Toxicokinetics of a Single 50 mg/kg Oral Dose of [2,3-14C]Acrylamide in White Leghorn Hens

A single oral dose of [2,3-¹⁴C]acrylamide (50 mg/kg) was administeredin water to adult white leghorn hens. Seven groups of threehens were euthanized between 2 and 120 hr after administration.Within 12 hr, the hens excreted 70% of the administered dose,and more than 99% within 48 hr. Blood, plasma, liver, and musclecontained the greatest percentage of administered dose at 4hr after dosing. Less than 0.02% of the administered dose appearedin brain at any time. Radiolabel accumulated in the eggs, with0.52% of the administered dose accumulated within 5 days. Bindingof radiolabel to erythrocytes was minimal. Elimination of radiolabel from all tissues were biphasic. Terminal eliminationhalf-lives for 14 were longer than 10 days, at which time lessthan 0.2% of the administered dose remains in the tissues. Distributionhalf-lives for ¹⁴C were longest for whole blood and shortestfor kidney. Radioactivity in the blood and plasma reached apeak at between 4 and 12 hr. Most of this radioactivity wasidentified as acrylamide, which disappeared biexponentiallywith terminal elimination half-lives longer than 10 days. Distributionhalf-lives for acrylamide were longest in brain and shortestin whole blood. These results show that orally administeredacrylamide is poorly absorbed and rapidly eliminated from hensand accumulates in their eggs in a nonextractable form.     

Computational high-throughput screening and <i>in vitro</i> approaches identify CB-006-3; A novel PI3K-BRAF^V600E dual targeted inhibitor against melanoma

Malignant melanoma is characterized by both genetic and molecular alterations that activate phosphoinositide 3-kinase (PI3K), and RAS/BRAF pathways. In this work, through diversity-based high-throughput virtual screening we identified a lead molecule that selectively targets PI3K and BRAF^V600E kinases. Computational screening, Molecular dynamics simulation and MMPBSA calculations were performed. PI3K and BRAF^V600E kinase inhibition was done. A375 and G-361 cells were used for in vitro cellular analysis to determine antiproliferative effects, annexin V binding, nuclear fragmentation and cell cycle analysis. Computational screening of small molecules indicates compound CB-006-3 selectively targets PI3KCG (gamma subunit), PI3KCD (delta subunit) and BRAF^V600E. Molecular dynamics simulation and MMPBSA bases binding free energy calculations predict a stable binding of CB-006-3 to the active sites of PI3K and BRAF^V600E. The compound effectively inhibited PI3KCG, PI3KCD and BRAF^V600E kinases with respective IC₅₀ values of 75.80, 160.10 and 70.84 nM. CB-006-3 controlled the proliferation of A375 and G-361 cells with GI₅₀ values of 223.3 and 143.6 nM, respectively. A dose dependent increase in apoptotic cell population and sub G₀/G₁ phase of cell cycle were also observed with the compound treatment in addition to observed nuclear fragmentation in these cells. Furthermore, CB-006-3 inhibited BRAF^V600E, PI3KCD and PI3KCG in both melanoma cells. Collectively, based on the computational modeling and in vitro validations, we propose CB-006-3 as a lead candidate for selectively targeting PI3K and mutant BRAF^V600E to inhibit melanoma cell proliferation. Further experimental validations, including pharmacokinetic evaluations in mouse models will identify the druggability of the proposed lead candidate for further development as a therapeutic agent for treating melanoma.     

腹腔镜脾切除术21例临床分析

目的：探讨腹腔镜脾切除术的安全性及临床效果。方法：回顾性分析21例腹腔镜脾切除术患者（16例肝炎后肝硬化及3例脾梗死,1例脾包虫病,1例血吸虫性肝硬化）的临床资料。结果：21例中2例中转开腹,19例成功完成腹腔镜脾切除术,其中1例行腹腔镜下脾大部切除术。平均手术时间为150min,平均术中失血485ml,术后24～48h胃肠蠕动恢复,术后平均住院时间为12d。结论：经过选择的患者行腹腔镜脾切除术安全可行,除血液系统疾病外还适用于肝硬化患者中需行脾切除者及脾脏本身病变者。     

腹腔镜腹壁切口疝补片修补术的应用体会

目的：探讨腹腔镜腹壁切口疝补片修补术的临床应用价值及安全性。方法：2005年8月至2006年10月我院为8例腹壁切口疝患者使用自膨胀式聚丙烯-膨化聚四氟乙烯双面复合型补片行腹腔镜腹壁切口疝修补术,其中2例联合行胆囊切除术。结果：8例手术均获成功,手术时间55～150min,平均85min,无手术死亡病例及并发症发生,患者术后8～24h后下床活动,1—2d排气,术后疼痛轻,2—3d后完全缓解,3—7d（平均4d）患者顺利康复出院。随访12～24个月无复发。结论：腹腔镜腹壁切口疝修补术安全可靠,具有创伤小、术后康复快、并发症少、不增加手术穿刺孔、可完成联合手术等优点,临床应用前景广阔。     

四川省凉山州艾滋病病毒感染者配偶感染状况调查

目的了解以吸毒感染为主的艾滋病高流行地区感染者配偶的HIV感染状况及危险因素,提出防治建议。方法 2008年1-3月通过入户调查,对凉山州布拖县和昭觉县226名HIV感染者的配偶开展艾滋病知识、态度和行为学调查,同时进行HIV血清学检测。结果感染者配偶HIV阳性检出率达到25.7%,调查对象按国家督导评估方案计算的知识知晓率为50.9%,71.7%的调查对象最近1个月与配偶发生过性行为,最近1次性行为安全套使用率仅为9.1%(11/121)。结论凉山地区HIV感染者的配偶感染状况严重,配偶间无保护性行为发生比例高,针对配偶间危险性行为的干预工作不足,应扩大检测,加强随访干预,提供适宜的预防技术。     

Variability in Postpacing Intervals Predicts Global Ventricular Activation Pattern during Tachycardia

Introduction: Assessment of ventricular activation pattern is critical to the successful ablation of ventricular tachycardia (VT). We have previously shown that the global atrial activation pattern during tachycardia can be rapidly and accurately assessed by calculating the postpacing interval variability (PPIV); PPIV was minimal in circuitous tachycardias and highly variable in centrifugal tachycardias. In the present study, we use the PPIV to determine the ventricular global activation pattern during VT. Methods: Patients with mappable VT were included. We defined global ventricular activation as either centrifugal (arising from a focus with radial expansion) or circuitous (gross macro‐reentrant circuit), based on the findings of electroanatomic mapping. PPIV was calculated as the difference in postpacing interval with right ventricular apical overdrive pacing during tachycardia at cycle lengths (CL) 10 ms and 30‐ms shorter than tachycardia, regardless of the origin of the tachycardia. We studied 20 patients with 23 VTs (11 centrifugal, mean CL 390 ± 36.1 ms; 12 circuitous, mean CL 418 ± 75.7 ms). Results: The mean PPIV was 45 ± 16 ms for patients with centrifugal VT and 6.7 ± 4.1 ms for patients with circuitous VT. Rank sum analysis of PPIV showed a significant difference between the two groups (P < 0.05). Conclusions: Our data suggest that the global ventricular activation pattern during VT can be rapidly and accurately defined by assessing the PPIV. This technique allows for a rapid confirmation of the tachycardia activation and significantly facilitates mapping and ablation. (PACE 2010; 33:129–134)     

QRS Duration Widening: Reduced Synchronization of Endocardial Activation or Transseptal Conduction Time?

Antegrade activation of the His-Purkinje system (HPS) results in synchronized activation of the right ventricular (RV) and left ventricular (LV) endocardia forming normal, narrow QRS duration (QRSD). An alteration in septal activation and transseptal conduction time have been reported to be the causes for QRSD widening seen with bundle branch block. However, reduced synchronization of activation ofRVand LV endocardia as another potential mechanism for QRSD widening has not been systematically studied. Fifteen consecutive patients underwent radiofrequency ablation (RFA) for treatment of supraventricular tachycardia. After RFA, mean QRSD in normal sinus rhythm was 86 ± 8 ms with mean HV interval of 40 ± 5 ms. Right atrial (RA), coronary sinus (CS), simultaneous (S) RA-CS, RVapex (RVA), LV apex (LVA), and SRVA-LVA pacing were performed. Mean QRSD with RA, CS, SRA-CS pacing was similar to normal sinus rhythm (87 ± 7, 87 ± 8 and 88 ± 8 ms respectively). Mean QRSD was significantly longer with SRVA-LVA and either RVA or LVA pacing alone compared to normal sinus rhythm (106 t 8, 146 ± 12 and 157 ± 13 ms, respectively). However, QRSD was significantly shorter with SRVA-LVA pacing compared to either RVA or LVA pacing alone (P < 0.0001). We conclude that shorter QRSD with SRVA-LVA pacing compared to either RVA or LVA pacing alone is due to elimination of transseptal conduction delay; longer QRSD with SRVA-LVA pacing compared to sinus or atrial paced rhythm is due to reduced synchronization of endocardial activation secondary to ectopic entry of impulses into the HPS network and inability to take advantage of the branching structure of the HPS. Therefore, in addition to transseptal conduction delay, reduced synchronization of endocardial activation is another potential mechanism for QRSD widening.