福司氟康唑合成新工艺

目的 优化福司氟康唑合成工艺。方法 以廉价易得氟康唑为起始原料,使用三氯氧磷进行氯磷酸酯化,之后与苄 醇进行缩合,得到中间体 c,将中间体 c 用 Pd/C 催化,以甲酸铵为氢供体,进行脱苄基,经过酸化,析晶,得福司氟康唑。结 果 总收率达 70.7%,纯度为 98.8%,产品结构经 1 H NMR 确证。结论 本文设计了一条新的合成路线,该合成过程操作简单, 起始原料便宜易得,反应条件温和,收率高,易于工业化。     

In vivo imaging of immediate early gene expression reveals layer-specific memory traces in the mammalian brain

The dynamic processes of formatting long-term memory traces in the cortex are poorly understood. The investigation of these processes requires measurements of task-evoked neuronal activities from large numbers of neurons over many days. Here, we present a two-photon imaging-based system to track event–related neuronal activity in thousands of neurons through the quantitative measurement of EGFP proteins expressed under the control of the EGR1 gene promoter. A recognition algorithm was developed to detect GFP-positive neurons in multiple cortical volumes and thereby to allow the reproducible tracking of 4,000 neurons in each volume for 2 mo. The analysis revealed a context-specific response in sparse layer II neurons. The context-evoked response gradually increased during several days of training and was maintained 1 mo later. The formed traces were specifically activated by the training context and were linearly correlated with the behavioral response. Neuronal assemblies that responded to specific contexts were largely separated, indicating the sparse coding of memory-related traces in the layer II cortical circuit.In the mammalian brain, memory traces in cortical areas are poorly understood. In contrast to the medial temporal lobe, particularly the hippocampus, which is involved in the temporary storage of declarative memories (1, 2), the neocortex is believed to store remote memories (3–6). However, remarkably little knowledge regarding the sites and dynamics of remote memory storage has been revealed at the cellular level owing to the complexity of the connections and the large number of neurons within the cortical circuit.In vivo electrophysiological recording of neuronal firing revolutionized neurobiology by linking neuronal activity with animal behavior. The small number of neurons recorded by the electrodes, however, was a limitation, as information coding and decoding may use an army of neurons forming neuronal assemblies (7, 8). Efforts to record the activity of larger populations of neurons in cortical volumes have been actively pursued by either increasing the number of electrode probes (7, 9–11) or using calcium indicator–based imaging (12–15) and immediate early gene (IEG)-based reporters (16–18). The expression of IEGs is correlated with the averaged neuronal activation on external stimuli (19, 20), implying that the marked neurons are involved in behavior (1, 21–25). Studies using in vivo imaging of IEGs have revealed cortical coding in the visual cortex and in other cortical areas, reflecting electrical activation in individual neurons (16, 17). Among IEGs, the expression of early growth response protein 1 (EGR1, also known as zif268) is associated with high-frequency stimulation and the induction of long-term plasticity during learning (26, 27). To measure neuronal activation in cortical circuits during a behavioral task, we used an EGR1 expression reporter mouse line in which the expression of the EGFP protein is under the control of the Egr1 gene promoter. We designed offline recording strategies to monitor task-associated neuronal activity by quantifying changes in cellular EGFP signals in the mouse cortex. Patterns of activated neuronal assemblies during different tasks were visualized in the entire cortical volume. Furthermore, through computer recognition-based reconstruction, we were able to track the activity-related cellular EGFP signals from multiple cortical areas for 2 mo to reveal memory-related changes in the cortical circuit.     

Interim response in diffuse large B cell lymphoma on CT: what is the optimal size reduction (ΔSPD) for predicting outcome?

European Radiology - To investigate whether there was an optimal interim size reduction (iΔSPD) cutoff value that could discriminate diffuse large B cell lymphoma (DLBCL) patients with poor...     

Protective Effects of Tight Glucose Control During Cardiopulmonary Bypass on Myocardium in Adult Nondiabetic Patients Undergoing Valve Replacement

Background

In this study, we aimed to evaluate the protective effect of tight glucose control during cardiopulmonary bypass on myocardium in adult nondiabetic patients undergoing isolated aortic valve replacement in a prospective and randomized trial.

Methods

Sixty-five adult nondiabetic patients undergoing selective isolated aortic valve replacement were enrolled and randomly assigned to an insulin group (patients received a continuous insulin infusion during surgery; n = 33) or a control group (patients were not administered insulin unless their blood glucose level exceeded 200 mg/dL; n = 32). Cardiac troponin I was assayed preoperatively, and then at 2, 6, 12, 24, and 48 hours after aortic cross-declamping. The pre-, intra-, and postoperative relevant data of all selected patients were analyzed.

Results

Tight glucose control reduced postoperative peak release by 48% for cardiac troponin I compared with the control group (0.48 ± 0.12 vs 0.71 ± 0.17 ng/mL; P < 0.0001). Patients with continuous insulin infusion had lower peak inotropic score during the first postoperative 24 hours and peak level of blood glucose (5.8 ± 2.2 vs 8.2 ± 3.1 μg/kg/min; P < 0.0001; 131.9 ± 23.8 vs 191.1 ± 38.5 mg/dL; P < 0.001, respectively), shorter duration of mechanical ventilation and intensive care unit stay and hospital stay compared with the control group (11.6 ± 2.9 hours vs 14.8 ± 3.5 hours; P = 0.0002; 28.4 ± 7.2 hours vs 36.5 ± 7.8 hours; P < 0.0001; 9.4 ± 3.3 days vs 11.5 ± 4.2 days; P = 0.0283, respectively).

Conclusions

Tight glucose control during cardiopulmonary bypass might provide myocardial protection in adult nondiabetic patients undergoing isolated aortic valve replacement.     

A role for activator of G-protein signaling 3 (AGS3) in multiple myeloma

Previous studies have demonstrated that activator of G-protein signaling 3 (AGS3; also known as GPSM1), a member of the AGS family, plays an important anti-apoptotic role through enhancing the phosphorylation of cyclic AMP response element-binding protein (p-CREB). In this report, we delineate the anti-apoptotic role of AGS3 in multiple myeloma (MM). To do this, we developed a cell apoptotic model induced by doxorubicin in MM. Our data indicate that decreased expression of AGS3 is correlated with reduced levels of p-CREB in the apoptotic model. The negative role of AGS3 in cell apoptosis was further confirmed by knocking down AGS3. The microenvironment has been shown to influence tumor cell phenotype in response to chemotherapy. Since cell adhesion-mediated drug resistance remains a major obstacle for successful treatment of MM, we constructed a cell adhesion model in MM and detected the changing of AGS3 protein expression. AGS3 siRNA reversed the high rate of MM cell adhesion to either fibronectin or HS-5 cells. Consistent with the reduced adhesion rate, the cells also exhibited reduced drug resistance to doxorubicin, mitoxantrone, and dexamethasone. Collectively, these data indicate that AGS3 may be represented as a good candidate for pursuing clinical trials in MM. Moreover, our data provide a clinical therapeutic target for MM and potentially other tumors that home and/or metastasize to the bone.     

Exploration and Preparation of a Dose-Flexible Regulation System for Levetiracetam Tablets via Novel Semi-Solid Extrusion Three-Dimensional Printing

Levetiracetam therapy is often associated with high levels of individual variation in the recommended dose required to achieve preferential treatment. Thus, a reliable and dynamic regulation system to accurately tailor dose is necessary. The main objective of this study is to explore and prepare a dose-flexible control system suitable for rapid release tablets equipped with high drug loading and a cylindrical model design. Semi-solid extrusion 3-dimensional printing was utilized to fabricate a series of tablets of increased volume. This method was compatible with 3 patterns to regulate the volumes to manipulate the tablet mass and achieve tailored personalized precision dosing. All tablets from each pattern exhibited a smooth surface and regular shape, as well as sufficient mechanical strength. A good linear correlation between the mass and theoretical volume of the tablets was maintained, regardless of the pattern used. The range of dose accuracy was between 103.3% and 96.2%, with an acceptable variation coefficient in the range of 0.6%-3.2%. Faster release behavior for levetiracetam can be achieved from the small-sized tablets due to their larger surface area/mass ratio. All the results demonstrated the potential and capability of semi-solid extrusion 3-dimensional printing as a novel pharmaceutical manufacturing technique to provide a dynamic and highly accurate controllable system for preparing patient-tailored medicines.