-adjuvant group = 1624) were included in our overall analysis. Based on our meta-analysis, LARC patients with pCR who received adjuvant chemotherapy showed a significantly improved overall survival (OS) when compared to patients with observation (HR = 0.65, 95% CI = 0.46-0.90, P = 0.01). In addition, investigations focused on this issue based on the National Cancer Database (NCDB) were systematically reviewed in our current study. Evidence from all three analyses demonstrated that LARC patients with clinical nodal positive disease that achieved pCR might benefit the most from additional adjuvant chemotherapy. CONCLUSION: Our meta-analysis indicated that adjuvant chemotherapy is associated with improved OS in LARC patients with pCR after neoadjuvant chemoradiotherapy and radical surgery.

Antitumor effect of axitinib combined with dopamine and PK-PD modeling in the treatment of human breast cancer xenograft.

Rising evidence has shown the development of resistance to vascular endothelial growth factor receptor (VEGFR) inhibitors in the practices of cancer therapy. It is reported that the efficacy of axitinib (AX), a VEGFR inhibitor, is limited in the treatment of breast cancer as a single agent or in combination with other chemotherapeutic drugs due to the probability of rising population of cancer stem-like cells (CSCs) caused by AX. The present study evaluated the effect of dopamine (DA) improving AX's efficacy on MCF-7/ADR breast cancer in vitro and in vivo, and developed a pharmacokinetic-pharmacodynamic (PK-PD) model describing the in vivo experimental data and characterizing the interaction of effect between AX and DA. The results showed that AX up-regulated the expression of breast CSC (BCSC) markers (CD44+/CD24-/low) in vivo, and DA significantly synergized the inhibitory effect on tumor growth by deducting the BCSC frequency. The PK-PD model quantitatively confirmed the synergistic interaction with the parameter estimate of interaction factor ψ 2.43. The dose regimen was optimized as 60 mg/kg AX i.g. b.i.d. combined with 50 mg/kg DA i.p. q3d in the simulation study on the basis of the PK-PD model. The model where DA synergistically enhances the effect of AX in an all-or-none manner provides a possible solution in modeling the agents like DA. Moreover, the outcome of AX and DA combination therapy in MCF-7/ADR breast cancer provided further insight of co-administering DA in the treatment of the possible CSC-causing AX-resisting breast cancer. And this combination therapy has the prospect of clinical translation.

Determination of multi-class antibiotic residues in compost by microwave-enhanced accelerated solvent extraction and ultra performance convergence chromatography with tandem mass spectrometry.

This work reports the development and application of a multi-class compound analysis method for the determination of 20 antibiotic residues in compost. Samples were processed by microwave-enhanced accelerated solvent extraction at 120°C for 7.5 min. Salting-out homogeneous liquid-liquid extraction was used to remove water and water-soluble impurities from the extract before ultra performance convergence chromatography with tandem mass spectrometry analysis. By using the supercritical fluid (carbon dioxide) and organic solvent (methanol) as the mobile phase, the 20 antibiotics and the internal standard were well separated in 8.2 min without obvious matrix effect. Method validation was performed and good trueness (relative error in the range of ±5.0%) and precision (inter- and intraday relative standard deviations < 10.8%) were obtained. Method detection and quantitation limits were 0.8-1.9 and 2.7-7.1 ng/g, respectively. Recoveries were assessed at three concentration levels (10, 60, and 400 ng/g) and acceptable mean values (70.4-111.9%) were found. This method has also been used to analyze real samples, and the average concentrations of antibiotics (excepting the concentrations < method quantitation limits) were determined up to 123.6 ng/g. The results showed the method could be helpful for the analysis of multi-class antibiotics in environmental samples.

Integrated pharmacokinetic/viral dynamic model for daclatasvir/asunaprevir in treatment of patients with genotype 1 chronic hepatitis C.

In order to develop an integrated pharmacokinetic/viral dynamic (PK/VD) model to predict long-term virological response rates to daclatasvir (DCV) and asunaprevir (ASV) combination therapy in patients infected with genotype 1 (GT1) chronic hepatitis C virus (HCV), a systematic publication search was conducted for DCV and ASV administered alone and/or in combination in healthy subjects or patients with GT1 HCV infection. On the basis of a constructed meta-database, an integrated PK/VD model was developed, which adequately described both DCV and ASV PK profiles and viral load time curves. The IC50 values of DCV and ASV were estimated to be 0.041 and 2.45 µg/L, respectively, in GT1A patients. A sigmoid Emax function was applied to describe the antiviral effects of DCV and ASV, depending on the drug concentrations in the effect compartment. An empirical exponential function revealed that IC50 changing over time described drug resistance in HCV GT1A patients during DCV or ASV monotherapy. Finally, the PK/VD model was evaluated externally by comparing the expected and observed virological response rates during and post-treatment with DCV and ASV combination therapy in HCV GT1B patients. Both the rates were in general agreement. Our PK/VD model provides a useful platform for the characterization of pharmacokinetic/pharmacodynamic relationships and the prediction of long-term virological response rates to aid future development of direct acting antiviral drugs.

MicroRNA-382 inhibits cell growth and migration in colorectal cancer by targeting SP1.

BACKGROUND: Emerging evidence showed that microRNAs (miRs) play critical roles in human cancers by functioning as either tumor suppressor or oncogene. MIR-382 was found to function as tumor suppressor in certain cancers. However, the role of MIR-382 in colorectal cancer (CRC) is largely unknown. Specificity protein 1 (SP1) is highly expressed in several cancers including CRC and is correlated with poor prognosis, but it is unclear whether or not MIR-382 can regulate the expression of SP1. METHODS: MIR-382 expression level was measured by reverse transcription-quantitative polymerase chain reaction. The connection between MIR-382 and SP1 was validated by luciferase activity reporter assay and western blot assay. Cell counting kit-8 assay and wound-healing assay were conducted to investigate the biological functions of MIR-382 in CRC. RESULTS: In this study, we found MIR-382 expression was downregulated in CRC tissues and cell lines, and the transfection of MIR-382 mimic decreased cell growth and migration. Furthermore, we identified SP1 was a direct target of MIR-382. Overexpression of MIR-382 decreased the expression of SP1, whereas MIR-382 knockdown promoted SP1 expression. We also observed an inversely correlation between MIR-382 and SP1 in CRC tissues. Additionally, we showed that knockdown of SP1 inhibited cell growth and migration and attenuated the effect of MIR-382 inhibitor on cell behaviors. CONCLUSIONS: In conclusion, the present study describes a potential mechanism underlying a MIR-382/SP1 link contributing to CRC development. Thus, MIR-382 may be able to be developed as a novel treatment target for CRC.

Tibiofemoral Contact Mechanics With Horizontal Cleavage Tears and Treatment of the Lateral Meniscus in the Human Knee: An In Vitro Cadaver Study.

BACKGROUND: Partial meniscectomy is one of the most commonly performed orthopaedic procedures for a meniscus tear. Decreased contact area and increased contact pressure have been seen in partial meniscectomies from treatment of various types of meniscal tears; however, the biomechanical effect of a horizontal cleavage tear in the lateral meniscus and subsequent treatment are unknown. QUESTIONS/PURPOSES: This study asked whether a horizontal cleavage tear of the lateral meniscus, resecting the inferior leaf, and further resecting the superior leaf would (1) decrease contact area and (2) increase peak contact pressure. METHODS: Eleven fresh-frozen human cadaveric knees were evaluated under five conditions of intact meniscus, horizontal cleavage tear, inferior leaf resection, and resection of the inferior and superior leaves of the lateral meniscus. Tibiofemoral contact area and pressure were measured at 0° and 60° knee flexion under an 800-N load, normalized to that at the intact condition of the corresponding knee flexion, and compared across the five previously described conditions. RESULTS: At 0° knee flexion, normalized contact area with inferior leaf resection (65.4% ± 14.1%) was smaller than that at the intact condition (100% ± 0.0%, p < 0.001); smaller than horizontal cleavage tear (94.1% ± 5.8%, p = 0.001) contact area; and smaller than repaired horizontal tear (92.8% ± 8.2%, p = 0.001) contact area. Normalized contact area with further superior leaf resection (50.5% ± 7.3%) was smaller than that at the intact condition (100% ± 0.0%, p < 0.001); smaller than horizontal cleavage tear (94.1% ± 5.8%, p < 0.001) contact area; and smaller than repaired horizontal tear (92.8% ± 8.2%, p < 0.001) contact area. At 60° flexion, normalized contact area with inferior leaf resection (76.1% ± 14.8%) was smaller than that at the intact condition (100% ± 0.0%, p = 0.004); smaller than horizontal cleavage tear (101.8% ± 7.2%, p = 0.006) contact area; and smaller than repaired horizontal tear (104.0% ± 13.3%, p < 0.001) contact area. Normalized contact area with further superior leaf resection (52.1% ± 16.7%) was smaller than that at the intact condition (100% ± 0.0%, p < 0.001); smaller than horizontal cleavage tear (101.8% ± 7.2%, p < 0.001) contact area; and smaller than repaired horizontal tear (104.0% ± 13.3%, p < 0.001) contact area. At 60° flexion, contact area with both leaf resection (52.1% ± 16.7%) was smaller than that with inferior leaf resection (76.1% ± 14.8%, p = 0.039). At 0° knee flexion, peak pressure increased to 127.0% ± 22.1% with inferior leaf resection (p = 0.026) and to 138.6% ± 24.3% with further superior leaf resection (p = 0.002) compared with that at the intact condition (100% ± 0.0%). At 60° flexion, compared with that at the intact condition (100% ± 0.0%), peak pressure increased to 139% ± 33.6% with inferior leaf resection (p = 0.035) and to 155.5% ± 34.7% (p = 0.004) with further superior leaf resection. CONCLUSIONS: Resection of the inferior leaf or both leaves of the lateral meniscus after a horizontal cleavage tear resulted in decreased contact area and increased peak contact pressure at 0° and 60° knee flexion. CLINICAL RELEVANCE: In vitro resection of one or both leaves of a horizontal cleavage tear of the lateral meniscus causes increases in peak pressure, consistent with other types of partial meniscectomies associated in a clinical setting with excessive loading and damage to knee cartilage. Clinical outcomes in patients undergoing partial leaf meniscectomy could confirm this theory. Avoidance of resection may be relatively beneficial for long-term function. The findings of this in vitro study lend biomechanical support for nonoperative management.

lgtF effects of Haemophilus parasuis LOS induced inflammation through regulation of NF-κB and MAPKs signaling pathways.

The lgtF gene encodes a glucosyltransferase responsible for adding a glucose to the first sugar of heptose I in the synthesis of lipooligosaccharides (LOS). To study the function of lgtF, we constructed an lgtF mutant (ΔlgtF) from Haemophilus parasuis SC096 using a natural transformation system. A highly purified preparation of LOS from ΔlgtF (ΔlgtF-LOS) exhibited an obvious truncation in structure compared to the LOS of the wild-type SC096 strain (WT-LOS). The ΔlgtF-LOS also displayed a significantly reduced ability to induce inflammatory cytokine mRNA expression of tumor necrosis factor alpha (TNF-α), interleukin-1α (IL-1α), IL-1ß, IL-6 and IL-8 in porcine alveolar macrophages (PAMs) in comparison with the WT-LOS. Furthermore, we also found that ΔlgtF-LOS-treated cells had significantly decreased phospho-p65 and phospho-p38, and inhibited IκBα degradation. These findings suggested that the lgtF gene mediated LOS induction of pro-inflammatory cytokines in PAMs by regulating the NF-κB and MAPKs signaling pathways during H. parasuis infection.

Isolation and characterization of a new enterovirus F in yak feces in the Qinghai-Tibetan Plateau.

An enterovirus (EV) strain, designated as SWUN-AB001, was isolated in the Qinghai-Tibetan Plateau from a yak with severe diarrheal disease. The complete genome of strain SWUN-AB001 was 7,382 bp in length and shared 35.1-68.5% nt identities with bovine EVs belonging to a candidate new type EV-F7. Using the sequence difference values in the VP1 gene as a criterion for demarcating a new serotype/genotype in the Enterovirus genus, strain SWUN-AB001 had only a 71.1% nt and a 79.2% aa identity, in the VP1 region, with the most closely matched EV, further indicating that a new type of EV had been identified. Phylogenetic analysis of the nt sequence of the viral polyprotein and of VP1 genes demonstrated that the virus fell within the EV-F cluster, but was located in a unique lineage. Furthermore, a large-scale surveillance study indicated that the prevalence of this EV in yaks was 31.05% (95% CI = 25.5-37.6%) in 235 animals with diarrhea and 24.13% (95% CI = 17.4-32.4%) in 116 healthy yaks. However, there was no significant difference in virus prevalence between diarrheal and healthy samples. Interestingly, in the Tibet region, diarrheal feces had a higher incidence of EVs than feces of healthy yaks (odd ratios = 6.03, 95% CI = 1.93-18.86), indicating that the incidence of EV was potentially correlated with the clinical symptom of diarrhea in yaks.

Preclinical PK/PD model for combined administration of erlotinib and sunitinib in the treatment of A549 human NSCLC xenograft mice.

AIM: Combined therapy of EGFR TKI and VEGFR TKI may produce a greater therapeutic benefit and overcome EGFR TKI-induced resistance. However, a previous study shows that a combination of EGFR TKI erlotinib (ER) with VEGFR TKI sunitinib (SU) did not improve the overall survival in patients with non-small-cell lung cancer (NSCLC). In this study we examined the anticancer effect of ER, SU and their combination in the treatment of A549 human NSCLC xenograft mice, and conducted PK/PD modeling and simulations to optimize the dose regimen. METHODS: ER (20, 50 mg·kg(-1)·d(-1)) or SU (5, 10, 20 mg·kg(-1)·d(-1)) alone, or their combination were administered to BALB/c nude mice bearing A549 tumors for 22 days. The tumor size and body weight were recorded daily. The experimental data were used to develop PK/PD models describing the quantitative relationship between the plasma concentrations and tumor suppression in different dose regimens. The models were further evaluated and validated, and used to predict the efficacy of different combination regimens and to select the optimal regimen. RESULTS: The in vivo anticancer efficacy of the combination groups was much stronger than that of either drug administered alone. A PK/PD model was developed with a combination index (φ) of 4.4, revealing a strong synergistic effect between ER and SU. The model simulation predicted the tumor growth in different dosage regimens, and showed that the dose of SU played a decisive role in the combination treatment, and suggested that a lower dose of ER (≤5 mg·kg(-1)·d(-1)) and adjusting the dose of SU might yield a better dosage regimen for clinical research. CONCLUSION: The experimental data and modeling confirm synergistic anticancer effect of ER and SU in the treatment of A549 xenograft mice. The optimal dosage regimen determined by the PK/PD modeling and simulation can be used in future preclinical study and provide a reference for clinical application.

Home-Based Versus Laboratory-Based Robotic Ankle Training for Children With Cerebral Palsy: A Pilot Randomized Comparative Trial.

OBJECTIVE: To examine the outcomes of home-based robot-guided therapy and compare it to laboratory-based robot-guided therapy for the treatment of impaired ankles in children with cerebral palsy. DESIGN: A randomized comparative trial design comparing a home-based training group and a laboratory-based training group. SETTING: Home versus laboratory within a research hospital. PARTICIPANTS: Children (N=41) with cerebral palsy who were at Gross Motor Function Classification System level I, II, or III were randomly assigned to 2 groups. Children in home-based and laboratory-based groups were 8.7±2.8 (n=23) and 10.7±6.0 (n=18) years old, respectively. INTERVENTIONS: Six-week combined passive stretching and active movement intervention of impaired ankle in a laboratory or home environment using a portable rehabilitation robot. MAIN OUTCOME MEASURES: Active dorsiflexion range of motion (as the primary outcome), mobility (6-minute walk test and timed Up and Go test), balance (Pediatric Balance Scale), Selective Motor Control Assessment of the Lower Extremity, Modified Ashworth Scale (MAS) for spasticity, passive range of motion (PROM), strength, and joint stiffness. RESULTS: Significant improvements were found for the home-based group in all biomechanical outcome measures except for PROM and all clinical outcome measures except the MAS. The laboratory-based group also showed significant improvements in all the biomechanical outcome measures and all clinical outcome measures except the MAS. There were no significant differences in the outcome measures between the 2 groups. CONCLUSIONS: These findings suggest that the translation of repetitive, goal-directed, biofeedback training through motivating games from the laboratory to the home environment is feasible. The benefits of home-based robot-guided therapy were similar to those of laboratory-based robot-guided therapy.

Baseline Sensitivity of Botrytis cinerea to the Succinate Dehydrogenase Inhibitor Isopyrazam and Efficacy of this Fungicide.

Isopyrazam is a new broad-spectrum, foliar-absorbed and -translocated succinate dehydrogenase inhibitor fungicide. In this study, 159 Botrytis cinerea isolates collected from different geographical regions of Shandong Province of China were characterized for baseline sensitivity to isopyrazam. Furthermore, the protective and curative activity of isopyrazam on strawberry fruit and the control efficacy in the field were also determined. In contrast to its mycelial growth, the spore germination of B. cinerea was inhibited completely by lower concentrations of isopyrazam, about 1 µg ml-1 on yeast-peptone-acetate medium. Frequency distributions of isopyrazam 50% effective concentration (EC50) values were unimodal curves, with mean EC50 values of 0.07 ± 0.04 (standard deviation) and 0.68 ± 0.36 µg ml-1 for the inhibition of spore germination and mycelial growth, respectively. In addition, there was no positive multiple resistance between isopyrazam and other classes of botryticides such as diethofencarb, iprodione, pyrimethanil, or SYP-Z048. In field trials conducted during 2014 and 2015, isopyrazam used at a concentration of active ingredient at 150 and 200 g ha-1 provided a control efficacy ranging from 76.7 to 87.8% on leaves and from 81.5 to 90.7% on fruit. These results suggest that isopyrazam has the potential to play an important role in the management of gray mold.

Lower-Limb Muscle-Activation Patterns During Off-Axis Elliptical Compared With Conventional Gluteal-Muscle-Strengthening Exercises.

CONTEXT: Gluteal-muscle strength has been identified as an important component of injury prevention and rehabilitation in several common knee injuries. However, many conventionally prescribed gluteal-strengthening exercises are not performed during dynamic weight-bearing activities, which is when most injuries occur. OBJECTIVES: To compare lower-limb muscle-activation patterns between conventional gluteal-strengthening exercises and off-axis elliptical exercises with motorized foot-plate perturbations designed to activate gluteal muscles during dynamic exercise. EVIDENCE ACQUISITION: Twelve healthy volunteers (26.1 ± 4.7 y) participated in the study. They performed 3 conventional exercises (single-leg squat, forward lunge, and clamshell) and 3 elliptical exercises (regular, while resisting an adduction force, and while resisting an internal-rotation torque). Gluteus medius (GMed) and maximus (GMax), quadriceps, hamstrings, and gastrocnemius muscle activations during each exercise were recorded using surface electromyography (EMG) and normalized to maximal voluntary isometric contraction (MVIC). EVIDENCE SYNTHESIS: Normalized GMed EMG was the highest during the adduction-resistance elliptical exercise (22.4% ± 14.8% MVIC), significantly greater than forward lunge (8.2% ± 3.8% MVIC) and regular elliptical (6.4% ± 2.5% MVIC) and similar to clamshell (19.1% ± 8.8% MVIC) and single-leg squat (18.4% ± 7.9% MVIC). Normalized GMax EMG during adduction-resistance (11.1% ± 7.6% MVIC) and internal-rotation-resistance elliptical (7.4% ± 3.8% MVIC) was significantly greater than regular elliptical (4.4% ± 2.4% MVIC) and was similar to conventional exercises. The single-leg squat required more muscle activation from the quadriceps and gastrocnemius than the elliptical exercises. CONCLUSIONS: Off-axis elliptical exercise while resisting an adduction force or internal-rotation torque activates gluteal muscles dynamically while avoiding excessive quadriceps activation during a functional weight-bearing activity compared with conventional gluteal-strengthening exercises.

Comparison of modern locked plating and antiglide plating for fixation of osteoporotic distal fibular fractures.

BACKGROUND: Fractures in osteoporotic patients can be difficult to treat because of poor bone quality and inability to gain screw purchase. The purpose of this study is to compare modern lateral periarticular distal fibula locked plating to antiglide plating in the setting of an osteoporotic, unstable distal fibula fracture. METHODS: AO/OTA 44-B2 distal fibula fractures were created in sixteen paired fresh frozen cadaveric ankles and fixed with a lateral locking plate and an independent lag screw or an antiglide plate with a lag screw through the plate. The specimens underwent stiffness, cyclic loading, and load to failure testing. The energy absorbed until failure, torque to failure, construct stiffness, angle at failure, and energy at failure was recorded. RESULTS: The lateral locking construct had a higher torque to failure (p=0.02) and construct stiffness (p=0.04). The locking construct showed a trend toward increased angle at failure, but did not reach statistical significance (p=0.07). Seven of the eight lateral locking plate specimens failed through the distal locking screws, while the antiglide plating construct failed with pullout of the distal screws and displacement of the fracture in six of the eight specimens. CONCLUSION: In our study, the newly designed distal fibula periarticular locking plate with increased distal fixation is biomechanically stronger than a non-locking one third tubular plate applied in antiglide fashion for the treatment of AO/OTA 44-B2 osteoporotic distal fibula fractures. LEVEL OF EVIDENCE: V: This is an ex-vivo study performed on cadavers and is not a study performed on live patients. Therefore, this is considered Level V evidence.

Pharmacokinetic model of unfractionated heparin during and after cardiopulmonary bypass in cardiac surgery.

BACKGROUND: Unfractionated heparin (UFH) is widely used as a reversible anti-coagulant in cardiopulmonary bypass (CPB). However, the pharmacokinetic characteristics of UFH in CPB surgeries remain unknown because of the lack of means to directly determine plasma UFH concentrations. The aim of this study was to establish a pharmacokinetic model to predict plasma UFH concentrations at the end of CPB for optimal neutralization with protamine sulfate. METHODS: Forty-one patients undergoing CPB during cardiac surgery were enrolled in this observational clinical study of UFH pharmacokinetics. Patients received intravenous injections of UFH, and plasma anti-FIIa activity was measured with commercial anti-FIIa assay kits. A population pharmacokinetic model was established by using nonlinear mixed-effects modeling (NONMEM) software and validated by visual predictive check and Bootstrap analyses. Estimated parameters in the final model were used to simulate additional protamine administration after cardiac surgery in order to eliminate heparin rebound. Plans for postoperative protamine intravenous injections and infusions were quantitatively compared and evaluated during the simulation. RESULTS: A two-compartment pharmacokinetic model with first-order elimination provided the best fit. Subsequent simulation of postoperative protamine administration suggested that a lower-dose protamine infusion over 24 h may provide better elimination and prevent heparin rebound than bolus injection and other infusion regimens that have higher infusion rates and shorter duration. CONCLUSION: A two-compartment model accurately reflects the pharmacokinetics of UFH in Chinese patients during CPB and can be used to explain postoperative heparin rebound after protamine neutralization. Simulations suggest a 24-h protamine infusion is more effective for heparin rebound prevention than a 6-h protamine infusion.

Model-based meta-analysis of the effects of non-selective and α1-selective GABAA receptor agonists in healthy volunteers.

PURPOSE: To quantify pharmacokinetic (PK) and pharmacodynamic (PD) relationships of various classes of GABAA agonists in healthy volunteers, in order to investigate the sensitivity of the biomarker responses due to differing GABAA-subtype selectivity and to explore the correlation between biomarker responses and side effects of these drugs. METHODS: A comprehensive search was conducted for published placebo-controlled clinical studies of non- and α1-selective GABAA drugs in healthy volunteers. PK/PD models were developed for concentrations and biomarker outcomes (saccadic eye movement (SEM), visual analogue scale (VAS), digit symbol substitution task (DSST), and critical flicker fusion test (CFFT)) extracted from included studies. Predicted responses and equivalent doses for biomarkers (based on predicted response) were used to compare drug effects. And the relationship between biomarkers and safety was explored by linear regression. RESULTS: A total of 2237 data from 163 articles were included. Based on PK and placebo effect modeling, linear biomarker-concentration relationships well fit the data. The α1-selective compounds had similar equivalent doses for VAS, DSST, and CFFT (4.7-6.7 mg), which were about three to seven times lower than that for SEM (14.4-35.5 mg), while such difference was less evident for non-selective drugs. DSST had the highest correlations with incidences of somnolence and dizziness. CONCLUSIONS: The integral PK/PD models of GABAA agonists were established in healthy volunteers. SEM was identified as the most sensitive biomarker in differentiating GABAA receptor α1 subtype selective compounds. The exploratory analysis implied that different relationships existed between the drug effects on biomarkers and the adverse event profiles in healthy volunteers.