Persistent serpentine supravenous hyperpigmented eruption associated with docetaxel

Various mucocutaneous reactions have been reported with the use of systemic docetaxel. We describe a 47-year-old man who developed a persistent serpentine supravenous hyperpigmented eruption (PSSHE), beginning at the site of docetaxel injection and spreading along the superficial venous network in the anterior aspect of the right forearm and distal arm. The eruption occurred after the first infusion of docetaxel following insufficient venous washing. A second infusion was administered through a vein in the other forearm, but this time, abundant venous washing was performed and a similar eruption did not occur. To our knowledge, this is the second report of docetaxel-induced supravenous discoloration and we discussed the terminology and mechanism of this unique reaction.     

The use of Terson lens capsule forceps when performing punch biopsy of the skin

When performing skin biopsy using the skin biopsy punch, it is recommended that Terson lens capsule forceps be used as an aid to avoid crush artifact. This is because secure yet gentle purchase of the specimen is allowed by a row of small inwardly directed tines that arise from the 2.5 mm horizontally placed grasping blades, which are inserted into the incision created by a 3mm biopsy punch. The instrument also has the extra advantages of being in the correct working position when held with the hand in the resting position between prone and supine, of allowing an uninterrupted line of vision to the wound during use and is of a shape that minimizes unintentional contact with tissue.     

Enhanced affective aggression in genetically bred hypercholinergic rats

Affective aggression was studied in pairs of Flinders Sensitive Line hypercholinergic rats (FSL) and Flinders Resistant Line (FRL) rats in shock-induced and apomorphine-induced fighting tests. FSL rats were significantly more aggressive in both tests. They had higher pain threshold, assessed by the jump-flinch method, than FRL rats. It is concluded that genetically developed cholinergic system supersensitivity has resulted in enhanced responsiveness to stimuli eliciting affective aggression.     

Evidence for humoral effects on the radiation response of rat foot skin.

The influence of perturbation of the physiologic state of the whole body on the outcome of radiation exposure has been examined in a rat foot model. Irradiation was carried out using 60Co gamma-rays. Moist desquamation was used as an endpoint. Rats were given a priming dose of 2 Gy, 4 Gy or 7 Gy to their whole body except their hind feet (partial body priming dose). After a variable time period both hind feet of these animals were irradiated with graded doses of 60Co gamma-rays. The incidence of moist desquamation in the irradiated feet of these animals was compared with the incidence of moist desquamation in animals that had not received the initial partial body priming dose. It was noticed that the incidence of moist desquamation in the rat foot skin of animals that received 7 Gy partial body priming dose 4 h prior to irradiation of their hind feet was significantly less than moist desquamation in control animals. The ED(50) value of 22.53+/-0.16 Gy for moist desquamation of the foot skin of control animals was significantly lower (p<0.01) than the value of 25.25+/-0.29 Gy obtained for animals that received a partial body priming dose of 7 Gy 4 h prior to irradiation of their hind feet. It was concluded that the response of rat foot skin to radiation was not purely the result of epidermal stem cell kill and that it can be modified by alterations in the overall physiological state of the animal's body brought about by a priming dose to the whole of the animal's body except the hind feet.     

优秀女子赛艇运动员比赛前后血乳酸、血尿素及血清肌酸激酶跟踪测试

目的:跟踪测试优秀女子赛艇运动员比赛前后血乳酸、血尿素及血清肌酸激酶的变化,探讨女子赛艇运动员机体能量物质代谢和赛后疲劳恢复的特点。方法:选取2005-07/09湖北省水上运动中心优秀女子运动员14名,其中国家健将级运动员7名,国家一级运动员7名;平均年龄(22±4)岁,训练年限(4.1±1.4)年,身高(174.2±3.1)cm,体质量(68.6±4.7)kg。14名运动员分别于2000m划艇比赛当日晨空腹、赛前15min、赛后5min,1h及24h抽取指尖血60μL,进行血乳酸、血尿素、血清肌酸激酶检测。结果:14名运动员全部进入结果分析。①比赛前后运动员血乳酸水平的变化:运动员空腹血乳酸水平为(1.22±0.45)mmol/L,赛前15min为(2.89±0.49)mmol/L。赛后5min血乳酸浓度高达(11.51±1.72)mmol/L,与空腹水平比较差异有显著性意义(t=3.077,P<0.01)。赛后24h血乳酸浓度显著下降至(1.76±0.24)mmol/L,与空腹水平基本接近(t=0.027,P>0.05)。②比赛前后运动员血尿素水平的变化:与空腹血尿素水平比较,运动员赛后5min血尿素浓度明显升高[(5.45±0.47),(6.13±1.00)mmol/L;t=2.416,P<0.05]。赛后24h血尿素浓度下降至(5.94±0.85)mmol/L,仍高于空腹水平(t=2.682,P<0.05)。③比赛前后运动员血清肌酸激酶活性的变化:与赛前比较,运动员赛后5min血清肌酸激酶活性明显升高[(3.38±1.58),(6.13±3.25)nkat/L;t=4.968,P<0.01]。赛后1h血清肌酸激酶活性开始下降,至赛后24h与赛前基本相似(t=1.537,P>0.05)。结论:①赛后5min血乳酸、血尿素、血清肌酸激酶活性显著高于赛前,赛后1h血乳酸消除迅速,但仍未恢复到正常水平。提示赛艇是一种以糖酵解系统为主、无氧 有氧代谢混合型供能的运动项目。②赛艇比赛使酸性产物生成增多,血乳酸、血尿素、血清肌酸激酶可作为运动强度和机能恢复的指标。③赛艇比赛后至少24h内,机体处于蛋白质降解增强状态,建议恢复期增加饮食糖和蛋白质摄入量,以促进合成代谢,加快功能恢复过程。     

Critical role of Aquaporin-1 and telocytes in infantile hemangioma response to propranolol beta blockade

Propranolol, a nonselective β-adrenergic receptor (ADRB) antagonist, is the first-line therapy for severe infantile hemangiomas (IH). Since the incidental discovery of propranolol efficacy in IH, preclinical and clinical investigations have shown evidence of adjuvant propranolol response in some malignant tumors. However, the mechanism for propranolol antitumor effect is still largely unknown, owing to the absence of a tumor model responsive to propranolol at nontoxic concentrations. Immunodeficient mice engrafted with different human tumor cell lines were treated with anti-VEGF bevacizumab to create a model sensitive to propranolol. Proteomics analysis was used to reveal propranolol-mediated protein alteration correlating with tumor growth inhibition, and Aquaporin-1 (AQP1), a water channel modulated in tumor cell migration and invasion, was identified. IH tissues and cells were then functionally investigated. Our functional protein association networks analysis and knockdown of ADRB2 and AQP1 indicated that propranolol treatment and AQP1 down-regulation trigger the same pathway, suggesting that AQP1 is a major driver of beta-blocker antitumor response. Examining AQP1 in human hemangioma samples, we found it exclusively in a perivascular layer, so far unrecognized in IH, made of telocytes (TCs). Functional in vitro studies showed that AQP1-positive TCs play a critical role in IH response to propranolol and that modulation of AQP1 in IH-TC by propranolol or shAQP1 decreases capillary-like tube formation in a Matrigel-based angiogenesis assay. We conclude that IH sensitivity to propranolol may rely, at least in part, on a cross talk between lesional vascular cells and stromal TCs.

Infantile hemangioma (IH), the most frequent tumor of infancy affecting 1 to 5 out of 100 newborns, is a noncongenital benign vascular tumor. Although most IHs are small, inconsequential, and regress spontaneously in many cases, medical treatment is needed in at least 15% of cases. The current first-line therapy for severe IH is systemic propranolol, a nonselective β-adrenergic receptor (ADRB) antagonist (1). Three subtypes of ADRBs (ADRB1, ADRB2, and ADRB3), which are coded by three distinct genes, belong to the superfamily of G protein–coupled receptors. They are characterized by a pocket containing binding sites for agonists (e.g., adrenaline and noradrenaline) and competitive antagonists (e.g., propranolol and timolol) (2). Although a role for ADRB in cancer progression was suggested long ago (3), our serendipitous observation of the efficacy of propranolol in treating IH (4) prompted many researchers to explore the anticancer properties of β-blockers.Although the therapeutic effect of propranolol is thought to be due to its ability to affect vasoconstriction, endothelial cell (EC) apoptosis, and/or inhibition of angiogenesis by modulating vascular endothelial growth factors (5, 6), the precise mechanism of its action is still under debate and largely unknown. Propranolol has been shown to have a growth inhibitory effect as a monotherapy on hemangioma cells in vitro (7–9). Nevertheless, growth inhibition was observed at doses 100- to 1,000-times higher than the plasmatic dose measured in treated IH patients (i.e., never above 0.5 µM) (10). It is then difficult to make the assumption that the effect of propranolol in IH can be mimicked and studied with such unrealistic doses. Indeed, the absence of an in vivo IH model that has shown a tumor growth inhibition induced by propranolol as well as difficulties in accessing IH patient samples before and after treatment have jointly hindered the quest to reveal its mechanism of action. Although several attempts have been made to create an in vivo IH model, a convincing antitumor effect of propranolol is still lacking (11–15). Of note, Lee et al. showed an effect of propranolol on vascular volume in a model of hemangioma cell–formed vessels in mice but without studying the effect on tumor growth (15). Considering this global effort and given the potential interest to identify a biomarker of malignant tumors sensitive to propranolol, we decided to explore the antitumor effect of propranolol in different tumor types in vivo. Retrospective clinical studies have shown that β-blocker use for hypertension is associated with improved cancer-specific survival compared with patients using other types of antihypertensive medications. For instance, a beneficial effect on survival was seen in breast cancer patients receiving the nonselective β-blocker propranolol but not with the β-1 antagonist atenolol (16). Additional studies showed a benefit of β-blocker use in patients with colorectal (17, 18) and pancreatic cancer (19). A prospective nonrandomized study of propranolol in the adjuvant setting for resected melanoma found an 80% reduction in melanoma recurrence (20). However, prospective clinical evidence supporting a role for propranolol in cancer treatment or prevention is limited. It is unlikely that beta blockade becomes an anticancer drug as a monotherapy, but combination therapy seems more promising (21). In this work, our hypothesis was that the antitumor effect of propranolol in malignant tumors was related to some common feature with the IH microenvironment. Since the increase of hypoxia-induced mediators has been shown in children with hemangioma (22, 23), we speculated that a hypoxic microenvironment could trigger the propranolol antitumor effect. We therefore chose a model of human malignant tumor cells xenografted in immunocompromised mice with continuous treatment of anti–vascular endothelial growth factor-(VEGF-A) bevacizumab (Avastin), hereafter abbreviated as Bev, in order to obtain a hypoxic tumor model (24). Tumor hypoxia induced by sunitinib and bevacizumab has already been used in mouse models in order to study specific drug sensitivity induced by up-regulation of HIF-1-α hypoxia (25). Sunitinib has also been used to assess propranolol antitumor efficacy in a melanoma model (26); nonetheless, bevacizumab is a more specific antiangiogenic drug than sunitinib.Using human malignant cell lines xenografted into immunodeficient mice as a model, we show in this study that propranolol induced the down-regulation of aquaporin-1 (AQP1), a transmembrane protein forming a channel for water and small solutes (27–30), and has a very pronounced effect on tumor growth in our mouse model (31–34). Looking for AQP1 expression in IH, we describe a special peripheral vascular layer made of dendritic cells named telocytes (TCs) with highly specific expression of AQP1, suggesting a key role in the exquisite sensitivity of IH to propranolol, which was verified in vitro with patients’ cells.