Effects of n-acetylcysteine in a rat model of ischemia and reperfusion injury

OBJECTIVE: Splanchnic artery occlusion shock (SAO) causes an enhanced formation of reactive oxygen species (ROS), which contribute to the pathophysiology of shock. Here we have investigated the effects of n-acetylcysteine (NAC), a free radical scavenger, in rats subjected to SAO shock. METHODS AND RESULTS: Treatment of rats with NAC (applied at 20 mg/kg, 5 min prior to reperfusion, followed by an infusion of 20 mg/kg/h) attenuated the mean arterial blood and the migration of polymorphonuclear cells (PMNs) caused by SAO-shock. NAC also attenuated the ileum injury (histology) as well as the increase in the tissue levels of myeloperoxidase (MPO) and malondialdehyde (MDA) caused by SAO shock in the ileum. There was a marked increase in the oxidation of dihydrorhodamine 123 to rhodamine in the plasma of the SAO-shocked rats after reperfusion. Immunohistochemical analysis for nitrotyrosine and for poly(ADP-ribose) synthetase (PARS) revealed a positive staining in ileum from SAO-shocked rats. The degree of staining for nitrotyrosine and PARS were markedly reduced in tissue sections obtained from SAO-shocked rats which had received NAC. Reperfused ileum tissue sections from SAO-shocked rats showed positive staining for P-selectin, which was mainly localised in the vascular endothelial cells. Ileum tissue section obtained from SAO-shocked rats with anti-intercellular adhesion molecule (ICAM-1) antibody showed a diffuse staining. NAC treatment markedly reduced the intensity and degree of P-selectin and ICAM-1 in tissue section from SAO-shocked rats. In addition, in ex vivo studies in aortic rings from shocked rats, we found reduced contractions to noradrenaline and reduced responsiveness to a relaxant effect to acetylcholine (vascular hyporeactivity and endothelial dysfunction, respectively). NAC treatment improved contractile responsiveness to noradrenaline, enhanced the endothelium-dependent relaxations and significantly improved survival. CONCLUSION: Taken together, our results clearly demonstrate that NAC treatment exert a protective effect and part of this effect may be due to inhibition of the expression of adhesion molecule and peroxynitrite-related pathways and subsequent reduction of neutrophil-mediated cellular injury.     

Surgical pathologic staging in apparent stage I endometrial carcinoma

A multicenter trial on apparent stage I endometrial carcinoma was performed to establish an intensive surgical staging, to formulate a treatment on the basis of the pathological extent of the disease and to determine the effectiveness of adjuvant medroxyprogesterone acetate therapy. The results of the first objective on 1,055 patients are herein reported. All patients had total abdominal hysterectomy, bilateral salpingo-oophorectomy, colpectomy of the superior third, and biopsy of lymph nodes positive or doubtful at radiological imaging or on surgical inspection. On the basis of the pathologic extent of the disease, patients were classified into five categories: disease outside the uterine corpus (RE); disease limited to endometrium (RO); disease with inner myometrial invasion and high or moderate grade (R1); disease with deep myometrial invasion or poor differentiation (R2); disease with positive retroperitoneal nodes (R3). One hundred and forty-six patients were RE, 163 RO, 382 R1, 341 R2 and 23 R3. The results showed a clinical understaging in 16% of the cases. According to the new FIGO classification, the relapse-free survival at 84 months was 96% for patients at stage IA, 92% for patients with stage IB-C, 86% for stage IIA-B, 76% for stage IIIA-B and 74% for patients at stage IIIC. These data confirm the importance of an intensive surgical staging in apparent stage I endometrial carcinoma.     

Lymph node involvement in primary carcinoma of the fallopian tube

Although the bad prognosis of primary fallopian tube carcinoma has been mostly ascribed to early lymphogenous dissemination, precise information regarding the characteristics of retroperitoneal spread are still missing. Our study was designed to evaluate the incidence and clinical significance of lymph node metastases in 33 patients with primary carcinoma of the fallopian tube. During primary surgery nine patients (27%) were submitted to systematic pelvic and para-aortic lymphadenectomy, whereas 24 received lymph node sampling. The clinicopathologic characteristics of the patients (intraperitoneal spread, grading, peritoneal cytology, depth of tubal infiltration and residual disease after primary surgery) were compared with lymphnodal status.
Overall 15 patients (45%) had positive nodes, that is, invaded by tumor; whereas 18 (55%) showed no lymphatic spread. Six patients (40%) had exclusively positive para-aortic lymph nodes; five (33%) had only tumor metastases in pelvic lymph nodes, three (20%) manifested simultaneously pelvic and para-aortic spread, and one patient with pure primary squamous cell carcinoma had a massive groin node metastasis as presenting sign of the tumor. The rate of lymphogenous metastases was not significantly related to progressive intra-abdominal dissemination, histologic grade or depth of tubal infiltration. On the other hand, the presence of residual disease after primary surgery and positive peritoneal cytology significantly increased the risk of nodal metastases. Patients with lymph node metastasis had a significantly ( P = 0.02) worse prognosis compared with patients without nodal involvement (median survival 39 vs 58 months).
Considering the high incidence of lymph node metastasis, correct staging of tubal carcinoma should include a thorough surgical evaluation of both pelvic and para-aortic lymph nodes. The role of systematic lymph node dissection in the treatment of tubal carcinoma remains controversial.     

Effects of water deprivation and angiotensin II intracerebroventricular administration on brain nitric oxide synthase activity

Intracranial administration of -arginine causes a reduction of the water intake induced by water deprivation or by intracerebroventricular (i.c.v.) injection of angiotensin II (angiotensin II), through the release of nitric oxide (NO) in the central nervous system. We studied the effects of i.c.v. angiotensin II (120 ng/rat) in association with i.c.v. -arginine (2.5–10 μg/rat) on blood pressure. We also studied the effects of both peripheral and central angiotensin II injection (1.5–6 mg kg⁻¹ i.p. and 30–120 ng rat⁻¹ i.c.v., respectively) on NO synthase activity in the cortex, diencephalon and brainstem, after water deprivation (24 h), conditions producing activation of the renin-angiotensin system. -arginine dose dependently antagonized the increase in blood pressure induced by i.c.v. angiotensin II (P<0.001). Peripheral administration of angiotensin II produced a dose-dependent reduction of NO synthase activity in the brainstem and cortex (P<0.001), but not in the diencephalon. Water deprivation produced similar effects on brain NO synthase activity. Angiotensin II i.c.v. injection caused NO synthase activity reduction in all brain regions studied (P<0.001). Our findings suggest that NO and angiotensin II could play opposite roles in brain regulation of blood pressure and drinking behaviour.     

Variability of the computerized single-breath nitrogen washout test in healthy adults. Results from a field survey in a French rural area

Summary. Within-subject (difference between paired tests, or coefficient of variation [c. var.] of three consecutive measurements) and between-subjects (standard deviation of the mean group) variability were assessed for the variables derived from the single-breath nitrogen (SBN₂) test in a group of healthy, asymptomatic subjects (n= 289) aged 20–64 years, from a rural area in North-East France. Duplicate measurements in 99 subjects showed excellent agreement between the two attempts (correlation coefficients between 0.94 and 0.98) for static lung volumes and the alveolar N₂ slope (PIII); closing volumes (CV) were more variable (r= 0.77 for absolute value, 0.79 for % VC) while closing capacities (CC) were in intermediate position (r= 0.86 for absolute value, and 0.88 for % TLC). The variability of three consecutive measures in 190 subjects showed the coefficients of variation to be low for static volumes and closing capacity (2.4–7.4%) and higher for PIII (15.1%) and CV or CV7VC (18.2 and 17.8%). The analysis of variance did not detect significant differences between the three sets of measurements, with the exception of a progressive increase of vital capacity (VC), and decrease in residual volume (RV) from test 1 to test 3, the total lung capacity being the same. Variability was uninfluenced by age or sex, except a higher c. var. for female VC as compared to males (2.8 vs. 2.2%, P= 0.02) and a higher variability of TLC (2.9 vs. 2.3%, P= 0.03) and VC (2.8 vs. 1.9%, P= 0.003) in people older than 40 years as opposed to those younger than 40 years.     

Low-dose cyclophosphamide versus adriamycin plus cyclophosphamide in advanced ovarian cancer

Summary After intensive staging 74 ovarian cancer patients were randomized to two arms balanced for stage and post-surgery residual tumor. The two regimens were CTX 100 mg/day continuously and ADM 50 mg/m² IV every 4 weeks plus CTX 100 mg/day. The response rates were respectively 42% and 52%. Median survival times were 13 and 14 months. The incidence of side effects was significantly higher in the combination-treatment arm. No other statistical differences were found.