BACKGROUND & AIMS: BACKGROUND AND PURPOSE:In patients with stage I seminoma treated with elective lymph node irradiation, testicular scatter doses are often thought to be responsible for later disturbances in fertility. We studied the influence of radiation field extensions and testicular doses on hormonal function.

MATERIALS AND METHODS:FSH (follicle stimulating hormone) and LH (luteinizing hormone) were evaluated before radiotherapy (RT) and by serial analyses after treatment for 4 years. Twenty-three patients were irradiated by hockey stick fields with a mean dose of 31.9 Gy (+/-4.7 SD) and a mean scatter dose of 54 8 cGy (+/-16.6 SD). Twenty-one patients received limited RT to the paraaortic nodes with 28.1 Gy (+/-2.4 SD). The mean testicular dose was only 25 cGy (+/-7.8 SD). All patients had normal pre-treatment hormonal values.

RESULTS:Six months after the end of RT, mean FSH values were significantly elevated in the hockey stick group (P = 0.032), returning to normal after 3 years. The increase in LH was also significant, but stayed within normal ranges. Limited RT resulted in a minimal, dose-dependent increase of FSH; no changes in LH were noted.

CONCLUSIONS:In patients with a normal hormonal status after semicastration, FSH is a reliable monitor for transient radiation-induced effects. To avoid treatment-related disturbances in spermatogenesis, scatter doses should be reduced to less than 20 cGy.

背景与目标： 背景和目的 : 在接受选择性淋巴结照射治疗的I期精原细胞瘤患者中，睾丸散射剂量通常被认为是后来生育力紊乱的原因。我们研究了辐射场扩展和睾丸剂量对激素功能的影响。
材料和方法 : 在放疗前 (RT) 和治疗4年后通过连续分析评估FSH (卵泡刺激素) 和LH (黄体生成素)。用平均剂量为31.9 Gy (/-4.7 SD) 和平均散射剂量为54 8 cGy (/-16.6 SD) 的曲棍球棒场照射了23例患者。21例患者接受了有限的主动脉旁淋巴结RT，28.1 Gy (+/-2.4 SD)。平均睾丸剂量仅为25 cgy (+/-7.8 SD)。所有患者的治疗前激素值均正常。
结果 : RT结束后六个月，曲棍球棒组的平均FSH值显着升高 (P = 0.032)，3年后恢复正常。LH的增加也很明显，但保持在正常范围内。有限的RT导致FSH的剂量依赖性增加最小; 未注意到LH的变化。
结论 : 在半去势后激素状态正常的患者中，FSH是瞬时辐射诱导作用的可靠监测仪。为避免与治疗相关的精子发生紊乱，应将散射剂量降低至20 cGy以下。

BACKGROUND & AIMS: :Etanercept is a recombinant human soluble tumor necrosis factor (TNF-alpha) receptor fusion protein that inhibits TNF-alpha, a major mediator in the pathogenesis of graft-versus-host disease (GVHD). The purpose of our study was to evaluate the safety and efficacy of etanercept therapy in 21 patients with steroid-refractory acute GVHD (aGVHD) (n = 13) and chronic GVHD (cGVHD) (n = 8). Etanercept 25 mg was given subcutaneously twice weekly for 4 weeks followed by 25 mg weekly for 4 weeks. At the time of initiation of etanercept, 14 patients had skin, 13 had gastro-intestinal, 5 had liver, 5 had pulmonary, and 4 had oral involvement. Twelve patients (57%) completed 12 doses of therapy. Overall, 11 of 21 patients (52%) responded to the treatment with etanercept, including 6 patients (46%) with aGVHD [n = 4 complete response (CR), n = 2 partial response (PR)] and 5 patients (62%) with cGVHD (n = 1 CR, n = 4 PR). Clinical responses were most commonly seen in patients with refractory gut aGVHD with 55% of the patients having a CR and 9% having a PR. CMV reactivation occurred in 48% of patients, bacterial infections in 14% of patients, and fungal infections in 19% of patients. Fourteen patients (67%) were alive after a median follow-up of 429 days (range 71-1007 days) since initiation of etanercept. Seven patients died, 3 of infections, 2 of refractory aGVHD, and 2 of disease progression. In conclusion, our preliminary data indicate that etanercept is well tolerated and can induce a high response rate in patients with steroid-refractory aGVHD and cGVHD, particularly in the setting of GI involvement.

背景与目标： : 依那西普是一种重组人可溶性肿瘤坏死因子 (TNF-α) 受体融合蛋白，可抑制TNF-α，TNF-α 是移植物抗宿主病 (GVHD) 发病机理中的主要介质。我们研究的目的是评估依那西普治疗21例类固醇难治性急性GVHD (aGVHD) (n = 13) 和慢性GVHD (cGVHD) (n = 8) 患者的安全性和有效性。依那西普25 mg，每周皮下注射两次，持续4周，然后每周注射25 mg，持续4周。在开始使用依那西普时，14例患者有皮肤，13例有胃肠道，5例有肝脏，5例有肺部，4例有口腔受累。12名患者 (57%) 完成12剂治疗。总体而言，21例患者中有11例 (52%) 对依那西普治疗有反应，其中6例 (46% 例) aGVHD [n = 4完全缓解 (CR)，n = 2部分缓解 (PR)] 和5例 (62%) cGVHD (n = 1 CR，n = 4 PR)。临床反应最常见于难治性肠道aGVHD患者，其中55% 患者具有CR，9% 患者具有PR。48% 患者发生CMV再激活，14% 患者发生细菌感染，19% 患者发生真菌感染。自依那西普开始以来，中位随访429天 (范围71-1007天) 后，有14名患者 (67%) 还活着。7例患者死亡，3例感染，2例难治性aGVHD，2例疾病进展。总之，我们的初步数据表明，依那西普具有良好的耐受性，并且可以在类固醇难治性aGVHD和cGVHD患者中诱导高反应率，尤其是在GI受累的情况下。

BACKGROUND & AIMS: Calcitriol has been widely used in the management of osteoporosis, but its efficiency is a matter of controversy. It is not known whether combinations of calcitriol and antiresorptive agents such as etidronate and calcitonin are superior to calcitriol alone in the treatment of postmenopausal osteoporosis. To make this determination, 30 Turkish women with postmenopausal osteoporosis between 45 and 68 years of age were randomized to receive either intermittent cyclical etidronate (400 mg/day, for 14 days) followed by 60 days of cyclical calcitriol therapy 0.25 microg twice daily (group 1; n = 10), or calcitriol 0.25 microg twice daily (group 2; n = 10), or calcitriol 0.25 microg/day in combination with 100 IU intranasal salmon calcitonin taken every other day (group 3; n = 10) through a 1-year period. Bone mineral density (BMD) of lumbar spine (L2 to L4) was determined for each patient by dual-photon absorptiometry (153Gd) at baseline, after 6 months, and at the end of the study. There was no significant difference among groups with respect to mean spinal BMD at baseline, after 6, and after 12 months. No significant spinal BMD changes occurred in any group from baseline, after 6 months, and after 12 months. Four patients in groups 1 and 2 and five patients in group 3 developed hypercalcemia at least once during therapy. Hypercalciuria occurred at least once in 9, 10, and 7 patients in groups 1, 2, and 3, respectively. One patient in group 2 developed a renal stone at the end of the study. Mean urine hydroxyproline levels did not change significantly in any group with respect to baseline. The data suggest that one-year treatment with calcitriol, given either alone or in combination with antiresorptive agents, does not improve spinal BMD in Turkish women with postmenopausal osteoporosis, and is associated with a high rate of adverse events.

背景与目标： 骨化三醇已广泛用于骨质疏松症的治疗，但其效率仍存在争议。尚不清楚骨化三醇和抗吸收剂 (如依替膦酸盐和降钙素) 的组合在绝经后骨质疏松症的治疗中是否优于单独的骨化三醇。为了做出这一决定，30名年龄在45至68岁之间的绝经后骨质疏松症土耳其妇女被随机分配接受间歇性周期性依替膦酸盐 (400毫克/天，持续14天)，然后接受60天的周期性骨化三醇治疗，0.25每天两次 (组1; n = 10)，或骨化三醇0.25 microg每天两次 (组2; n = 10)，或骨化三醇0.25 microg/天与100 IU鼻内鲑鱼降钙素组合，每隔一天服用 (组3; n = 10)，持续1年。在基线，6个月后和研究结束时，通过双光子吸收法 (153Gd) 测定每位患者的腰椎 (L2至L4) 的骨矿物质密度 (BMD)。在基线，6个月后和12个月后，各组之间的平均脊柱BMD没有显着差异。从基线，6个月后和12个月后，任何组均未发生明显的脊柱BMD变化。第1组和第2组中的4名患者和第3组中的5名患者在治疗期间至少出现一次高钙血症。高钙尿症分别在第1、2和3组的9、10和7名患者中至少发生一次。第2组中的一名患者在研究结束时出现了肾结石。任何组的平均尿羟脯氨酸水平相对于基线没有明显变化。数据表明，单独或与抗吸收剂联合使用骨化三醇治疗一年不会改善土耳其绝经后骨质疏松症妇女的脊柱BMD，并且与不良事件的发生率很高有关。

BACKGROUND & AIMS: Evidence relating dietary sodium and blood pressure comes from a variety of sourcesanimal experiments, observational epidemiologic studies, migration studies, and randomized controlled trials. In this review, we examine new findings in each of these areas published during 1995 and 1996. Results from both observational epidemiologic studies and randomized controlled trials demonstrated a dose-response association between dietary sodium and blood pressure in humans. The relationship of dietary sodium to blood pressure was modified by age, race, body weight, and initial level of blood pressure. On average, a 100-mmol decrease in urinary sodium was associated with a reduction of approximately 3 mm Hg in systolic and a 2 mm Hg in diastolic blood pressure. In a general population, this blood pressure reduction would substantially reduce the societal burden of cardiovascular and renal diseases.

背景与目标： 有关饮食钠和血压的证据来自各种来源的动物实验，观察性流行病学研究，迁移研究和随机对照试验。在这篇综述中，我们研究了1995年和1996发表的每个领域的新发现。观察性流行病学研究和随机对照试验的结果表明，饮食钠与人类血压之间存在剂量反应关联。饮食钠与血压的关系因年龄，种族，体重和血压的初始水平而改变。平均而言，尿钠降低100 mmol与收缩压降低约3毫米Hg和舒张压降低2毫米Hg相关。在一般人群中，这种血压降低将大大减轻心血管和肾脏疾病的社会负担。

BACKGROUND & AIMS: The De Materia Medica of the Greek Dioscorides reports about 200 plants used for the treatment of pathologies of the urogenital tract during the 1st century AD. On the basis of explicit and implicit affirmations by Dioscorides, a theoretical system concerning the specific properties of these plants has been attempted. Comparison of the species reported by Dioscorides and Pliny the Elder for renal affections does not support the thesis of a close relationship between De Materia Medica and the Naturalis Historia.

背景与目标： 希腊diosccorides的《本草》报道了公元1世纪用于治疗泌尿生殖道病变的200种植物。在diosccorides的显性和隐性肯定的基础上，尝试了有关这些植物特定特性的理论体系。Dioscarides和Pliny the Elder报道的肾脏感染物种的比较不支持本草与自然历史之间密切关系的论点。

BACKGROUND & AIMS: There is evidence that neutrophil functions such as chemotaxis and oxygen radical formation are disturbed in rheumatoid arthritis (RA). Medication might also influence these functions. Cyclic formation and depolymerisation of actin microfilaments is crucial in cell motility, but this phenomenon has not been studied in RA. The aim of this study was to investigate basal and dynamic (formyl-methionyl-leucyl-phenylalanine (fMLP)-induced) neutrophil actin polymerisation in ten RA patients (a) during therapy with non-steroidal anti-inflammatory drugs (NSAIDS) and (b) after stopping NSAIDS> The results were compared with those of ten age-matched controls. Basal F-actin content in RA patients with NSAIDS was significantly lower than in RA patients without NSAIDS and controls35.5 (25.0-49.0), 50.5 (27.0-75.0) and 52.5 (32.0-85.0), respectively. Conversely, upon stimulation with fMLP, the actin polymerisation curve of RA patients with NSAIDS was higher than for RA patients without NSAIDS and controls. These results suggest that, in RA, the effects orf NSAIDS on neutrophil functions might be related to changes in the actin polymerisation-depolymerisation cycle.

背景与目标： 有证据表明，类风湿性关节炎 (RA) 的中性粒细胞功能 (例如趋化性和氧自由基形成) 受到干扰。药物也可能影响这些功能。肌动蛋白微丝的循环形成和解聚对细胞运动至关重要，但尚未在RA中研究这种现象。这项研究的目的是研究10名RA患者 (a) 在非甾体类抗炎药 (nsaid) 治疗期间的基础和动态 (甲酰基-甲硫氨酸-亮氨酸-苯丙氨酸 (fMLP) 诱导的) 中性粒细胞肌动蛋白聚合反应 (a) 和 (b) 停止nsaid后的结果进行比较有十个年龄匹配的对照。患有NSAIDS的RA患者的基础F-肌动蛋白含量显着低于没有NSAIDS和对照组的RA患者35.5 (25.0-49.0)，50.5 (27.0-75.0) 和52.5 (32.0-85.0)。相反，用fMLP刺激后，患有NSAIDS的RA患者的肌动蛋白聚合曲线高于没有NSAIDS的RA患者和对照组。这些结果表明，在RA中，orf nsaid对中性粒细胞功能的影响可能与肌动蛋白聚合-解聚周期的变化有关。

BACKGROUND & AIMS: OBJECTIVE:To review the data on the efficacy of oxcarbazepine (OXC) in bipolar disorder (BD) and to provide recommendations for clinicians on the use of this medication in treating BD. METHOD:Using the terms oxcarbazepine and bipolar disorder, oxcarbazepine and mania, or oxcarbazepine and bipolar depression, we conducted a computer-aided search of MEDLINE for the years 1950 to 2005. RESULTS:Case reports, retrospective chart reviews, open prospective studies, and double-blind studies reported the efficacy and effectiveness of OXC in treating BD. The data indicate that OXC has efficacy in treating acute mania and may be a useful add-on in treating acute bipolar depression and in BD prophylaxis. OXC is generally well-tolerated. CONCLUSION:We recommend using OXC as monotherapy or as add-on therapy in refractory mania, but we recommend it be used predominantly as an add-on treatment for other phases of BD in patients who have not improved with well-established treatments or in patients who have difficulty tolerating adequate dosages.

背景与目标：

BACKGROUND & AIMS: :In an open, multi-centre study in general practice, a comparison was made of the efficacy, tolerability and acceptability of a neomycin/dexamethasone preparation administered by metered-dose spray ('Otomize') and a framycetin/gramicidin/dexamethasone preparation ('Sofradex') administered as drops in 60 patients with otitis externa. Patients were allocated at random to receive one or other preparations 3-times daily for 10 days and were followed-up again 14 days after cessation of therapy. Clinical assessments were carried out under observer blind conditions on entry (Day 0) and on Days 10 and 24 of the severity of erythema, swelling and debris in the affected ear(s). A global assessment of clinical outcome was made by the doctor on Day 10. There were no significant differences in the two groups at the start of treatment. Significant improvement occurred in both groups from Day 0 to Day 10 and from Day 10 to Day 24 in all symptoms, with the proportion symptom-free in the 'Otomize' group significantly greater than in the 'Sofradex' group at 24 days, and approaching significance at 10 days. Significantly more patients in the 'Otomize' group were rated as having a good clinical outcome by the physician, and fewer patients experienced discomfort on application. Few side-effects were reported by either treatment group, none necessitating discontinuation of therapy.

背景与目标： : 在一项常规的开放，多中心研究中，比较了通过定量喷雾 ('Otomize') 和framycetin/gramicidin/地塞米松制剂的疗效，耐受性和可接受性。地塞米松制剂 ('Sofradex') 以滴剂形式在60例外耳道炎患者中使用。患者被随机分配接受一种或其他制剂，每天3次，持续10天，并在停止治疗后14天再次随访。在进入 (第0天) 以及受影响的耳朵中红斑，肿胀和碎屑的严重程度的第10天和第24天，在观察者盲条件下进行临床评估。医生在第10天对临床结果进行了全面评估。治疗开始时两组无显著差异。在所有症状中，两组从第0天到第10天以及从第10天到第24天均出现显着改善，“otomize” 组无症状的比例在24天显着高于 “sofradex” 组，并在10天接近显着性。医生将 “otomize” 组中的更多患者评为具有良好的临床结果，并且更少的患者在应用中出现不适。任何治疗组都很少报告副作用，没有必要停止治疗。

BACKGROUND & AIMS: -2

背景与目标： -2

BACKGROUND & AIMS: :A 29-year-old man was admitted to our institution 10 days after he had undergone an urgent exploratory laparotomy at a local army hospital after a terrorist bombing attack. On admission, deep second-degree and third-degree burns involving 25% of the upper and lower extremities were present, together with a 25 x 10-cm abdominal full-thickness blast injury defect on the left side, an infected eviscerated midline incision, and a colostomy on the right side of the abdomen. The patient underwent a second laparotomy, at which time the intraabdominal abscess was drained, and the abdominal cavity was irrigated with saline. A jejunal perforation was found and sutured. The abdominal cavity was left open and covered with a Bogota bag for temporary closure. On postburn day 18, the patient underwent débridment and grafting of the third-degree burns to the left and right arm and right lower extremities. After several débridment sessions (postburn days 16, 18, 20, 22, and 24), an abdominal skin release and reapproximation were performed (postburn day 26). On postburn day 36, split-thickness skin grafts were placed directly on the granulated tissue of the intestines and on a defect in the left flank and iliac regions. Postoperatively, the patient did well. He was discharged on postburn day 78 with all wounds well healed. In our opinion, temporary closure followed by direct application of meshed split-thickness skin grafts to exposed abdominal viscera represents a simple method of reconstruction that can be safely performed, with minimal risk, on critically ill patients.

背景与目标： : 一名29岁的男子在恐怖爆炸袭击后在当地一家军队医院接受紧急剖腹探查术10天后被送入我们的机构。入院时，出现了涉及上下肢25% 的深二度和三度烧伤，左侧有25x10 cm的腹部全层爆炸伤缺损，感染的内脏中线切口，以及腹部右侧的结肠造口术。患者接受了第二次剖腹手术，此时引流了腹腔内脓肿，并用盐水冲洗了腹腔。发现空肠穿孔并缝合。腹腔保持开放状态，并用波哥大袋覆盖，以暂时关闭。在烧伤后第18天，患者接受了三度烧伤的移植，并将其移植到左，右臂和右下肢。经过几次缓解 (烧伤后第16、18、20、22和24天) 后，进行了腹部皮肤释放和重新逼近 (烧伤后第26天)。在烧伤后的第36天，将厚度分开的皮肤移植物直接放置在肠的颗粒状组织以及左侧和ili区的缺损处。术后，患者表现良好。他在烧伤后第78天出院，所有伤口均愈合良好。在我们看来，暂时封闭，然后直接将网状厚度的皮肤移植物应用到暴露的腹部内脏上，代表了一种简单的重建方法，可以对危重病人安全地进行，风险最小。

BACKGROUND & AIMS: OBJECTIVE:To identify and review early complications in the operative treatment of patella fractures. DESIGN:Retrospective review. SETTING:Single tertiary care institution with multiple surgeons, including generalists and fellowship trained subspecialists. PATIENTS:A consecutive series of eighty-seven patella fractures over a five year period was reviewed. Patients treated nonoperatively or with partial or total patellectomy were excluded. Minimum follow-up to fracture healing (four months) was available in fifty-one fractures. INTERVENTION:Modified tension band wire fixation was used in forty-nine fractures, whereas two fractures were treated with tension band wires threaded through cannulated screws. OUTCOME MEASURES:Early complications such as loss of reduction or fixation, infection, or soft-tissue problems were evaluated. RESULTS:Displacement of > or = 2 mm before healing was noted in eleven fractures. The displacement could be attributed to technical errors in five cases, and to patient noncompliance with postoperative activity restrictions in another five cases. Two cases of superficial infection were documented. Nine patients with symptomatic hardware required hardware removal. CONCLUSIONS:Twenty-two percent of fractures treated with tension band wiring and early motion displaced > or = 2 mm within the early postoperative period. Technical errors or patient noncompliance were identified as factors. The incidence of early complications in operatively treated patella fractures is higher than previously reported.

背景与目标：

BACKGROUND & AIMS: STUDY DESIGN:Clinical case series. OBJECTIVE:To describe a series of patients with progressive sagittal decompensation caused by failure at the caudal end of an instrumented lumbar fusion. SUMMARY OF BACKGROUND DATA:Lumbar kyphosis in association with global sagittal decompensation can be a disabling problem, particularly as a late complication of distraction instrumentation. Although kyphosis at the rostral end of instrumented fusions secondary to adjacent segment degeneration has been well described, substantially less has been documented about failure and kyphosis at the caudal end. METHODS:Patients who have a progressive lumbar kyphosis and sagittal decompensation requiring operative revision were retrospectively reviewed, and radiographic measurements of lumbar lordosis and sagittal balance were performed to study this problem. RESULTS:There were 13 patients identified. The most common mode of caudal junctional decompensation was related to failure of the most distal fixation. Sagittal decompensation occurred even in the presence of satisfactory lumbar lordosis. Revision surgery and improved sagittal balance were achieved typically using the technique of pedicle subtraction osteotomy and extension of the instrumentation to the sacrum. Osteoporosis, hip osteoarthritis, and substance abuse were commonly observed associations. CONCLUSIONS:Fixation failure at the caudal end of lumbar-instrumented fusion should be considered in patients with progressive sagittal decompensation. The high potential for failure of L5 pedicle screws after the index surgery warrants serious consideration of extending such fusions into the sacrum/ilium.

背景与目标：

BACKGROUND & AIMS: :Fludarabine and alemtuzumab are routinely used for treatment of B-cell chronic lymphocytic leukemia (B-CLL). The present study aimed to compare the expression of signaling molecules and cytokine production by T cells of B-CLL patients in long-term unmaintained remission/plateau phase following fludarabine or alemtuzumab treatment with that of indolent/untreated B-CLL patients and healthy donors. The frequency and intensity of TCR-CD3zeta chain, p56lck, p59fyn, ZAP-70, PI3-kinase and interferon (IFN)-gamma/interleukin (IL)-4 production in CD4 and CD8 T cells was examined by flow cytometry. T-cell function was assessed by stimulation with purified protein derivative (PPD) and phytohemagglutinin (PHA). Despite a reduction in number, the expression of IFN-gamma/IL-4 in T-cells in patients was significantly higher than in healthy donors. The intensity of most signaling molecules in treated patients was relatively unaffected vs. healthy donors but lower than untreated-indolent patients. However, the total number of T cells which expressed each of the signaling molecules was decreased in patients, with no difference between fludarabine- and alemtuzumab-treated patients. The T-cell response to PHA but not PPD was reduced in treated patients. The results suggest that, despite some alterations in signaling molecules and a reduction in T-cell number, overall T-cell functions may be relatively well preserved long-term after treatment with fludarabine and alemtuzumab.

背景与目标： : 氟达拉滨和阿仑单抗通常用于治疗b细胞慢性淋巴细胞白血病 (b-cll)。本研究旨在比较在氟达拉滨或阿仑单抗治疗后长期未维持缓解/平台期的b-cll患者的T细胞与惰性/未治疗的b-cll患者和健康的T细胞的信号分子表达和细胞因子产生供体。通过流式细胞术检查CD4和CD8 T细胞中TCR-CD3zeta链，p56lck，p59fyn，ZAP-70，PI3-kinase和干扰素 (IFN)-γ/白细胞介素 (IL)-4产生的频率和强度。通过纯化蛋白衍生物 (PPD) 和植物血凝素 (PHA) 刺激来评估T细胞功能。尽管数量减少，但患者T细胞中IFN-γ/IL-4的表达显着高于健康供体。与健康供体相比，接受治疗的患者中大多数信号分子的强度相对不受影响，但低于未经治疗的惰性患者。然而，在患者中表达每种信号分子的T细胞总数减少，而氟达拉滨和阿仑单抗治疗的患者之间没有差异。在治疗的患者中，T细胞对PHA的反应降低，但对PPD的反应降低。结果表明，尽管信号分子发生了一些变化，T细胞数量减少，但在用氟达拉滨和阿仑单抗治疗后，总体T细胞功能可能长期保持良好。

BACKGROUND & AIMS: :1. Tolerance to the hypotensive effect of nitroglycerin (NG) blocks preconditioning induced by rapid ventricular pacing (RVP) in rabbits. In the present work the effect of continuous versus intermittent treatment with transdermal nitroglycerin on the pacing-induced preconditioning phenomenon was studied in conscious rabbits. 2. RVP (500 beats min-1 over 5 min) increased left ventricular end-diastolic pressure (LVEDP) from baseline 4.1 +/- 0.9 to postpacing 13.8 +/- 2.9 mmHg (P < 0.001) with a right intraventricular ST-segment elevation of 1.25 +/- 0.13 mV, two indicators of myocardial ischaemia. These changes were significantly attenuated when the RVP period was preceded by a preconditioning pacing of the same rate and duration with an interpacing interval of 5 min. 3. Protection by preconditioning was abolished when the animals had been made tolerant to the vasodilator effect of 30 micrograms kg-1 NG by the application of transdermal NG (approx. 0.07 mg kg-1 h-1) over 7 days. Furthermore, transdermal NG per se attenuated both RVP-induced ST-segment elevation and LVEDP-increase over the 7 day period. 4. With intermittent transdermal NG treatment (12 h 'patch on' vs 'patch off'), neither development of vascular tolerance nor attenuation of the NG- or preconditioning-induced anti-ischaemic effects were observed. However, the severity of pacing-induced myocardial ischaemia was significantly increased during the 'patch off' periods. 5. In a second set of experiments, postpacing changes in cardiac cyclic GMP and cyclic AMP levels were determined by means of radioimmunoassay in chronically instrumented anaesthetized open-chest rabbits with the same NG-treatment protocols. Preconditioning reduced postpacing increase in cyclic AMP with an increase in cyclic GMP concentrations in hearts of the untreated animals and in those given patches intermittently during both 'patch on' and 'patch off' periods. However, the preconditioning effect on either cyclic nucleotide was blocked in the tolerant animals. 6. Transdermal NG increased resting levels of both cardiac cyclic nucleotides in the non-tolerant but not in the tolerant state. The postpacing increase in cyclic AMP content was inhibited by transdermal NG, independent of vascular tolerance development, whereas an cyclic GMP content was exclusively seen in the non-tolerant animals. 7. We conclude that the anti-ischaemic effect of NG is independent of the cyclic GMP mechanism in the tolerant state. While intermittent NG therapy prevents development of vascular tolerance and preserves preconditioning, the nitrate-free periods yield an increased susceptibility of the heart to ischaemic challenges.

背景与目标： : 1。对硝酸甘油 (NG) 的降压作用的耐受性阻断了兔快速心室起搏 (RVP) 引起的预处理。在本工作中，在清醒的兔子中研究了经皮硝酸甘油连续治疗与间歇治疗对起搏诱导的预处理现象的影响。2. RVP (500搏动min-1超过5分钟) 使左室舒张末期压 (LVEDP) 从基线4.1 +/- 0.9增加至起搏后13.8 +/- 2.9 mmHg (P <0.001)，右室ST段抬高1.25 +/- 0.13 mV，心肌缺血的两个指标。当在RVP期之前进行相同速率和持续时间的预处理起搏并间隔5分钟时，这些变化会显着减弱。3.当通过在7天内应用透皮NG (约0.07 mg kg-1 h-1) 使动物耐受30微克kg-1 NG的血管舒张作用时，取消了预处理的保护。此外，透皮NG本身在7天内减弱了RVP诱导的ST段抬高和LVEDP升高。4.间歇性经皮NG治疗 (12 h “贴剂” vs “贴剂”)，既没有观察到血管耐受性的发展，也没有观察到NG或预处理诱导的抗缺血作用的减弱。然而，起搏引起的心肌缺血的严重程度在 “修补” 期间显着增加。5.在第二组实验中，通过放射免疫分析法确定了具有相同NG治疗方案的慢性仪器麻醉开胸兔的心脏循环GMP和循环AMP水平的起搏后变化。预处理在未处理的动物心脏和给定的补片中，在 “补片” 和 “补片” 期间间歇性地减少了循环AMP的起搏后增加，循环GMP浓度增加。然而，在耐受性动物中，对任一环核苷酸的预处理作用均被阻断。6.透皮NG在非耐受状态下增加了两个心脏环核苷酸的静息水平，但在耐受状态下不增加。经皮NG抑制了循环AMP含量的起搏后增加，与血管耐受性的发展无关，而在非耐受性动物中仅观察到循环GMP含量。7.我们得出结论，在耐受状态下，NG的抗缺血作用与循环GMP机制无关。尽管间歇性NG疗法可防止血管耐受性的发展并保留预处理，但无硝酸盐期会增加心脏对缺血性挑战的敏感性。

BACKGROUND & AIMS: :In addition to their role in cellular homeostasis, pathways that regulate autophagy affect both tumorigenesis and tumor response to treatment. Therefore, understanding the regulation of autophagy in treated cancer cells is relevant to the discovery of molecular targets for the development of anti-cancer drugs. Our recent report points to radiation-induced inactivation of the mTOR pathway as an underlying mechanism of radiation-induced autophagy in the human breast cancer cell line MCF-7. Most importantly, radiation-induced inactivation of this pathway was detrimental to cell survival and was associated with reversal of mitochondrial ATPase activity and mitochondrial hyperpolarization, decreased level of eukaryotic initiation factor 4G (eIF4G) and increased phosphorylation of p53. Future analysis of the interrelationship among these events and the role each of them plays in cell survival following radiation will increase our ability to employ the mTOR pathway in anti-cancer therapy.

背景与目标： : 除了它们在细胞内稳态中的作用外，调节自噬的途径还影响肿瘤发生和肿瘤对治疗的反应。因此，了解治疗癌细胞中自噬的调控与发现抗癌药物开发的分子靶标有关。我们最近的报告指出，辐射诱导的mTOR途径失活是辐射诱导的人乳腺癌细胞系MCF-7自噬的潜在机制。最重要的是，辐射诱导的该途径的失活对细胞存活有害，并且与线粒体ATPase活性和线粒体超极化的逆转，真核起始因子4G (eIF4G) 水平降低和p53磷酸化增加有关。对这些事件之间的相互关系以及它们在辐射后的细胞存活中所起的作用的未来分析将提高我们在抗癌治疗中采用mTOR途径的能力。