Combined Therapy of Teicoplanin and Caffeic Acid Phenethyl Ester (CAPE) in the Treatment of Experimental Mediastinitis in the Rat

Abstract

Post-sternotomy mediastinitis affects 1-3% of patients undergoing cardiac surgery and is lethal in 10-47% of these patients.

We investigated the effect of an antioxidant/anti-inflammatory agent, caffeic acid phenethyl ester (CAPE), in the attenuation of inflammatory response induced by methicillin-resistant Staphylococcus aureus (MRSA) infection in a rat experimental mediastinitis model. Rats, divided into six equal groups, received MRSA precolonized stainless steel wire pieces implanted into their mediastinal spaces. Control group and CAPE control group received saline and CAPE 10 μmol/kg.day^?1 respectively, where Group A received a single dose of teicoplanin 24 mg/kg i.m. for the first day and then 12 mg/kg.day^?1. Group B received teicoplanin as in Group A plus CAPE 10 μmol/kg. day^?1 intra-peritoneally. Group C received teicoplanin 60 mg/kg i.m. for the first day and then 30 mg/kg.day^?1 and Group D received teicoplanin as in Group C plus CAPE 10 μmol/kg.day^?1. By the end of 14 days rats were sacrificed and serum malondialdehyde (MDA), myeloperoxidase (MPO), nitric oxide (NO), urea and creatinine levels were evaluated. Mediastinal organ tissues were collected for histopathological analysis.

Infection rates in all the drug-treated groups were lower than the control groups (P = 0.002) but statistical significance was attained only between the groups A and D (P = 0.018). In connective tissues and the peribronchial area polymorphonuclear leukocytic (PNL) infiltration in the treatment groups, although becoming very close, did not reach statistical significance (P = 0.053, P = 0.075, respectively). PNL infiltration especially in the peribronchial tissues of the Group B animals was found to be significantly less than the Control and CAPE Control groups with P values of 0.013 and 0.010, respectively. MDA and MPO levels were significantly lower in the treatment groups (P < 0.001 and P < 0.001 respectively). Levels of the degradation products of NO were lower in treatment groups compared to two control groups (P = 0.003, P = 0.005). NO levels in Group D were lowest among all treatment groups (P = 0.001).

It has been demonstrated that although bacterial colonization can be controlled in mediastinitis, the inflammatory response persists. The combination of an antioxidant / anti-inflammatory agent, CAPE, added to standard antibiotic therapy might be effective in the treatment of post-sternotomy mediastinitis due to MRSA.     

Comparison of the efficacy of tigecycline and teicoplanin in an experimental methicillin-resistant Staphylococcus aureus osteomyelitis model

We evaluated the efficacy of tigecycline and teicoplanin in a rat model of MRSA osteomyelitis. Osteomyelitis was induced with an intramedullary injection of 10(8 )colony-forming units (cfu) of MRSA. After osteomyelitis formation was confirmed on Day 14, infected rats were randomly divided into three groups: tigecycline (n=13), teicoplanin (n=13), and no-treatment control (n=14). A 28-day antibiotic therapy with a subcutaneous injection of tigecycline (14 mg/kg twice daily) or intramuscular administration of teicoplanin (20 mg/kg daily) was administered. Rats were then sacrificed, and the tibias were harvested. The bones were weighed and then cultured. Our results indicated that bacterial growth was significantly reduced in teicoplanin and tigecycline groups, compared to the control group (p=0.019 and p=0.006, respectively). However, no difference was detected between the two antibiotic groups (p=1.000). No bacterial growth was detected in 7 out of 13 and 9 out of 13 specimens of the teicoplanin and tigecycline treated groups, respectively. Although this result was numerically in favor of tigecycline, the difference was not statistically significant (p=0.427). In conclusion, tigecycline, a novel antibiotic, appears as an effective alternative to teicoplanin in the treatment of osteomyelitis caused by MRSA.     

幽门螺杆菌相关性胃疾病血清IL-8和NO含量的检测及意义

目的　检测幽门螺杆菌 (HP)相关性胃疾病患者血清白细胞介素 8(IL 8)和NO浓度 ,探讨其与HP感染的关系 ,以及HP感染引起胃上皮细胞增殖与凋亡失衡 ,导致胃癌形成的可能分子机制。方法　以ELISA法检测血清IL 8浓度 ,镀铜镉粒还原法检测血清NO浓度。结果　IL 8浓度在正常组织 (2 2 .5 0± 1.87pg ml)、浅表性胃炎 (34.99± 7.89pg ml)、萎缩性胃炎 (6 5 .2 7± 10 .6 0pg ml)及胃癌 (94 .84± 11.0 9pg ml)组间差异有显著性 (P <0 .0 1) ;萎缩性胃炎组NO浓度 (39.93± 5 .4 3μmol L)明显高于胃癌组 (37.0 2± 4 .13μmol L ,P <0 .0 5 ) ,其余各组间差异无显著性。HP(+)组IL 8和NO浓度显著高于HP(- )组 (77.30± 2 0 .92pg ml,39.16± 14 .4 0pg ml,P <0 .0 1;39.77± 5 .5 7μmol L ,35 .35±5 .2 4 μmol L ,P <0 .0 1) ;CagA(+)HP组IL 8和NO浓度显著高于HP(- )组 (83.4 5± 16 .92pg ml,6 6 .2 4± 2 3.2 1pg ml,P <0 .0 1;4 0 .97± 4 .5 9μmol L ,37.6 2± 6 .5 8μmol L ,P <0 .0 5 )。浅表性胃炎及萎缩性胃炎组的IL 8与NO呈正相关 (r分别为 0 .881和 0 .995 ) ,正常组和胃癌组无相关性。结论　血清IL 8和NO浓度与CagA(+)HP菌株感染密切相关 ;血清IL 8和NO浓度测定与HP菌株CagA分型联合检测将有助     

Optimal teicoplanin dosage regimens for methicillin-resistant Staphylococcus aureus infections in endocarditis patients and renal failure patients

This study aimed to assess whether traditional initial loading and maintenance doses of teicoplanin were appropriate in endocarditis and renal failure patients with methicillin-resistant Staphylococcus aureus (MRSA) infections and to recommend optimal dosage regimens. Pharmacokinetic parameters and physicochemical properties of teicoplanin were performed to develop pharmacokinetic models using GastroPlus^TM. Concentration–time curves of teicoplanin in endocarditis and renal failure patients with MRSA infections were simulated by changing clearance (CL) and volume of distribution of the central compartment (V_c). Different teicoplanin dosage regimens were assessed according to the target trough concentration, and optimal teicoplanin dosage regimens were recommended. Dosage regimen of four teicoplanin doses of 6 mg/kg q12 h followed by 6 mg/kg qd is recommended for renal failure patients infected by MRSA. And optimal dosage regimen is five teicoplanin doses of 15 mg/kg q12 h followed by doses of 12 mg/kg qd for endocarditis patients infected by MRSA.     

An unpredicted side effect of prophylactic antibiotic use

Abstract

Introduction and Objective:

We investigated the effects of cefazolin sodium (CS), on wound healing in rats.

Material and Method:

Forty rats in which an incisional wound model was created by removing two skin strips (4×1 cm), and suturing the wound edges, were included. Four groups were formed in a randomized way with each having 10 rats. The Control group (Group 1) received 1 cc 0·9% NaCl twice daily, whereas Group 2 received single-dose preoperative 30 mg/kg CS, Group 3 received single-dose preoperative 30 mg/kg CS followed by the same dose for three postoperative days, and Group 4 received single-dose preoperative 30 mg/kg CS followed by the same dose for seven postoperative days (via i.p. route). On the first day of the study, as the wound was created, a skin strip of 1×1 cm area was collected for bacteriologic examination. On the third day, specimens were acquired from the incision for histopathologic examination. The rats were sacrificed on the seventh day and more specimens were gained for histopathologic, tensiometric, and bacteriologic tests.

Result:

Group 4 demonstrated disrupted normal skin flora; reduced inflammatory cell density, fibroblastic activity, and collagen density; and decreased wound tensile strength. The histopathologic findings with Groups 2 and 3 were as same as with Group 4 and wound tensile strength showed no significant difference compared with the Control group. Group 2 revealed no significant difference compared with the Control group with regard to all parameters.

Discussion:

Seven-day CS therapy had a negative effect on wound healing and changed the normal skin flora.     

N-nitroso compounds in the gastrointestinal tract of rats and in the feces of mice with induced colitis or fed hot dogs or beef

Because colonic N-nitroso compounds (NOC) may be a cause of colon cancer, we determined total NOC levels by Walters' method in the gastrointestinal tract and feces of rodents: (i) feces of C57BL mice fed chow and semi-purified diets contained 3.2 +/- 0.4 and 0.46 +/- 0.06 NOC/g, respectively (P < 0.01, mean +/- SD). (ii) NOC levels for gastrointestinal contents of three groups of Sprague-Dawley rats fed chow diet were 0.9 +/- 0.05 (diet), 0.2 +/- 0 (stomach), 0.3-0.4 (small intestine), 0.7-1.6 (cecum and colon) and 2.6 +/- 0.6 (feces) nmol/g. NOC precursor (NOCP) levels (measured as NOC after mild nitrosation) for two rat groups fed chow diet showed a 16-fold increase from stomach to proximal small intestine (mean, 6.2 micromol/g), and a 1.7-fold increase from distal colon to feces (mean, 11.6 micromol/g). (iii) Eight Min and five C57BL/6J mice received 4% dextran sulfate sodium in drinking water on days 1-4 to induce acute colitis. This increased fecal NOC levels 1.9-fold on day 5 in both strains (P < or = 0.04), probably due to NO synthase-derived nitrosating agents in the colon. (iv) Following studies on humans fed beef [Hughes et al. (2001) Carcinogenesis, 22, 199], Swiss mice received semi-purified diets mixed with 18% of beef plus pork hot dogs or sautéed beef for 7 days. On day 7, individual 24-h fecal NOC outputs were determined. In three hot dog and two beef groups with 5 mice/group, mean fecal NOC output/day was 3.7-5.0 (hot dog) and 2.0-2.9 (beef) times that for control groups fed semi-purified diet alone (P < 0.002 for each of combined groups). These groups showed little change in fecal NOCP output. (v) Initial purification of rat fecal NOCP by adsorption-desorption and HPLC is described. Results should help evaluate the view that colonic NOC causes colon cancer associated with colitis and ingestion of red and nitrite-preserved meat.     

Addition of fusidic acid impregnated bone cement to systemic teicoplanin therapy in the treatment of rat osteomyelitis

We compared the efficacy of the combination of fusidic acid impregnated bone cement and systemic teicoplanin to systemic teicoplanin alone in implant-related osteomyelitis model in the rats. Foreign bodies were implanted into the medullary channels of 30 rat tibias after intramedullary inoculation of methicillin-resistant Staphylococcus aureus. Following proof of induction of osteomyelitis in the rats on the 21st day, a bone cement rod including 1/40 ratio of fusidic acid was inserted into the medullary channel of the tibias in the study group. Teicoplanin was administered i.m. at 20 mg/kg/day for 14 days to both the study and control groups. At the end of the treatment, the tibias were examined macroscopically, microbiologically and histopathologically. The elimination rate with the teicoplanin+fusidic acid combination was 81.8%, while with teicoplanin alone was 55.6% (p=0.33). Although the difference between the two groups was not statistically significant, the combination treatment had a positive effect in eliminating the microorganism.     

Arterial infusion chemotherapy for liver metastases from colorectal cancer--therapeutic effects of different protocols

The therapeutic effects of different protocols for arterial infusion chemotherapy were compared in patients with multiple liver metastases from colorectal cancer. A total of 49 patients with colorectal multiple liver metastases treated in our hospital since 1988 were the subjects. In order to compare the therapeutic effects on the regression of cancer and the survival rate, the subjects were assigned into Groups A-D, which were treated using different protocols. Group A received ADR, EPI, CDDP or 5-FU alone at first. If this drug was not effective, it was replaced with another of those mentioned here, and so on. Group B received CDDP 50 mg on day 1, 5-FU 500 mg/day from day 2 to day 7 and 5-FU 500 mg/day for 2 weeks thereafter (FP treatment). Group C received CDDP 50 mg at the time of reservoir insertion and 5-FU 1,000 mg for 5 hours thereafter (WHF treatment). Group D received 5-FU 1,000 mg for 24 hours on day 1, day 3, and day 5 of every week with combination of CDDP 5-10 mg/day from day 1 to day 5 and none on day 6 and day 7 (intermittent F + low-dose P treatment) for 3 weeks. The response rate was 33% for Group A (n = 18), 46% for Group B (n = 13), 25% for Group C (n = 8) and 80% for Group D (n = 10), showing significant differences between Group D and other groups. The 1-year survival rate was 50% for Group A, 46% for Group B, 29% for Group C and 89% for Group D. Significant differences in survival rate were found between Group B and D, and Group C and D.     

PEG －rhG －CSF 预处理对 BUCY 方案致小鼠骨髓抑制模型骨髓造血恢复的影响

目的：研究聚乙二醇化粒细胞集落刺激因子（PEG －rhG －CSF）预处理后不同时间间隔对 BUCY 方案致小鼠骨髓抑制模型骨髓及外周血象恢复情况的影响，为进一步扩展 PEG －rhG －CSF 的临床应用范围提供理论依据。方法：BLAB／c 雌性小鼠50只，随机分为5组（n ＝10）。实验组（Group6、Group10、Group13、Group16）皮下注射 PEG －rhG －CSF 70mg·kg －1，给药后的第6、10、13及16天给予白消安（BU）35mg·kg －1· d －1连续4天，之后给予环磷酰胺（CY）50mg·kg －1·d －1连续2天。粒细胞缺乏组（Model）给予 BU 35mg· kg －1·d －1连续4天，之后给予 CY 50mg·kg －1·d －1连续2天。结果：经 BUCY 方案处理后，除 Group6组白细胞于第5天开始下降外，其余各组白细胞均于第3天开始下降；各组的（Model、Group6、Group10、Group13、Group16）白细胞最低值分别出现在第11、9、9、11及11天，白细胞恢复正常的时间分别为第19、23、23、21及19天。第19天时 Model 和 Group16组的骨髓病理结果均已趋于正常，其他组骨髓组织还存在不同程度的空泡结构，表现为低增生骨髓状态。结论：使用 PEG －rhG －CSF 后16天对于 BUCY 方案引起的小鼠骨髓抑制模型的骨髓恢复已无影响，临床5天用药的3周化疗方案可以尝试性使用 PEG －rhG －CSF 预防粒细胞降低。     

Irinotecan plus gemcitabine vs irinotecan for the second-line treatment of patients with advanced non-small-cell lung cancer pretreated with docetaxel and cisplatin: a multicentre, randomised, phase II study

To compare irinotecan (CPT-11)+gemcitabine vs CPT-11 alone as second-line treatment for patients with advanced non-small cell lung cancer (NSCLC) progressing after docetaxel-cisplatinum-based therapy. A total of 147 evaluable, pretreated patients, with NSCLC, received either gemcitabine (1000 mg m(-2), days 1 and 8)+CPT-11 (300 mg m(-2), day 8) (Group A, n=76) or CPT-11 (300 mg m(-2), day 1) (Group B, n=71), every 3 weeks. All patients were evaluable for response and toxicity. The objective response rate was 18.4% (95% CI: 9.71-27.14%) and 4.2% (95% CI: 0-8.90%) (P=0.009) for groups A and B, respectively. No significant differences between the two groups in terms of the median duration of response, time to tumour progression, overall survival and 1-year survival were observed. The CPT-11/gemcitabine regimen significantly improved the patients' quality of life ('general mood today' (P=0.014), 'coughing' (P=0.003) and 'intensity of symptoms' (P=0.034)) compared with CPT-11. More cycles had to be delayed (P=0.001) and required prophylactic growth factor support (P=0.001) in Group A than B. Three (3.9%) patients in Group A and eight (11.3%) in Group B developed febrile neutropenia (P=0.09); one patient died of sepsis in each group. Three additional (Group A, n=1; Group B, n=2) treatment-related deaths were observed. Grade 3-4 haematologic toxicity was comparable in the two groups except anaemia (P=0.03 in favour of CPT-11). Other nonhaematologic toxicities were mild and similar in the two groups. CPT-11+gemcitabine resulted in a higher response rate and better control of disease-related symptoms than CPT-11 alone, but without any improvement in the overall survival.     

Neuroprotective interactions in rats between paclitaxel and cisplatin

Paclitaxel and cisplatin are associated with dose-limiting neurotoxicity that may result from their differing effects on microtubule stability in peripheral nerves. We hypothesized that such different actions of paclitaxel and cisplatin could be exploited to minimize their neurotoxicity by giving them in combination. Paclitaxel (9-18 micromol/kg/week or 7.7-15.4 mg/kg/week) and cisplatin (5-10 micromol/kg/week or 1.5-3 mg/kg/week) were given alone and in combination to female Wistar rats. Treatment was given once per week for a total of 7-10 weeks. Paclitaxel and cisplatin were given 24 h apart when they were given in combination. Changes in sensory nerve conduction velocity (SNCV) and dorsal root ganglia (DRG) morphology were measured. The nature of their interaction was analyzed using an isobologram. Their antitumor activity alone or in combination was also determined in C57B1/6 mice bearing colon 38 tumors. Reductions in SNCV occurred with paclitaxel alone (P = 0.009), cisplatin alone (P = 0.012), and cisplatin given 24 h before paclitaxel (P < 0.0001). In contrast, there was no significant change in SNCV with paclitaxel given 24 h before cisplatin (P = 0.11). An isobologram showed that the SNCV effects of the drug combinations were less than additive or antagonistic. Cisplatin-induced morphometric changes in DRG neurons were less marked when cisplatin was given with paclitaxel (P = 0.004). Concentrations of platinum in dorsal root ganglia, sural nerves, and sciatic nerves were not altered by giving paclitaxel before cisplatin. Tumor growth delays (TGD) were greater after treatment with paclitaxel (23.4 micromol/kg or 20 mg/kg) given 24 h before cisplatin (23.3 micromol/kg or 7 mg/kg) (TGD = 7.5 days) than after paclitaxel (23.4 micromol/kg or 20 mg/kg) (TGD = 2.0 days) or cisplatin (23.3 micromol/kg or 7 mg/kg) (TGD = 3.5 days) alone. Paclitaxel and cisplatin antagonized each other's neurotoxicity in Wistar rats. Combining cytotoxic agents with opposing effects on peripheral nerves has potential for minimizing neurotoxicity in patients.     

Caffeic acid phenethyl ester ameliorated ototoxicity induced by cisplatin in rats

Caffeic acid phenethyl ester (CAPE), an active component of propolis, exhibits antioxidant properties. This experimental study was designed to determine the effect of CAPE on ototoxicity induced with cisplatin. Twenty-four adult Wistar albino rats were divided into four groups: cisplatin (n=6), saline (n=6), CAPE (n=6), and cisplatin plus CAPE (n=6). Rats were tested before and 5 days after cisplatin treatment with or without chemo protection. The Distortion Product Otoacoustic Emissions (DPOAEs) were elicited from the control and experimental animals utilizing the standard commercial Otoacoustic Emission (OAEs) apparatus. The animals in all groups were sacrificed under general anesthesia on the fifth day following last OAE measurements. For biochemical investigations, the blood samples were drawn from inferior vena cava. On day 0, the initial baseline DPOAEs measurement results presented similar values while comparing the groups in drug free phase (p>0.05). On day 5, intrasubject measurement parameters of DPgrams and I/O functions of cisplatin group were significantly deteriorated (p<0.05). The second measurements of the other groups revealed no significant differences between their DPgrams and I/O functions in all frequencies (p>0.05). Among the biochemical parameters, plasma xanthine oxidase (XO) activity was found to be more elevated in the cisplatin group than the saline group (p<0.05). CAPE led to more decreased XO activity than cisplatin (p<0.05). The results of this study show that prophylactic administration of CAPE for cisplatin ototoxicity ameliorated hearing deterioration in rats.     

All-trans and 9-cis retinoic acids, retinol and beta-carotene chemopreventive activities during the initial phases of hepatocarcinogenesis involve distinct actions on glutathione S-transferase positive preneoplastic lesions remodeling and DNA damage

Chemopreventive activities of all-trans retinoic acid (AtRA), 9-cis retinoic acid (9cRA), retinol (ROL) and beta-carotene (betaC) were evaluated during hepatocarcinogenesis. Rats received 1 mg/100 g body wt AtRA (AtRA group), 9cRA (9cRA group), ROL (ROL group), 7 mg/100 g body wt betaC (betaC group) or corn oil (CO group, controls). Hepatocyte nodule incidence was reduced (P < 0.05) in betaC group (46%), but not (P > 0.05) in AtRA (92%), 9cRA (92%) and ROL (82%) groups, compared with the CO group (100%). Multiplicity of these preneoplastic lesions (PNL) was different (P < 0.05) between CO group (44 +/- 9) and 9cRA (11 +/- 4), ROL (7 +/- 3) and betaC (4 +/- 2) groups, except for AtRA group (27 +/- 9; P > 0.05). Number/cm(2) liver section, mean area (mm(2)) and percent liver section area occupied by total (persistent + remodeling) placental glutathione S-transferase (GST-P) positive PNL was reduced (P < 0.05) in AtRA (107 +/- 13; 0.12 +/- 0.06; 13.9 +/- 3.9), 9cRA (71 +/- 12; 0.12 +/- 0.06; 6.8 +/- 2.2), ROL (96 +/- 13; 0.11 +/- 0.22; 6.8 +/- 2.0) and betaC (106 +/- 13; 0.08 +/- 0.03; 10.8 +/- 2.5) groups compared with CO group (166 +/- 14; 0.18 +/- 0.09; 28.6 +/- 5.2). Percent of remodeling GST-P positive PNL was increased (P < 0.05) in 9cRA (92 +/- 1), ROL (96 +/- 1) and betaC (93 +/- 1) groups, but not (P > 0.05) in AtRA group (90 +/- 2), compared with the CO group (86 +/- 1). Compared with the CO group, all groups present in PNL reduced (P < 0.05) cell proliferation and no differences (P > 0.05) in apoptosis. DNA damage [comet length (mum)] was reduced (P < 0.05) in ROL (87.9 +/- 2.6) and betaC (89.2 +/- 4.0) groups, but not in AtRA (94.8 +/- 4.1) and 9cRA (94.2 +/- 1.5) groups, compared with the CO group (100.4 +/- 3.9). AtRA, 9cRA, ROL and betaC presented chemopreventive activities against hepatocarcinogenesis. These involve inhibition of cell proliferation, but not induction of apoptosis. Increased remodeling of GST-P positive PNL relates to 9cRA, ROL and betaC actions, while inhibition of DNA damage relates to ROL and betaC actions.     

Long term administration of granulocyte-macrophage colony stimulating factor decreases development of 1-2 dimethylhydrazine-induced colon cancer in rats

BACKGROUND AND OBJECTIVES: The antitumoral activities of granulocyte-macrophage colony stimulating factor (GM-CSF) were shown earlier. In this study, the effects of GM-CSF were investigated on colon cancer induced by 18 weeks of 1-2 dimethylhydrazine (DMH) administration in rats. METHODS: Four groups received subcutaneous saline (n = 20), 15 mg/kg DMH (n = 30), DMH +6 microg/kg GM-CSF (n = 30), and DMH +12 microg/kg (n = 30) GM-CSF. RESULTS: The average number of tumors (2.8 vs. 1.5) and mean tumor volume (179 +/- 36 vs. 27 +/- 9 mm(3); means +/- SEM) were reduced in DMH + GM-CSF groups as compared to the DMH group (n = 30, P < 0.01). DMH-induced enhancement of free radicals and lipid peroxidation were decreased in DMH + GM-CSF group (n = 8-12, P < 0.05). The magnitude of DMH-induced alterations in superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities was lowered in the DMH + GM-CSF group (n = 12-16, P < 0.05). DMH-induced increases in the total nitrite/nitrate levels and the nitric oxide synthase (NOS) activity (n = 10-12, P < 0.05) were also reduced in the DMH + GM-CSF group (n = 8-9, P < 0.05). CONCLUSIONS: The results indicate that GM-CSF inhibits the development of DMH-induced colon cancer in rats and suggest that inhibition of oxidative stress and NO pathway are involved in the observed antitumoral effects.     

Effect of indomethacin on N-(4-(5-nitro-2-firyl)-2-thiazolyl)formamide-induced urinary tract carcinogenesis

The effects of indomethacin on the urinary bladder and renalpelvis in rats treated with N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide(FANFT) were studied. Two hundred female Sprague-Dawley ratswere divided into four groups. Group 1 received control dietwithout added chemicals. Group 2 was treated with indomethacin(1 mg/kg per day) in the drinking water throughout the experiment.Groups 3 and 4 received 0.2% FANFT in the diet for seven weeksfollowed by control diet. In addition to FANFT, Group 4 receivedindomethacin, 1 mg/kg per day, for the entire experiment. Therats were sacrificed after 92 weeks. There were no urothelialtumors in the control group, one renal pelvic tumor in the indomethacingroup, 4 tumors in the FANFT group and 10 urothelial tumorsin the FANFT ⁺ indomethacin group. The difference between Groups3 and 4 was statistically significant (P < 0.05). Moderateand severe hyperplasia of the renal pelvic and papillary epitheliumwas found in 15 of 48 rats in Group 2 (indomethacin only) ascompared with 6 of 49 control rats (P < 0.05). Moderate andsevere hyperplasia was equally frequent in Groups 3 and 4 (14and 17 animals in each group, respectively). Twenty-four ratsin Group 2 had mammary tumors as compared to 12 animals in Group1 (P < 0.01). Five of the tumors in Group 2 were adenocarcinomas.There was no difference between the number of mammary tumorsin Groups 3 and 4 (36 and 32 animals in each group, respectively).The results suggest that indomethacin enhances FANFT-inducedurinary tract carcinogenesis. Indomethacin also seems to exertsome tumorigenic activity in the mammary gland.     

Spontaneous and nitrosourea-induced primary tumors of the central nervous system in Fischer 344 rats exposed to frequency-modulated microwave fields

In a 2-year bioassay, we exposed Fischer 344 rats to a frequency-modulated (FM) signal (836.55 MHz +/- 12.5 KHz deviation) simulating radiofrequency exposures in the head of users of hand-held mobile phones. We tested for effects on spontaneous tumorigenicity of central nervous system (CNS) tumors in the offspring of pregnant rats and also for modified incidence of primary CNS tumors in rats treated with a single dose of the neurocarcinogen ethylnitrosourea (ENU) in utero. ENU dosage (4 mg/kg) was selected to give an expected brain tumor incidence of 10-15% over the mean life span of 26 months. Pregnant dams (n = 102) were randomly assigned to six groups. Their offspring were treated as cohorts in each of the six groups (n = 90 per group; total, n = 540): Sham ENU/Sham Field, Sham ENU/Field Exposed, ENU/Sham Field, ENU/Field Exposed, ENU/Cage Control, and Sham ENU/Cage Control. Intermittent field exposures began on gestation day 19 and continued until weaning at 21 days, resuming thereafter at 31 days and continuing until experiment termination at 731-734 days. Energy absorption rates (SARs) in the rats' brains were similar to localized peak brain exposures of a phone user (female, 236 g, 1.0 W/kg; male, 450 g, 1.2 W/kg). Of the original 540 rats, 168 died before the termination of the experiment. In these rats, ENU significantly reduced survival from a mean of 708 days in three groups without ENU treatment to 645 days in three groups treated with ENU (P < 0.0005). There were no effects on survival attributable to FM field exposure in either ENU-treated or in sham-treated groups. Spontaneous CNS tumor incidence in control groups was 1.1-4.4% but sharply higher in rats receiving ENU (14.4-22.2%; P < 0.0001). No FM field-mediated changes were observed in number, incidence, or histological type of either spontaneous or ENU-induced brain tumors, nor were gender differences detected in tumor numbers. These negative findings with FM fields contrast with our study using standard digital phone fields pulsed on and off at 50/se, where a trend was noted toward reduced incidence of both spontaneous and ENU-induced CNS tumors (W. R. Adey et al., Radiat. Res., 152: 293-302, 1999). Although consistent but not attaining significance in the experiment overall (spontaneous CNS tumors, P < 0.08 one-tailed; P < 0.16 two-tailed; ENU-induced CNS tumors, P < 0.08 one-tailed, P < 0.16 two-tailed), the trend was significant (P < 0.015 one-tailed, P < 0.03, two-tailed) in rats that received ENU and died prior to experiment termination, with a primary brain tumor as the cause of death. We discuss differences in the signaling structure of digital and FM fields. Certain bioeffects induced by either amplitude-modulated or pulsed radiofrequency fields at athermal levels have not been seen with fields of similar average power but unvarying in intensity (continuous wave or frequency-modulated fields).     

术后辅助治疗对局部进展期（pT3N0M0）食管鳞癌远期生存影响的回顾性分析

  目的  探讨术后辅助治疗对于pT3N0M0食管鳞癌患者远期生存的影响。  方法  回顾性分析兰州大学第二医院2010年1月至2014年4月收治的食管鳞癌患者资料,并分为4组:单纯手术组,手术+放疗组,手术+化疗组,手术+放化疗组。收集患者的临床病理资料及远期随访结果。  结果  2010年1月至2014年4月共纳入177例患者,中位年龄61（43~78）岁。其中单纯手术组79例,术后辅助治疗组98例,其中手术+放疗组28例,手术+化疗组38例,手术+放化疗组32例。术后辅助治疗的总生存率和无瘤生存率均高于单纯手术组（P=0.012,P=0.007）。组间比较结果显示:手术+放疗组总生存率和无瘤生存率高于单纯手术组（P=0.038,P=0.011）,手术+放化疗组仅总生存率高于单纯手术组（P=0.031）。  结论  pT3N0M0食管鳞癌患者可以从术后辅助放疗和放化疗中获益,尤其放疗可以达到局部区域控制的显著效果。      

Liver resections in over‐75‐year‐old patients: Surgical hazard or current practice?

OBJECTIVES: To assess the safety of hepatic resections in the very old patient by comparing the outcome in patients younger and older than 75 years. METHODS: Thirty-two resections in 31 patients > or =75 years (Over-75 Group) were compared with 164 resections in 162 patients <75 years (Control Group). Indications for resection, concomitant diseases, previous abdominal surgery, type of resection, associated surgical procedures, use/length of portal clamping, intra-operative blood losses and transfusions, and length of operation were preliminarily compared. The outcome was evaluated in terms of post-operative mortality, morbidity, transfusions, and postoperative hospitalization. RESULTS: Mean age was 76.0 +/- 2.3 years (range 75-83) in the Over-75 Group and 58.4 +/- 10.7 years (range 23-74) in the Control Group. The over-75 group included more hepatomas (43.8% vs. 26.8%, P = 0.09), chronic liver disease (31.3% vs. 28.7%, P = 0.03) and concomitant diseases (62.5% vs. 32.9%, P = 0.002). The two groups were comparable (P = n.s.) when evaluated for all other variables. The 30-day mortality rate was 3.6% in the Control Group and none in the Over-75 Group. Postoperative surgical complications occurred in 37 patients (22.6%) in the Control Group and 1 patient (3.1%) in the Over-75 Group, with statistically significant differences (P = 0.01), and incidence of medical complications was 13.4% in the Control Group and 3.1% in the Over-75 Group. Median postoperative hospitalization and transfusions were not statistically different. CONCLUSIONS: Hepatic resections in over-75-year-old patients are not a surgical hazard and may be carried out relatively safely as long as an accurate selection of the patient is performed.     

Does Intensive Treatment with High Dose Chlorambucil and Prednisone as First Line and Cladribine as Second Line Influence the Survival of the Patients with Chronic Lymphocytic Leukemia?

Cladribine (2-CdA) and fludarabine are the new purine analogs introduced in the treatment of chronic lymphocytic leukemia (CLL). Despite the high response rate, their influence on survival is still uncertain. The aim of this study was a retrospective analysis and comparison of the response rate and survival of CLL patients treated with high dose chlorambucil (HDChl) as first and 2-CdA as second line, with an historical group of patients never treated with purine analogs who received standard doses of chlorambucil (SDChl). We analyzed 347 patients with CLL treated between January 1985 and January 2000. Group A (190 patients) received HDChl (12 mg/m²) with prednisone (P) 30 mg/m² daily for 7 days monthly as first line and in refractory or early relapsed patients 2-CdA (0.12 mg/kg/day) for 5 days with or without P (30mg/m²) as second line. Group B (157 patients) received continuous SDChl (4-8 mg/m²/day) and P as first line and COP or CHOP as second line. The overall response rate (OR) for the first line was 48,4% in group A and 38,9% in group B (p = 0.09). 148 patients in group A and 52 in group B received the second line treatment and the second OR was 19.6% and 13.5%, respectively (p=0.4). At the time of analysis, 124 patients died in group A and 139 in group B. Median survival was 65 months and 50 months, respectively. In group A, survival was longer in advanced Rai stage patients (p = 0.001) but in early Rai stage was similar for both groups (p = 0.4). We suggest that intensive treatment with HDChl as first line and 2-CdA as second line should be applied in more advanced rather than in less advanced stages of CLL until the final results of randomized clinical trials are available.     

Comparison of lipid peroxidation and myocardial damage induced by adriamycin and 4'-epiadriamycin in mice

Adriamycin (ADM) and 4'-epiadriamycin (4'-ADM) were given to mice in a single dose of 15 mg/kg body weight (i.p.). Twenty-five mice were alloted to 3 groups. One group (Group I; n = 8) was given ADM; another group (Group II; n = 9) was similarly treated with 4'-ADM, and a control group (n = 8) received an equivalent volume of 0.9% NaCl solution. Mice were sacrificed 4 days after the described treatment. A complete autopsy was carried out in each animal. Hydroperoxide-initiated chemiluminescence and malonaldehyde formation were measured in mouse heart homogenates. Control mice showed a maximal photoemission of 52 +/- 2 (X 10(-3)) (mean values +/- S.E.M.) cpm/mg protein and a formation of 20 +/- 4 nmol malonaldehyde/g organ after a 2 hr-incubation. The ADM-treated mice showed a 24% enhanced hydroperoxide-initiated photoemission and a 370% increased malonaldehyde formation. The 4'-ADM-treated mice showed a 15% increased hydroperoxide-stimulated chemiluminescence and an 85% increased malonaldehyde formation. Vitamin A (5000 IU), vitamin E (85 IU) and vitamins A and E (same doses as before) given as a single dose i.p. 1 day before doxorubicin administration were able to decrease the hydroperoxide-initiated chemiluminescence by 24%, 26% and 44%, respectively. Microscopically, only scarce isolated microvacuolated subendocardial fibers were found in the ADM-treated animals. Our data showing that 4'-ADM lacks a statistically significant effect in increasing heart peroxidation as compared to ADM may explain its lower myocardial toxicity.