Gli1 induces G2/M arrest and apoptosis in hippocampal but not tumor-derived neural stem cells

Sonic hedgehog (Shh) is necessary for sustaining the proliferation of neural stem cells (NSCs), yet little is known about its mechanisms. Whereas Gli1, Gli2, and Gli3, the primary mediators of Shh signaling, were all expressed in hippocampal neural progenitors, Shh treatment of NSCs induced only Gli1 expression. Acute depletion of Gli1 in postnatal NSCs by short-hairpin RNA decreased proliferation, whereas germline deletion of Gli1 did not affect NSC proliferation, suggesting a difference in mechanisms of Gli1 compensation that may be developmentally dependent. To determine whether Gli1 was sufficient to enhance NSC proliferation, we overexpressed this mitogen and were surprised to find that Gli1 resulted in decreased proliferation, accumulation of NSCs in the G2/M phase of cell cycle, and apoptosis. In contrast, Gli1-expressing lineage-restricted neural precursors demonstrated a 4.5-fold proliferation enhancement. Expression analyses of Gli1-expressing NSCs identified significant induction of Gadd45a and decreased cyclin A2 and Stag1 mRNA, genes involved in the G2-M transition and apoptosis. Furthermore, Gadd45a overexpression was sufficient to partially recapitulate the Gli1-induced G2/M accumulation and cell death of NSCs. In contrast to normal stem cells, tumor-derived stem cells had markedly higher basal Gli1 expression and did not undergo apoptosis with further elevation of Gli1. Our data suggest that Gli1-induced apoptosis may serve as a protective mechanism against premature mitosis and may give insight into mechanisms by which nonmalignant stem cells restrain hyperproliferation in the context of potentially transforming mitogenic signals. Tumor-derived stem cells apparently lack these mechanisms, which may contribute to their unrestrained proliferation and malignant potential.     

Ten Tips for Pharmacy Faculty Members for Successfully Navigating Promotion and Tenure

This paper presents 10 key tips or recommendations for successful navigation of the promotion and tenure process. The 10 key tips are: know institutional expectations, develop an action plan at least two to three years in advance; identify your balance of teaching, scholarship, service; synergize activities and develop a niche; prioritize time to activities of high-impact to promotion and tenure; track achievements in the format expected for promotion and tenure application; seek out faculty guidance on promotion and tenure; meet with mentor(s) regularly to review progress; have a well-written personal statement; and have your final dossier reviewed by colleagues. Faculty members are more likely to be successful through timely and appropriate planning, balancing and synergizing activities, tracking activities and achievements, developing a well-written personal statement, and requesting help from experienced colleagues.     

Evaluation and Treatment of Acute and Subacute Hearing Loss: A Review of Pharmacotherapy

Among various forms of hearing loss, there are acute (within 72 hrs) or subacute (weeks to months) presentations that may be reversible with early pharmacological intervention. The workup of a patient presenting with hypoacusia includes the usual history and physical examination in conjunction with an audiometric assessment in order to categorize the hearing loss as conductive, sensorineural, or mixed. Sudden sensorineural hearing loss and autoimmune inner ear disease are acute and subacute forms of sensorineural hypoacusia most likely to be reversed with prompt pharmacological intervention. Systemic or local corticosteroid therapy has the most evidence of benefit in patients with sudden sensorineural hypoacusia and is the best available first line therapy noted in clinical practice guidelines. Alternative immunosuppressant therapies have not been well studied, and many have serious toxicities that further complicate the benefit‐risk assessment. There are no randomized comparisons of corticosteroid dosing regimens that evaluated clinically important outcomes, so expert opinion must serve as the basis for dosing recommendations. Clinicians need to involve patients with hypoacusia in the shared decision‐making process, since partial or complete reversal of hearing loss can have substantial quality‐of‐life implications for affected patients.     

影响盐酸维拉帕米脉冲释放片体外“时滞”的因素考察

目的：考察影响盐酸维拉帕米脉冲片控时效果的因素。方法：通过外溶出的方法考察脉冲控释片的时滞,主要包括溶出条件和处方因素两方面。结果：介质的酸碱度不影响制剂的控时效果;转速不影响制起崩时间,但对溶出速度有一定的影响;粘度越大的介质,释药时滞也越大。包衣用量增加、控时层中亲水性成分PEG6000含量减小、控时层中PEG类型的分子量的增加,均能使药物释放滞后时间明显增大;包衣颗粒大小对控时效果基本没有影响。结论：溶出条件作用因素的考察为进一步的体内研究奠定了基础;处方因素的考察为制剂的时滞调控和释药特征研究作了准备。     

围手术期出血的处理

引言 任何大手术都存在对止血系统的挑战,一些失血总是不可避免的。然而,围手术期大出血仍是外科手术的主要并发症,导致发病率和死亡率升高。对血液供应的安全性和可靠性的担心,需要我们共同努力节约地使用血液制品,以减少异体血液的接触,从而减少输血传播的疾病。因此围手术期出血的处理需要迅速评估,有条理地诊断,以及制定适当的治疗方案。围手术期出血存在两个主要原冈。第一是手术出血,由于在手术部位不能手术控制出血的血管直接造成的。外科手术出血通常以单部位出血为特点,仪局限于手术部位。精细的技术,耐心认真     

Comparison of enoxaparin and unfractionated heparin in endovascular interventions for the treatment of peripheral arterial occlusive disease: a randomized controlled trial

Summary. Background: Although unfractionated heparin (UFH) is an effective antithrombotic agent in endovascular interventions for the treatment of peripheral occlusive arterial disease (PAOD), it produces a highly variable anticoagulant response. Intravenous (i.v.) enoxaparin might be an effective and safe alternative. Patients and methods: In a prospective, open‐label, randomized, single‐center trial, 210 patients with PAOD (Fontaine stage IIb to IV) were randomly assigned in a 1 (UFH): 2 (enoxaparin) fashion to receive an i.v. bolus of 60 units UFH per kg body weight or 0.5 mg enoxaparin per kg body weight, respectively, before endovascular intervention. The primary composite endpoint assessed the clinical performance of enoxaparin by comparing the peri‐interventional rate of thromboembolia/occlusion (efficacy) of endovascularly reconstructed areas, of bleeding according to the Global Utilization of Streptokinase and t‐PA for Occluded Coronary Arteries (GUSTO) criteria (safety) and of any necessary re‐intervention for any percutaneous transluminal angioplasty (PTA)‐related bleeding. The secondary endpoint evaluated anti‐factor (F)Xa levels during intervention. Results: The primary composite endpoint showed a better performance of enoxaparin (10.5% vs. 2.5% absolute difference – 8.0%; P < 0.05). The concomitant use of acetylsalicylic acid (ASA) significantly (P < 0.05) increased the risk of a complication in the UFH group, but not in the enoxaparin group. Within 15 min, anti‐Xa levels were reached by 63.7% of patients treated with enoxaparin and only by 39.1% with UFH. Conclusion: Enoxaparin has a better performance than UFH in endovascular interventions for the treatment of PAOD. In patients with concomitant use of ASA, the risk of complications with UFH increases significantly compared with enoxaparin.