Ro5-4864 promotes neonatal motor neuron survival and nerve regeneration in adult rats

The translocator protein (18 kDa; TSPO), formerly known as the peripheral benzodiazepine receptor, is an outer mitochondrial membrane protein that associates with the mitochondrial permeability transition pore to regulate both steroidogenesis and apoptosis. TSPO expression is induced in adult dorsal root ganglion (DRG) sensory neurons after peripheral nerve injury and a TSPO receptor ligand, Ro5-4864, enhances DRG neurite growth in vitro and axonal regeneration in vivo . We have now found that TSPO is induced in neonatal motor neurons after peripheral nerve injury and have evaluated its involvement in neonatal and adult sensory and motor neuron survival, and in adult motor neuron regeneration. The TSPO ligand Ro5-4864 rescued cultured neonatal DRG neurons from nerve growth factor withdrawal-induced apoptosis and protected neonatal spinal cord motor neurons from death due to sciatic nerve axotomy. However, Ro5-4864 had only a small neuroprotective effect on adult facial motor neurons after axotomy, did not delay onset or prolong survival in SOD1 mutant mice, and failed to protect adult DRG neurons from sciatic nerve injury-induced death. In contrast, Ro5-4864 substantially enhanced adult facial motor neuron nerve regeneration and restoration of function after facial nerve axotomy. These data indicate a selective sensitivity of neonatal sensory and motor neurons to survival in response to Ro5-4864, which highlights that survival in injured immature neurons cannot necessarily predict success in adults. Furthermore, although Ro5-4864 is only a very weak promoter of survival in adult neurons, it significantly enhances regeneration and functional recovery in adults.     

Evaluation of ceftriaxone dosing regimens based on PK/PD models and Monte Carlo simulations

In the present study, we optimized the ceftriaxone dosing regimens based on pharmacokinetic/pharmacodynamic (PK/PD) principles using Monte Carlo simulation (MCS). Based on PK/PD theory, MCS was performed using Crystal Ball software combining PK and PD parameters with 10 000 simulation runs to calculate the probability of target attainment (PTA) and cumulative fraction of response (CFR) for the seven clinically common dosing regimens of ceftriaxone (1 g qd, 1.5 g qd, 1 g bid, 2 g qd, 1 g tid, 1.5 g bid, and 2 g bid). A %fT ≥ 50 as the target value expected to achieve satisfactory clinical efficacy and a dosing regimen with an obtained CFR ≥ 90% or the ability to achieve the highest PTA was used as a reasonable choice for empirical antimicrobial therapy, i.e. the clinically optimal regimen. All eight pathogenic bacteria had a CFR > 90% when the dosing regimen was 2 g bid and 1 g tid, seven pathogenic bacteria had a CFR > 90% when the dosing regimen was 1 g bid and 1.5 g bid, except for Pseudomonas aeruginosa, and all pathogenic bacteria had a CFR< 90% when the dosing regimen was 1 g qd and 1.5 g qd. The dosing regimens of 2 g bid and 1 g tid were effective against all eight pathogenic bacteria infections, and 1 g bid and 1.5 g bid dosing regimens were effective against the other seven pathogenic bacteria except for Pseudomonas aeruginosa.     

Pharmacokinetic/pharmacodynamic modelling of 2-acetyl-4(5)-tetrahydroxybutyl imidazole-induced peripheral lymphocyte sequestration through increasing lymphoid sphingosine 1-phosphate

1. 2-Acetyl-4(5)-tetrahydroxybutyl imidazole (THI) has been shown to reduce rodent peripheral blood lymphocytes through increasing lymphoid sphingosine 1-phosphate (S1P) by inhibiting S1P lyase. The objective of this study was to characterize the relationship between systemic THI exposure, splenic S1P concentrations, and lymphopenia in rats.

2. Following the oral administration of 10 and 100?mg kg^?1 THI to male rats, THI was rapidly absorbed and reached a plasma peak level at 1?h post-dosing. Splenic S1P increased and reached the peak level at 24?h. Blood lymphocyte count decreased as the splenic S1P level increased. THI plasma concentration was linked to splenic S1P concentration using an indirect model incorporated with a four-step signal transduction model. In turn, the S1P level was directly coupled with blood lymphocyte number. The integrated model simultaneously captured the splenic S1P and blood lymphocyte responses.

3. This pharmacokinetic–biomarker–pharmacodynamic model resolved the remarkable discrepancy between plasma THI concentration and the pharmacological response and quantitatively described the relationship of THI exposure, S1P, and lymphopenic response.

     

双极电凝和PK刀用于腹腔镜子宫切除术的比较

目的：比较双极电凝和PK刀在腹腔镜子宫切除术中的应用情况。方法：回顾分析我院2006年1月至12月66例腹腔镜子宫切除患者的临床资料。其中双极电凝组33例,PK刀组33例。比较两组患者的术中出血量、手术时间等指标。结果：所有手术均获成功,无中转开腹及严重并发症发生。PK刀组在手术出血量和手术时间上均显著少于双极电凝组。结论：与双极电凝相比,PK刀具有止血效果佳,热辐射损伤小,器械操作简单、易学等优点,极大提高了妇科腹腔镜子宫切除术的手术质量。     

寻常型银屑病和汗孔角化症患者外周血Vγ9Vδ2 T细胞的表型分析

 目的 比较斑块状寻常型银屑病（psoriasis vulgaris,PV）和汗孔角化症（porokeratosis,PK）患者的外周血Vγ9Vδ2 T细胞比例和表型的变化。方法 采用流式细胞术来检测PV组（n=33）、PK组（n=19）及正常对照（normal control,NC）组（n=33）的外周血单个核细胞（peripheral blood mononuclear cell,PBMC）中CD3、Vγ9、Vδ2、CLA、CD27、CD45RA的表达。结果 与NC组相比较,Vγ9Vδ2 T细胞占总T细胞的比例和CLA⁺Vγ9Vδ2 T细胞占总Vγ9Vδ2 T细胞的比例分别在PV组（t=-2.349,P=0.022 4;t=-3.277,P=0.001 7）和PK组（t=-2.226,P=0.030 6;t=-2.901,P=0.005 5）出现显著减少;Vγ9Vδ2 T细胞分化成T_CM的比例在PV组和PK组分别出现明显下降（t=-4.932,P<0.0001;t=-2.572,P=0.013 1）;同时,T_EMRA的比例在PV组和PK组均出现明显升高（t=3.849,P=0.0003;t=2.236,P=0.0353）;T_EM比例的下降仅在PV组具有统计学意义（t=-3.303,P=0.001 8）。结论 PV和PK患者的外周血Vγ9Vδ2 T细胞的比例和表型具有相似性,该细胞可能迁移至皮肤,参与皮肤的自身炎症应答。     

Peripheral benzodiazepine receptors and glucose metabolism in human gliomas

Peripheral benzodiazepine receptors (PBR) are increased in gliomas and augmented glucose metabolism is seen in malignant brain tumors. We investigated the relationship between PBR density (B_max) and glucose utilization rate (GUR) in 17 patients with cerebral gliomas of different grades. PBR B_max was assessed by [³H]PK-11195in vitro binding in surgical specimens and GUR was measured by Positron Emission Tomography with [¹⁸F]2-Fluorodeoxyglucose before the surgery. In untreated tumors there was a positive correlation between PBR B_max and GUR (2^r = 0.84). This correlation was not observed in patients who had been treated with radiation and/or chemotherapy prior to surgery (r² = 0.13). In addition, in untreated patients, the increase in PBR density and GUR appeared to be related to the degree of malignancy.     

Prokineticin 2/Bv8 is expressed in Kupffer cells in liver and is down regulated in human hepatocellular carcinoma

AIM： TO study the implication of prokineticin 1 （PKI/EGVEGF） and prokineticin 2 （PK2/13v8） in hepatocellular carcinoma angiogenesis.
METHODS： The gene induction of PK1/EG-VEGF and PK2/Bv8 was investigated in 10 normal, 28 fibrotic and 28 tumoral livers by using real time PCR. Their expression was compared to the expression of VEGF （an angiogenesis marker）, vWF （an endothelial cell marker） and to CD68 （a monocyte/macrophage marker）. Furthermore, the rnRNA levels of PK1/EG-VEGF, PK2/Bv8, prokineticin receptor 1 and 2 were evaluated by real time PCR in isolated liver cell populations. Finally, PK2/Bv8 protein was detected in normal liver paraffin sections and in isolated liver cells by immunohistochernistry and immunocytochemistry.
RESULTS： PK2/Bv8 mRNA but not PK1/EG-VEGF was expressed in all types of normal liver samples examined. In the context of liver tumor development, we reported that PK2/13v8 correlates only with CD68 and showed a significant decrease in expression as the pathology evolves towards cancer. Whereas, VEGF and vWF mRNA were significantly upregulated in both fibrosis and HCC,as expected. In addition, out of all isolated liver cells examined, only Kupffer cells （liver resident macrophages） express significant levels of PK2/Bv8 and its receptors, prokineticin receptor 1 and 2.
CONCLUSION： In normal liver PK2/Bv8 and its receptors were specifically expressed by Kupffer cells. PK2/Bv8 expression decreased as the liver evolves towards cancer and did not correlate with HCC angiogenesis.     

Role of intravenous cloxacillin for inpatient infections

One of the issues of antibiotic treatment is to warrant its optimal effectiveness while minimizing the risk for emergence of resistance. The time above minimal inhibiting concentration (MIC) (T>MIC) is the best predictive pharmacological parameter of effectiveness for antibiotics with time-dependent activity, such as cloxacillin. Cloxacillin is the first line antibiotic in a great number of clinical situations generated by methicillin sensitive staphylococci, because of its intrinsic properties: bactericidal effect, tissue distribution and safety. The most recent anti-staphylococcal agents do not improve treatment of MSSA infections compared to penicillin M and especially cloxacillin. Cloxacillin has a narrow microbiological spectrum. This ecological feature is in line with the recommendation to use antibiotics with the narrowest spectrum to reduce the pressure of selection. The consensus is to have T>MIC for at least 40% of the dosing interval and is achieved by infusing 2g of cloxacillin per day (T>MIC=50%) or four infusions of 3g per day (T>MIC=42%) in adults.     

Treatment option for sepsis in children in the era of antibiotic resistance

Sepsis caused by multidrug-resistant microorganisms is one of the most serious infectious diseases of childhood and poses significant challenges for pediatricians involved in management of critically ill children. This review discusses the use of pharmacokinetic/dynamic principles (i.e., prolonged infusion of β-lactams and vancomycin, once-daily administration of aminoglycosides and rationale of therapeutic drug monitoring) when prescribing antibiotics to critically ill patients. The potential of ‘old’ agents (i.e., colistin, fosfomycin) and newly approved antibiotics is critically reviewed. The pros and cons of combination antibacterial therapy are discussed and finally suggestions for the treatment of sepsis caused by multidrug-resistant organisms are provided.